Clinical trial NCT01763346
Conditions: Prediabetes Type 2 Diabetes Obesity
Keywords: type 2 diabetes prediabetes obesity gastric banding metformin
Sponsor: University of Southern California
Start date: 2013-06-01; Completion date: 2018-06-01
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Weight loss achieved through gastric banding will be superior to treatment with metformin in preserving or restoring pancreatic beta cell function in people with prediabetes or mild type 2 diabetes.

Detailed description:
BetaFat is a 2-arm, unblinded study to compare gastric banding to treatment with metformin over a 24-month period in moderately obese adults with pre- or mild type 2 diabetes. The primary outcome will be change in β-cell compensation for insulin resistance, which the investigators will compare between groups. Secondary analyses will include other potential markers of β-cell health and potential mediators of treatment-specific effects. The main focus will be on mediators related to obesity. Clinically, the project will serve as a test of concept for use of gastric banding relatively early in the spectrum of obesity and β-cell disease. Biologically, the results will provide crucial information on potential mediators of β-cell failure and its arrest or reversal in the context of obesity. Those mediators will guide the development of more effective treatment and monitoring for the β-cell disease that causes type 2 diabetes.

Arms: arm 1: subjects receiving metformin arm 2: subjects receiving LAP-BAND
Interventions: intervention 1: Metformin intervention 2: gastric banding
Intervention descriptions: intervention 1: metformin 1000 mg bid intervention 2: LAP-BAND

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Beta Cell Restoration through Fat Mitigation 
The BetaFat Study 
A Participating Study in the  
The Restoring Insulin Secretion (RISE) Consortium 
 
NCT Number: 01763346 
 
PROTOCOL 
 
Date: August 28, 2016  
Version 1.7 
 
 
 
 
CONFIDENTIAL 
 
 


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CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Title Page  
 
 
 
 
 
 
 
 
 
1 
Table of Contents 
 
 
 
 
 
 
 
 
2 
1. EXECUTIVE SUMMARY 
 
 
 
 
 
 
 
6 
 
1.1  The RISE Consortium 
 
 
 
 
 
 
 
6 
1.2  Specific Aims and Objectives  
 
 
 
 
 
6 
1.3  Overall Design and Study Interventions 
 
 
 
 
7 
2. BACKGROUND and SIGNIFICANCE  
 
 
 
 
 
8 
2.1 Type 2 Diabetes: The Problem and its Importance 
 
 
8 
2.2 Disease Modification: Focus on Detrimental Effects of Obesity 
8 
2.3 Rationale for Interventions  
 
 
 
 
 
9 
2.4 Rationale for Outcome Measures 
 
 
 
 
 
11 
2.4.1 Intravenous-Based Tests 
 
 
 
 
 
11 
2.4.2 Oral Based Tests  
 
 
 
 
 
 
12 
2.4.3 Biomarkers 
 
 
 
 
 
 
 
12 
3. STUDY DESIGN  
 
 
 
 
 
 
 
 
13 
3.1 Overview and Rationale 
 
 
 
 
 
 
13 
3.2  Primary Endpoints 
 
 
 
 
 
 
 
13 
3.3 Secondary Endpoints  
 
 
 
 
 
 
14 
3.3.1 Hyperglycemic clamp-derived ß-cell measures 
 
 
14 
3.3.2 OGTT-derived ß-cell measures 
 
 
 
 
14 
3.3.3 Fasting measures of glycemia and β-cell function  
 
15 
3.3.4 -cell Function 
 
 
 
 
 
 
 
15 
3.3.5 Insulin Sensitivity 
 
 
 
 
 
 
15 
3.3.6 Blood and Urine Biomarkers  
 
 
 
 
15 
3.3.7 Physical and Body Composition Measures  
 
 
15 
3.4 Treatments 
 
 
 
 
 
 
 
 
16 


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3.4.1 Metformin Arm  
 
 
 
 
 
 
16 
3.4.2 Gastric Band Arm  
 
 
 
 
 
 
16 
3.4.3 FDA Compliance  
 
 
 
 
 
 
17 
3.5 Inclusion and Exclusion Criteria 
 
 
 
 
 
17 
3.5.1 Inclusion Criteria  
 
 
 
 
 
 
17 
3.5.2 Exclusion Criteria  
 
 
 
 
 
 
17 
4. RECRUITMENT and RANDOMIZATION 
 
 
 
 
 
18 
4.1 Sources of Participants  
 
 
 
 
 
 
18 
4.2 Recruitment 
 
 
 
 
 
 
 
 
19 
4.3 Informed Consent 
 
 
 
 
 
 
 
19 
4.4 Screening  
 
 
 
 
 
 
 
 
19 
4.5 Randomization  
 
 
 
 
 
 
 
19 
4.6 Masking  
 
 
 
 
 
 
 
 
20 
5. PARTICIPANT MANAGEMENT 
 
 
 
 
 
 
20 
5.1 Overview  
 
 
 
 
 
 
 
 
20 
5.2 Drug Distribution 
 
 
 
 
 
 
 
20 
5.3 Adherence Measures  
 
 
 
 
 
 
20 
5.4 Retention  
 
 
 
 
 
 
 
 
21 
6. DATA COLLECTION 
 
 
 
 
 
 
 
 
22 
6.1 Pre-screening and Screening Eligibility Measurements  
 
22 
6.2 Main Study Procedures 
 
 
 
 
 
 
22 
6.2.1 Fasting Blood and Urine Samples 
 
 
 
 
23 
6.2.2 Oral Glucose Tolerance Test  
 
 
 
 
23 
6.2.3 Hyperglycemic Clamp  
 
 
 
 
 
23 
6.2.4 DEXA Scans 
 
 
 
 
 
 
 
24 
6.2.5 MRI Scans  
 
 
 
 
 
 
 
24 
6.2.6 Physical Measures 
 
 
 
 
 
 
24 
6.2.7 Questionnaires 
 
 
 
 
 
 
 
24 
6.2.8 Safety Measures  
 
 
 
 
 
 
25 
6.3 Visit Windows 
 
 
 
 
 
 
 
 
25 
 
7. SAFETY/HUMAN SUBJECTS PROTECTION 
 
 
 
 
25 
7.1 Data and Safety Monitoring Board (DSMB) 
 
 
 
25 


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7.2 Data and Safety Monitoring Plan 
 
 
 
 
 
26 
7.2.1 Informed Consent 
 
 
 
 
 
 
26 
7.2.2 Safety Review Plan and Monitoring  
 
 
 
26 
7.2.3 Confidentiality 
 
 
 
 
 
 
 
26 
7.3 Expected Side Effects  
 
 
 
 
 
 
27 
7.3.1 Metformin  
 
 
 
 
 
 
 
27 
7.3.2 Gastric Band 
 
 
 
 
 
 
 
28 
7.4 Risk Management 
 
 
 
 
 
 
 
28 
7.4.1 Metformin  
 
 
 
 
 
 
 
28 
7.4.2 Gastric Band 
 
 
 
 
 
 
 
28 
7.4.3 DEXA Scans 
 
 
 
 
 
 
 
29 
7.4.4 MRI Scans  
 
 
 
 
 
 
 
29 
7.4.5 Other indications to Interrupt/Discontinue Interventions 
29 
7.4.6 Hyperglycemia 
 
 
 
 
 
 
 
29 
7.4.7 Glucose and Arginine Infusions 
 
 
 
 
30 
7.5 HIPAA – Protection of Patient Information 
 
 
 
30 
8. ADVERSE EVENT REPORTING 
 
 
 
 
 
 
30 
8.1 Definition of Serious Adverse Events 
 
 
 
 
30 
8.2 Non-serious Adverse Events  
 
 
 
 
 
31 
8.3 Reporting Adverse Events 
 
 
 
 
 
 
31 
8.4 Tracking Adverse Events 
 
 
 
 
 
 
31 
8.5 Emergency Unmasking  
 
 
 
 
 
 
32 
9. STATISTICAL CONSIDERATIONS 
 
 
 
 
 
 
32 
9.1 Primary Outcomes and Analysis 
 
 
 
 
 
32 
9.2 Secondary Outcomes and Analyses  
 
 
 
 
32 
9.3 Sample Size/Power Calculations 
 
 
 
 
 
33 
9.4 Interim Analysis Plans  
 
 
 
 
 
 
34 
9.5 Stopping Rules  
 
 
 
 
 
 
 
34 
9.6 Handling of Missing Data 
 
 
 
 
 
 
34 
10. DATA PROCESSING and MANAGEMENT  
 
 
 
 
34 
10.1 Data Management System  
 
 
 
 
 
34 
10.2 Data Transfer  
 
 
 
 
 
 
 
35 


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10.2 Quality Control 
 
 
 
 
 
 
 
35 
10.4 Back-up, Data Security and Confidentiality 
 
 
 
35 
10.5 Tracking Study Progress 
 
 
 
 
 
 
36 
10.6 Archiving and Study Close-out Including Repository  
 
36 
11. STUDY ADMINISTRATION  
 
 
 
 
 
 
36 
11.1 Organization (Including Sponsors)  
 
 
 
 
36 
11.2 Central Laboratories and Reading Centers 
 
 
 
38 
11.3 Training and Certification 
 
 
 
 
 
 
38 
11.4 Site Visits 
 
 
 
 
 
 
 
 
39 
11.5 Study Website  
 
 
 
 
 
 
 
39 
11.6 Conflict of Interest Policy 
 
 
 
 
 
 
39 
11.7 Publications and Presentations Policy 
 
 
 
 
40 
 
11.8 Ancillary Studies Policy 
 
 
 
 
 
 
41 
11.9 Protocol Amendments 
 
 
 
 
 
 
41 
11.10 Repository for Storage and Distribution of Data and Samples 
41 
12. STUDY TIMELINE 
 
 
 
 
 
 
 
 
42 
13. LITERATURE CITED  
 
 
 
 
 
 
 
43 
Appendix 1: Contraindications to Lab Band  
 
 
 
 
50 
 
Appendix 2: Consent Form 
 
 
 
 
 
 
 
51 
 
 


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1. EXECUTIVE SUMMARY 
1.1 The RISE Consortium 
 
The RISE Consortium is a collaborative effort involving investigators at 7 clinical centers 
who will determine the feasibility of different interventions in adults and children to preserve 
ß-cell function in individuals with prediabetes or mild, recently diagnosed type 2 diabetes. The 
Consortium involves three protocols:  
 Three adult centers will perform a randomized, blinded, placebo-controlled trial 
comparing metformin, insulin glargine followed by metformin, or metformin plus 
liraglutide.  
 Four pediatric centers will perform a randomized trial comparing metformin with 
metformin plus liraglutide.  
 One adult center will perform a randomized trial comparing metformin with gastric band 
surgery.  
To the greatest degree possible, the three protocols will use the same inclusion and exclusion 
criteria, study procedures, time line and outcome measures to allow for comparisons between 
groups and interventions. The protocol for the single adult center comparing metformin to 
gastric banding is presented here and is called the BetaFat Study 
1.2 Specific Aims and Objectives 
 
 
Type 2 diabetes (T2D) develops from progressive loss of pancreatic β-cell compensation 
for chronic insulin resistance. The loss of compensation occurs for years prior to the 
development of diabetes and continues after the diagnosis is made. Loss of compensation is 
caused by loss of β-cell mass and reduced function of individual β-cells. Several lines of 
evidence suggest that obesity and its adverse metabolic effects are primary drivers of falling β-
cell compensation. First, obesity is a well-known risk factor for T2D. Second, weight gain is an 
important predictor of falling β-cell compensation, an effect explained in our prior studies by 
insulin resistance and separate effects of low-grade inflammation and falling adiponectin levels. 
Third, treatment of obesity with lifestyle modification reduces the risk of diabetes in a pattern 
that suggests slowing, but not arrest of the β-cell disease. Protection is limited by weight re-
gain, even in the relatively controlled setting of clinical trials. Fourth, treatment with 
thiazolidindiones, which mitigate some of the metabolic effects of obesity, can slow or even 
stop the loss of β-cell compensation. The protective effect is closely related to “unloading” of β-
cells through amelioration of insulin resistance; it occurs only in a subset of treated individuals. 
These four findings point to mitigation of excess adiposity as an important approach to arrest or 
reverse the β-cell disease that causes T2D. The findings also highlight important limitations in 
current behavioral and pharmacological approaches to β-cell preservation.  
The present proposal seeks to expand clinical and scientific knowledge about β-cell 
preservation or restoration through mitigation of the metabolic effects of obesity. Specifically, 
we propose to compare weight loss induced by gastric banding to the standard pharmacological 
approach, metformin, for effects on β-cell function in pre- and mild T2D. Banding will reduce 


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adverse effects of obesity through weight loss that is more than can be sustained with lifestyle 
modification and which occurs without the potential confounding effect of direct stimulation of 
insulin secretion seen with operations that bypass the foregut. Metformin treatment will 
reduce insulin resistance and lower glucose levels. By comparing changes in β-cell function 
between treatment groups, we will compare the most commonly used medical monotherapy to 
a surgical approach for long-term effects on β-cell health. By examining changes in potential 
mediators of fat-induced β-cell deterioration, we may identify mechanisms for β-cell 
preservation that could serve as future therapeutic targets or markers of response to 
treatment. Based on data from weight loss and metformin in extant diabetes prevention trials 
and the greater weight loss expected with banding, we hypothesize that gastric banding will 
be more effective than metformin treatment at preserving or restoring β-cell function. We 
propose three specific aims to test this hypothesis and examine potential mechanisms for β-cell 
preservation or restoration. 
AIM 1 – Clinical Study: We will conduct a prospective, randomized, 24-month study in obese 
individuals with pre-diabetes or mild T2D using two different approaches to mitigate the 
metabolic effects of obesity: (a) gastric banding and (b) metformin.  
AIM 2 – Impact on β-cell Health: We will compare changes in markers of β-cell health, 
primarily β-cell compensation for insulin resistance, between groups. We predict that 
banding will improve β-cell health more than metformin will. 
AIM 3 – Mechanisms Linking Fat to β-cell Health: We will measure body fat (total and 
regional by DEXA, abdominal distribution by MRI), along with potential circulating 
mediators of β-cell decline and use regression methods to identify mechanisms by which 
obesity may influence β-cell health and identify clinical markers thereof.  
 
1.3 Overall Design and Study Interventions 
BetaFat is a two arm, unblinded study in which volunteers with prediabetes or drug-naïve, 
recent onset, mild type 2 diabetes will be randomized to:  (1) metformin or (2) gastric banding. 
The study will recruit patients over a 27-month period and follow each individual for a total of 
24 months on study intervention.  The primary outcomes will be β-cell compensation for insulin 
resistance, measured in two ways as defined below.  The anticipated duration of the BetaFat 
study is five years, including pre-trial preparation and post-trial analysis and reporting. 
ß-cell function, -cell function, insulin sensitivity and glucose tolerance will be assessed using 
intravenous and oral tests. Both intravenous and oral tests will be obtained at baseline and 
after 12 and 24 months of therapy. Use of oral and intravenous tests will allow us to examine 
different aspects of β-cell function. Such use will also allow us to examine how well relatively 
simple measures of ß-cell function, -cell function and insulin sensitivity (i.e., from fasting 
samples and oral glucose tolerance tests) correlate to more sophisticated measures (i.e., from 
glucose clamp studies) in the prediction of β-cell decline and/or response to treatment. Finally, 
a series of adipokines/inflammatory markers will be measured to determine whether they 
predict changes in ß- and -cell function, insulin sensitivity and glucose tolerance without and 
with therapy.  


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Clinically, the project will serve as a test of concept for use of gastric banding relatively early in 
the spectrum of obesity and β-cell disease. We will derive information on the extent of weight 
loss necessary to fully arrest or reverse the β-cell disease, as well as potential clinical markers 
for successful treatment. Biologically, the results will provide crucial information on potential 
mediators of β-cell failure and its arrest or reversal in the context of obesity. Those mediators 
will guide the development of more effective strategies for prevention and early treatment of 
T2D with the aim of arresting or reversing the progressive β-cell disease. 
2 BACKGROUND and SIGNIFIGANCE 
2.1. Type 2 Diabetes: The Problem and its Importance 
 
Type 2 diabetes is epidemic in developed and developing countries, where the disease 
affects approximately 5-10% of adults. Approximately twice as many people have impaired 
glucose levels and are at high risk for T2D. Prevalence and incidence rates of T2D and impaired 
glucose levels are on the rise, shadowing increasing rates of obesity. Projections place the 
number of people with diabetes in excess of 400 million by 2030 if nothing is done to stem 
these rising tides. Morbidity and mortality from acute and, especially chronic complications of 
T2D will follow. Thus, development of effective strategies to prevent T2D and/or treat it once it 
develops  is an extremely important public health issue across the globe.  
2.2 Disease Modification: Focus on Detrimental Effects of Obesity 
 
The biology of T2D is characterized by progressive loss of pancreatic β-cell compensation 
for chronic insulin resistance (1-3). The progressive β-cell disease is present for years during the 
development of diabetes and it continues for many years after the diagnosis is made. The 
clinical face of this progressive disease is hyperglycemia that becomes harder and harder to 
treat. Many patients end up with severe insulin deficiency which, with their insulin resistance, 
makes it difficult or impossible to maintain low risk glucose levels. Arrest or reversal of this 
progressive β-cell disease is fundamental to effective prevention and treatment of T2D.  
 
Toxicity from glucose and fatty acids (4), protein malfolding (5-7), and oxidative stress (8) 
are some processes that have been implicated in the loss of β-cell mass and function. In our 
own longitudinal studies of Hispanic women at high risk for T2D, declining β-cell compensation 
was most closely associated with weight gain (9). The association was explained statistically by 
covariate adjustment for three independent factors: increasing insulin resistance, rising levels 
of C-reactive protein and falling levels of adiponectin. These findings suggest that obesity drives 
progressive β-cell decompensation both indirectly (through insulin resistance and β-cell loading) 
and directly (through circulating adipocytokines acting on β-cells).  
 
Based on these observations, we believe that mitigating the detrimental effects of 
obesity on β-cells is the most attractive strategy for arresting or reversing the progressive β-
cell disease that causes and worsens T2D.  
 
Theoretically, mitigation could be accomplished by reducing body fat or by ameliorating 
its adverse effects on β-cells. Clinical studies of prevention and early treatment of T2D support 
both approaches. Lifestyle modifications in the Finnish Diabetes Prevention Study (DPS) (10) 


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and the U.S. Diabetes Prevention Program (DPP) (11) achieved relatively modest weight loss 
that was partially sustained during 4-6 years of follow-up. The result was a 58% reduction in the 
diabetes incidence rate in each study. Protection from diabetes was more closely associated 
with weight loss than with increased physical activity (11). On average, the onset of diabetes 
was delayed ~2 years during the active treatment phase of the DPP (Fig 2 of REF (11)).  It is not 
clear how many subjects actually stopped progressing toward diabetes, but clearly many did 
not. Thus, modest weight loss may slow, but not arrest deterioration to T2D.   
 
We used thiazolidinediones to modify fat biology in the absence of weight loss. Subjects 
were Hispanic women with recent gestational diabetes. We observed a 55% reduction in 
diabetes rates over ~3.5 years (TRIPOD) (12).  Importantly, β-cell compensation was fully 
stabilized in ~1/3 of the treated women. Protection from diabetes was very closely associated 
with β-cell “unloading”, the term we have used to describe reductions in insulin secretory 
demands that occurred in response to insulin sensitization. The relationship between unloading 
and protection from diabetes was confirmed in a second study (PIOOD) (13).  At least two other 
studies have demonstrated diabetes risk reductions of 62-72% with TZDs (14;15).  
 
These studies demonstrate three concepts that are fundamental to the present 
proposal. First, reducing body fat or reducing its adverse metabolic effects in moderately obese 
individuals (average BMI was 30-35 in all studies) can slow rates of deterioration toward T2D. 
Second, the β-cell disease that causes T2D can be stopped through sufficient β-cell “unloading” 
or, possibly, related mechanisms. Third, neither modest weight loss nor TZD treatment is fully 
and uniformly effective in arresting progression toward and to T2D. There is great need to 
develop more potent approaches to β-cell preservation or restoration in pre- and mild T2D. The 
present proposal is designed as a test of concept for one such approach – weight loss induced 
by gastric banding – using metformin treatment as a comparator. 
2.3 Rationale for Interventions 
We considered a number of approaches. We rejected approaches based on stimulation of 
insulin secretion because our own data (12;13) and data from ADOPT (16) support the opposite 
approach. GLP-1 based therapies could have direct effects to enhance β-cell mass based on 
rodent studies (17), but available human data don’t support such an effect in humans (18) . The 
limits of lifestyle interventions are apparent from the DPP and DPS (10;11). Thiazolidinediones 
(TZDs) have a strong effect to preserve β-cell function in pre-diabetes (12;13), but the one 
available TZD, pioglitazone, has recently been linked to an increase in bladder cancer (19). 
Finally, basal insulin treatment could reduce insulin secretory demands, but had only a small 
effect on diabetes risk reduction in the ORIGIN trial (20). Thus, we concluded that we could 
either take an approach that would combine two or more of these approaches in a 
mechanistically logical fashion, or we could take a bolder approach directed at what we believe 
to be a primary drive of β-cell decline – adverse metabolic effects of obesity. We chose the 
latter option and believe we can make important contributions to studies that will operate 
under the RISE Consortium.  
We chose gastric banding as the primary experimental treatment because (a) it induces 2-3 
times the weight loss that can be achieved and sustained with even aggressive lifestyle 


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programs like the DPP ((21) and Figure 2.1); (b) It can reverse T2D (21); (c) it is not associated 
with the large stimulation of insulin secretion that appears to occur with foregut exclusion 
operations (22); (d) it is relatively non-invasive and safe compared to other bariatric 
procedures; and (e) the LapBand has recently been approved by the FDA for clinical use down 
to a BMI of 30 kg/m2. The trend toward lower BMI thresholds for gastric banding provides both 
an opportunity and a need to study carefully the metabolic impact of the procedure in the 
presence of moderate obesity. We will apply banding to people with moderate obesity to 
maximize improvement in insulin sensitivity for any degree of weight loss (Figure 2.2).  
Figure 2.1: Weight Loss in USC Gastric Band Program 
 
 
 
 
 
 
 
 
Data are from 83 obese individuals with T2D who had follow-up for at least two years. Results were 
achieved without the intensive approach to band adjustment that we propose for this project.  
 
Figure 2.2: Relationships between BMI and Insulin Sensitivity 
 
 
 
 
 
 
 
 
Data are from 1221adults (mean age 35 years, mean BMI 29.6 kg/m2). Insulin sensitivity (SI) was 
measured with IVGTT-minimal model.  
We chose metformin as the comparator for two main reasons. First, we will include people 
with mild T2D; standards of care dictate that they should receive medical therapy and 
metformin is the drug most often recommended in this context (23). Metformin is also the only 
drug that has been recommended for use in diabetes prevention (24). Thus, we will be 
comparing gastric banding to the current standard of medical monotherapy early in the course 
of T2D.  
20
30
40
50
0
2
4
6
8
10
12
SI
Normal (n=232)
Impaired (n=95)
Diabetic (n=11)
Males
BMI  < 35
Slope: -0.225
BMI >35
Slope: -0.059
Body Mass Index (kg/m 2)
20
30
40
50
60
0
2
4
6
8
10
12
Body Mass Index (kg/m2)
SI
Normal (n=517)
Impaired (n=269)
Diabetic (n=70)
Females
BMI >35
Slope: -0.018
BMI < 35 
Slope: -0.176
140
160
180
200
220
240
260
280
0
5
10
15
20
25
W
eight (lb)
Month after Band Operation


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We will study people with pre- and mild T2D because we have observed a fairly linear decline in 
β-cell compensation across this range (9). We are also confident that we can assess insulin 
sensitivity and secretion across this range. Thus, we will be able to test for arrest or reversal of 
falling β-cell compensation. Overall, this approach and our expertise β-cell biology and 
preservation in humans put us in very strong position to make unique and important 
contributions to the RISE Consortium. 
2.4 Rationale for Outcome Measures 
We plan to employ technically complex “gold standard” measures for a high degree of scientific 
rigor in this relatively small study, together with simpler surrogate measures that could be 
applied in larger studies and in clinical settings. The complex measures will be made with 
intravenous stimuli (glucose, arginine). The simpler measures will be made in the fasting state 
(HOMA, biomarkers) and in response to oral glucose. 
2.4.1 Intravenous-Based Tests of ß- and -cell Function and Insulin Sensitivity 
Glucose tolerance is dependent on ß-cell function and insulin sensitivity, and both of these can 
be quantified using the hyperglycemic clamp (25). Although α-cell function dysregulation occurs 
in type 2 diabetes, the exact role of -cell function in determining glucose tolerance is not well 
defined. 
The acute insulin response to intravenous glucose (AIRg), also known as the first-phase insulin 
response, occurs within the first ten minutes following glucose administration and is a sensitive 
marker of ß-cell function that decreases as the fasting glucose level rises. A potential limitation 
of this measure is that it becomes zero or negative when fasting glucose approaches the 
diabetic range (26). Since we will include people in this range, the AIRg is not the ideal primary 
outcome.  
The second-phase insulin response to intravenous glucose begins at the time of glucose 
administration and continues for as long as the glucose level remains elevated. It is frequently 
quantified as part of a hyperglycemic clamp. Unlike AIRg, this particular response generally 
persists even when the fasting glucose concentration is in the diabetic range. 
The prevailing glucose level modulates the ß-cell secretory response to non-glucose 
secretagogues such as peptides and amino acids. By performing hyperglycemic clamps with the 
addition of arginine, it is possible to quantify the maximum insulin response (AIRmax), which 
has been shown to correlate with β-cell mass in animal studies (27). 
Normally, ß-cell responses are modulated by the prevailing insulin sensitivity. Thus, adjusting 
the proposed β-cell measures for the degree of insulin sensitivity (SI) provides a measure of 
compensation for insulin resistance, a measure of β-cell function that declines consistently 


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during progression to and of T2D (3;28). The most widely used approach is calculation of a 
disposition index, a product of measures of insulin sensitivity and secretion based on 
demonstration of a hyperbolic relation between the two variables. AIRg (29;30), second phase 
insulin (31), and AIRmax (32;33) have been shown to have such relationships. Insulin sensitivity 
can be calculated from the hyperglycemic clamp as the ratio of steady state glucose infusion 
rates to steady state plasma insulin levels. We plan to examine relationships between β-cell 
measures and insulin sensitivity from the hyperglycemic clamp and use the disposition index or 
another, more appropriate method to adjust beta cell function for insulin sensitivity in primary 
and secondary analyses. 
The reciprocal of glucose’s ability to potentiate the ß-cell response is its ability to suppress the 
-cell response. This function can also be measured using hyperglycemic clamps along with 
arginine. The minimum acute glucagon response at maximal glycemic suppression (AGRmin) is 
greater in people with type 2 diabetes, indicative of impaired -cell regulation (30). 
2.4.2 Oral-Based Tests of ß- and -cell Function and Insulin Sensitivity 
The oral glucose tolerance test (OGTT) also provides measures of islet function and has been 
used in large clinical trials. The early insulin response (insulinogenic index) is an important 
determinant of glucose tolerance (14). This response, when used in combination with a fasting 
measure of insulin sensitivity (1/fasting insulin, HOMA), provides another estimate of ß-cell 
function termed the oral disposition index (DIo) (20). Using modeling approaches such as those 
developed by Mari et al (63) and Cobelli et al (ref), it is possible to obtain a number of 
additional parameters of ß-cell function and insulin sensitivity. In addition, insulin secretion 
rates can be calculated from the OGTT (64). Finally, overall glucose tolerance can be calculated 
from the glucose excursion during the test (57). 
Physiological glucagon suppression during an OGTT is an important determinant of glucose 
tolerance and provides an estimate of -cell function. In individuals with type 2 diabetes, this 
response is increased compared to normal subjects (2; 26; 27). 
These OGTT-based measures will be made in the study and will be used to determine their 
relationship to assessments made using intravenous tests both at baseline and with 
intervention. OGTT-derived measures can be evaluated for cross-sectional relationships with 
clamp-derived measures and for value as prospective predictors of therapeutic response.  
2.4.3 Biomarkers 
The detailed measures of β-cell function that we will be making provide an opportunity to 
identify biomarkers that can predict deterioration of β-cell function and/or response to 


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interventions that can mitigate such deterioration. The identification of such biomarkers is an 
important ancillary goal of the RISE Consortium. Because of budget constraints, the focus 
during this stage of the project will be on collecting patient specimens that can used in the 
future for identification of biomarkers once the main outcomes of the study are known. We will 
collect samples that can be used to examine previously described peptide markers of diabetes 
risk (e.g., adiponectin, ferritin, ApoB, C-reactive protein, IL-2 receptor A (34-37) and evolving 
markers of β-cell mass regulation (e.g., prolactin, DNA fragments and methylation, GLP-1, GIP, 
HSP90nucleic acids (38-42). We will also collect serum samples that can be analyzed using 
genomic, micro-RNA, proteomic and metabolomics approaches comparing for example 
responders to non-responders to the study interventions.   
3 STUDY DESIGN  
3.1 Overview and Rationale  
The BetaFat study protocol described herein will involve 88 adults who are 20 – 65 years old 
and who have prediabetes or drug-naïve, recent onset and mild type 2 diabetes. Additional 
inclusion and exclusion criteria are defined below. Participants will be randomized over a 27 
month period to either metformin or gastric banding in an open treatment format. The primary 
outcome will be rate of change in ß-cell compensation for insulin resistance, as defined below. 
Figure 3 provides an overview of the types and timing of main study procedures.  
3.2 Primary Endpoints  
The primary objective of the RISE Study is to evaluate the effects of randomized treatment on 
ß-cell function, measured by hyperglycemic clamp techniques. Given that insulin and C-peptide 
are both used in quantifying ß-cell function, each of them will be measured in certain or all tests 
in part to avoid the problem of collinearity when performing the statistical analyses. Two co-
primary endpoints are specified:  


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 Change between baseline and end study in ß-cell function measured as the second 
phase response (steady-state of the hyperglycemic clamp; 100-120 minutes of glucose 
infusion). This will be calculated as mean C-peptide at steady state, adjusted for insulin 
sensitivity (ratio of the glucose infusion rate:plasma insulin concentration at steady 
state). 
 Change between baseline and end study in ß-cell function measured as AIRmax 
(arginine-induced acute insulin response at hyperglycemia glucose; ß-cell secretory 
capacity) [30]. This will be calculated as the incremental area under the C-peptide curve 
from 0-10 minutes following arginine injection at a plasma glucose ≥450 mg/dl, adjusted 
for insulin sensitivity measured by the hyperglycemic clamp. 
3.3 Secondary Endpoints  
The following secondary endpoints are pre-specified for analysis.  
3.3.1  Hyperglycemic clamp-derived ß-cell measures  
a. First phase insulin response (incremental insulin area from 0-10 minutes after initial 
glucose bolus) 
b. First phase C-peptide response (incremental C-peptide area from 0-10 minutes after 
initial glucose bolus) 
c. Disposition index derived from a and b, using hyperglycemic clamp-derived measure of 
insulin sensitivity (glucose disposal rate/insulin: GDR/I)  
d. Second phase insulin response, with adjustment for insulin sensitivity  
e. AIRmax response to arginine calculated using insulin concentrations and adjusted for 
insulin sensitivity 
3.3.2  OGTT-derived ß-cell measures  
a. Early insulin response to oral glucose (insulinogenic index: ∆ insulin from 0-30 minutes/∆ 
glucose from 0-30 minutes [∆I/∆G])  
b. Early C-peptide response to oral glucose (analogous to (a)) 
c. Oral disposition index (DIo; insulinogenic index adjusted for insulin sensitivity) 
d. Modeled parameters of ß-cell function (ß-cell glucose sensitivity, rate sensitivity and 
potentiation factor; static, dynamic, and total ß-cell glucose sensitivity) 
e. Ratios of incremental insulin/glucose (iAUCins/iAUCg) and C-peptide/glucose (iAUCc-
p/iAUCg) responses from 0-120 minutes  
f. Incremental glucose (iAUCg) response as a measure of glucose tolerance  
g. 2-hour glucose 


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h. GLP-1 total and incremental response to oral glucose load (samples will be collected, 
and measured for this analysis if funding allows) 
3.3.3  Fasting measures of glycemia and β-cell function  
a. Glucose 
b. Proinsulin/insulin ratio 
c. HOMA %B (using the Oxford calculator) 
d. HbA1c 
3.3.4 -cell Function 
a. Glucagon suppression in response to sustained hyperglycemia during the clamp (the 
decrement in glucagon concentration from baseline to nadir value at 100-120 minutes) 
b. Acute glucagon response arginine (the incremental increase in glucagon concentration 
from pre-arginine baseline for the 10 minutes after the arginine injection) 
c. OGTT-derived measures: integrated glucagon response from 0-120 minutes 
d. Fasting sample-derived measures: glucagon 
3.3.5 Insulin Sensitivity 
a. glucose disposal rate at steady state (100-120 minutes) divided by ambient insulin 
concentrations during hyperglycemic clamp 
b. Matsuda index and model-derived insulin sensitivity from OGTTs 
c. 1/fasting insulin, HOMA-S (using the Oxford calculator), and QUICKI from fasting 
samples 
3.3.6 Blood and Urine Biomarkers  
a. Adipokines/inflammatory markers including C-reactive protein (CRP): adiponectin; 
others contingent on funding (see above in Section 2.4.3) 
b. Non-esterified fatty acids  
c. Urine albumin/creatinine ratio  
d.  DNA for future genetic analysis 
3.3.7 Physical and Body Composition Measures 
a. Physical measures: blood pressure, body weight, body mass index, waist circumference;  
b. Total fat and lean mass; regional fat and lean mass by dual-energy X-ray absorptiometry 
(DEXA) 
c. Visceral, subcutaneous, hepatic and pancreatic fat by abdominal magnetic resonance 
imaging (MRI) 


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3.4 Treatments 
3.4.1 Metformin Arm 
Metformin will be given at a dose of 2000 mg/d, titrated over four weeks. Study medication will 
be withheld the morning of each CTU visit and a new supply will be dispensed at the end of 
each visit. Medication compliance will be monitored by pill counts. Participants will be 
monitored for gastrointestinal side effects that are associated with metformin. Individuals who 
develop side effects will be given the option of reducing the dose. Individuals who continue to 
have intolerable side effects will be given the options to change to an extended release 
preparation at maximum tolerated dose or to discontinue metformin. Handling drop-outs and 
missing data is discussed under Data Analysis (section 9.6) 
 
3.4.2 Gastric Band Arm 
The LapBand will be placed and participants will be followed according to standard clinical 
practice under the supervision of Dr. Namir Katkhouda. Costs for these procedures will be paid 
by Allergan in the form of an unrestricted research grant. Pre-operative evaluation will include 
a psychological evaluation, a cardiac evaluation with EKG and stress testing, evaluation by an 
anesthesiologist, a chest X-ray and clinical lab testing (CBC, chemistries, UA, PT/PTT, hepatitis 
panel and, for women, pregnancy test). Participants also meet with the bariatric nutritionist for 
education on dietary restrictions that will apply once the band is in place.  
Surgeries for placement of LapBands will be performed by Dr. Namir Katkhouda at the Keck 
Hospital of USC. The procedure is done laparoscopically on outpatients. Patients see Dr. 
Katkhouda 2 weeks after surgery for wound check and suture removal. Band adjustments are 
performed by Dr. Katkhouda, members of his bariatric surgical team, and/or Dr. Elizabeth 
Beale. Adjustments will commence ~4 weeks after surgery and will recur every 1-3 months at 
the time of regular research visits. Adjustments will be made based on specific criteria 
consisting of symptoms of satiety and hunger, dietary history, and weight loss. Patients will 
revert to liquid diet for 24-48 hours after band adjustments and advance diet over the next 3-5 
days. The bariatric team has an on-call system to evaluate and treat patients who have 
symptoms related to their bands. Post-operative laboratory assessments include CBC; 
chemistries; vitamin B1, B6 and B12 levels; ferritin; and 25(OH) vitamin D (see Table 2 for 
testing schedule).  
Although both groups will be on active treatment, it is possible that glycemic control could 
deteriorate to a point of needing additional therapies. We will be monitoring HbA1C at six 
month intervals. If a value is >8.0%, we will repeat it in one month and, if it remains >8.0% we 


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will consider the subject to have reached a safety endpoint for the trial. We will perform end-of 
study visits (scheduled for 24 months in Table 3) and refer the subject for care of his/her 
diabetes.  
3.4.3 FDA Compliance 
Participants will have BMI 30-40 kg/m2 and either type 2 diabetes or impaired glucose levels. 
Metformin is approved by the FDA for use in people with type 2 diabetes regardless of BMI. The 
LapBand is approved by the FDA for use in individuals with BMI>30 kg/m2 and type 2 diabetes. 
An Investigational Device Exemption has been obtained from the FDA for inclusion of 
individuals with pre-diabetes.   
3.5 Inclusion and Exclusion Criteria 
3.5.1 Inclusion Criteria 
1. Completion of at least two months in a diet, exercise and behavioral modification program 
within past two years 
2. Fasting plasma glucose >90 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus 
HbA1C ≤7.0%. There is no lower limit for the A1C and no upper limit for the OGTT 2-hour 
glucose  based on prior studies that allow us to identify people with falling β-cell function.  
3. Age 22-65 years 
4. Body mass index (BMI) 30-40  kg/m2 
5. For participants with diabetes, known duration <1 year 
6. No history of use of antidiabetic medications except during pregnancy 
3.5.2 Exclusion criteria  
1. Contraindications to LapBand(see Appendix 1) 
2. Contraindication to MRI (claustrophobia; permanent metal objects such as pacemakers, 
prostheses, aneurysm clips) 
3. Underlying disease(s) likely to (a) limit life span to less than study duration and/or (b) 
increase risk of intervention outside of the study and/or (c)  limit ability to participate in 
outcomes assessment and/or (d) limit participation 
4. An underlying disease known to have important effects on glucose metabolism 
5. Active infections 


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6. Renal disease (serum creatinine ≥1.4 mg/dl for men; ≥1.3 mg/dl for women) or serum 
potassium abnormality (<3.4 or >5.5 mmol/l) 
7. Anemia (hemoglobin <11g/dl in women, <12 g/dl in men)  or known coagulopathy 
8. Cardiovascular disease, including uncontrolled hypertension and symptomatic congestive 
heart failure. Participants must be able to safely tolerate administration of fluid/volume 
challenges during clamp studies. 
9. Serum AST or ALT >3 times upper limit of normal in local clinical lab 
10. Excessive alcohol intake 
11. Suboptimally treated thyroid disease 
12. Conditions or behaviors likely to affect the conduct of the BetaFat Study 
a. Unable or unwilling to give informed consent 
b. Unable to adequately communicate with clinic staff 
c. Another household member is a participant or staff member in BetaFat 
d. Current or anticipated participation in another intervention research project that would 
interfere with any of the interventions/outcomes in BetaFat 
e. Likely to move away from participating clinic in next 2 years 
f. Current (or anticipated) pregnancy and lactation. 
g. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct 
of the BetaFat study 
h. Weight loss >7% in past two months for any reason except postpartum weight loss. 
13. Additional conditions may serve as criteria for exclusion at the discretion of the local site. 
Further details pertaining to exclusion criteria are specified in the Manual of Procedures. 
4. 
RECRUITMENT AND RANDOMIZATION  
4.1 Sources of Participants 
There are two primary recruitment sources where we can access existing information on age, 
BMI and A1C or glucose levels to greatly enhance efficiency of screening. The first source is the 
clinical care database (EHR) of Kaiser Permanente Southern California (KPSC – Dr. Xiang). The 
second source is the Ambulatory Care Network (ACN) of Los Angeles County (Drs. Beale and 
Buchanan). These two sources provide access to thousands of individuals likely to meet 
recruitment criteria.  
 


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4.2 Recruitment 
The primary recruitment technique is prescreening of electronic and clinical medical records to 
identify patients who appear to meet the age, BMI, A1C and medication criteria for the study to 
limit screen failure rates. In particular, for recruitment from the Ambulatory Care Network of 
Los Angeles County DHS, a search will be made of the LAC+USC Healthcare Network Affinity 
database by authorized query writers to identify patients who meet criteria for the BetaFat 
study as well as necessary contact information. On approval of this study by the USC HS IRB this 
list will be released to the BetaFat study team for storage on the secure, password protected 
study server. Although study data will be recorded on REDCap, the list of recruits from Affinity 
will not be uploaded to REDCap. Back-up recruitment techniques may include notices placed on 
bulletin boards at the medical centers, newspaper and radio advertisements and public service 
announcements, and referral from colleagues. Selection is based solely on the participant's 
ability to meet the criteria stated in the protocol and his/her willingness to participate in the 
study.  
4.3 Informed Consent  
Consent is obtained in a quiet setting prior to the initiation of any study procedures. The 
subject is provided adequate time to read and understand the written consent and ask 
questions as necessary. If they choose, they may take additional time to discuss the study with 
family and/or physicians outside the clinic setting. Subjects are not consented until they 
demonstrate adequate understanding of all aspects of the study and consent process. A copy of 
the consent is given to the subject. A model consent form appears in Appendix 2. 
In the event a significant protocol change occurs, the informed consent will be adjusted 
appropriately and sites will submit the revised documents to their Institutional Review Board 
(IRB) for approval. Local IRBs will determine whether it is necessary to re-consent participants. 
The clinical site for BetaFat will submit to the BetaFat Data Center stamped IRB approval letters 
and current copies of all consent forms prior to study initiation, and annually thereafter. These 
records will be maintained by the BetaFat Data Center as a local archive.  
4.4 Screening 
Screening will take place on the Clinical Trials Unit (CTU) at USC. Individuals will have a history 
and physical exam directed at study inclusion/exclusion criteria, will provide blood for clinical 
laboratory screening, and will have plasma glucose measured before and two hours after 75g 
oral glucose challenge. Qualified individuals will be asked to return for baseline testing and 
randomization. 


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4.5 Randomization  
Individuals who complete baseline testing (described below, section 6.2) will be randomized 1:1 
to banding or metformin using permuted block randomization stratified by gender, BMI (30-35 
vs. 35-40 kg/m2) and diabetes (no vs. yes when IDE approved) to minimize skewing. Individuals 
assigned to metformin will be given study medications and instructions at the end of the 
second baseline visit, to begin treatment the following day. Individuals assigned to gastric 
banding will be scheduled for pre-operative screening with the goal of having them undergo 
operation within two weeks.  
4.6 Masking  
No masking will be employed. The study team and each individual participant will be aware of 
his/her treatment allocation.  
5. 
PARTICIPANT MANAGEMENT 
5.1 Overview 
Study treatment interventions are described above (Section 3.4). They will be provided free of 
charge to BetaFat participants. HbA1c will be monitored every 6 months. Procedures to be 
followed for rising HbA1c levels are described in Section 7.4.4. Beyond the treatment of the 
glucose-aspect of pre-diabetes and diabetes care, the research study will not assume 
responsibility for the medical care of the participant. Non-glucose aspects of diabetes care (e.g., 
blood pressure, lipids) and non-diabetes related medical problems will be referred to the 
participant’s primary care provider. When a potential treatment could affect the study’s 
outcome(s), the study’s physician will discuss the choices with the participant’s primary care 
provider. When a potential treatment could affect the study’s outcome(s), the RISE physician 
may discuss the choices with the participant’s primary care provider. RISE Study labs will be 
shared with the provider, with the participant’s permission. For those participants who do not 
have a primary care provider, the study staff will help find appropriate medical care. 
5.2 
Drug Distribution 
Metformin will be obtained from the same distributor used by other studies in the RISE 
consortium. The local research pharmacy of the USC Clinical Research Organization (CRO) will 
organize and maintain inventory. Sufficient medication is kept on hand to allow medication 
distribution for the next 3 month period. This would include medications required for the next 
12 randomized enrollees (i.e., on average 3 initial distributions for each of the 4 treatment 
arms) plus all of the upcoming distributions to enrolled participants who will be returning 
within 3 months. Expiration dates of all medications will be double checked and documented 


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on arrival at the CRO pharmacy and at the time of distribution to participants to ensure that the 
provided supplies will not expire during the current treatment interval.  
5.3 
Adherence Measures 
Adherence is documented, monitored, and addressed as part of participant care and 
management and to monitor whether procedures are being implemented and followed. 
Adherence refers to all study procedures – not only taking the prescribed amount of study drug, 
but also attending scheduled study visits and completing procedures at those visits. The goal is 
to maintain high levels of adherence in all participants. Primary adherence measures will 
address visit attendance and completion of study procedures and medication adherence. 
Participants will be instructed to bring all study medication (including empty bottles) to study 
visits for assessment of medication compliance. 
5.4 
Retention  
Retention refers to efforts to prevent participant dropout or withdrawal from the study. It is 
critically important to successfully engage and retain participation over the course of the trial. 
For purposes of sample size estimation, investigators have predicted an annual withdrawal rate 
of 10% during the 24-month treatment periods and have adjusted sample size to meet study 
requirements. However, lower rates of attrition are desirable.  
The Study Coordinator at each site is primarily responsible for monitoring participant attrition 
and initiating team conferences for retention strategies or dropout recovery rates. Subjects 
missing scheduled visits will be contacted within 24 hours of the scheduled visit to reschedule 
and discuss strategies to improve compliance. If the subject can’t be contacted, a certified 
letter will be sent to encourage continuation in the trial even if they no longer wish to take the 
study medication. Study staff may implement additional efforts to personalize the study. 
Attrition is monitored regularly by the Data Center and the RISE Consortium Recruitment and 
Retention Committee. An attempt is made to collect data on the reason for leaving the study in 
the case of a participant who withdraws. Studies in the RISE Consortium are encouraged to 
share their ideas and experiences via regular communication and conference calls for Study 
Coordinators. The BetaFat Data Center will prepare monthly reports on visit completion, 
compliance with the BetaFat Study protocol and participants on inactive follow-up. 
Potential participants will be provided introductory material that will emphasize the 
importance of completing the study regardless of treatment assignment. We will emphasize 
this importance during the screening, enrollment and baseline testing procedures. Should 
dropout rates exceed the projected 10% per year, we will explore several options: (a) we may 


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intensify messaging about the importance of participation and identify reasons for drop-outs, 
targeting them for retention efforts; (b) we may increase overall enrollment if the difference 
between real and projected drop-outs is small (budgets limit large increases in enrollment); (c) 
we will examine projected completion in relation to power, noting that our current 80% power 
threshold is below the projected effect size, so that we may be able to tolerate some excess 
loss to follow-up; (d) if dropouts are occurring after 12 months, we may consider changing the 
primary outcomes to rates of change in the two primary beta cell measures, as we have used in 
prior observational studies with different durations of follow-up. Note that we plan to assess 
main outcomes at 12 and 24 months on treatment, allowing this approach. 
6 DATA COLLECTION 
6.1 Pre-screening and Screening Eligibility Measurements  
Prescreening:  Prescreening for potential eligibility is done using clinical databases at Kaiser 
Permanente Southern California and the Ambulatory Care Network of Los Angeles County. 
Participants are eligible to continue screening procedures if they have an A1C within six months 
that was 5.8-7.0% and are 20-65 years old with BMI 30-40 kg/m2. For Kaiser, letters are sent to 
potential participants describing the purpose of the study and providing individuals the 
opportunity to opt in to be contacted. For the ACN, potential participants are contacted 
directly. In both cases, a study recruiter interviews potential subjects by phone to determine 
potential eligibility and interest in the study.  
Screening: Participants who meet pre-screening eligibility criteria are invited to the USC Clinical 
Trials Unit to provide informed consent and complete screening, including a directed history 
and physical exam, clinical laboratory tests, and a 2-hr, 75 g OGTT. 
Table 6.1: Data Collection during Screening
STEP
TEST / PROCEDURE
COMMENTS
1) Pre-screening
HbA1C, BMI (EHR), age, ICD-9 codes
Contact if A1C 5.8-7.0%, age 20-
65, BMI 30-40 kg/m2  
Phone Screening questionnaire
Initial review of eligibility 
2) Screening
fasting and 2-hr glucose (75 gram OGTT; 
measured at central lab), A1C 
Eligibility: fasting glucose >90 
mg/dl; 2-h glucose 140 mg/dl, 
AIC <7.0% 
Clinical eligibility labs (local clinical lab)* 
Laboratory eligibility criteria
Targeted history and physical exam, Beck 
Depression Inventory 
Eligibility evaluation
* potassium, TSH, creatinine, ALT, AST, , hemoglobin, urine pregnancy test for women 


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6.2 Main Study Procedures  
The timing of major study procedures is illustrated in the Figure 3, Section 3 above. Data to 
determine main study outcomes using hyperglycemic clamp procedures will be obtained at 
baseline and study end, which will be defined as either the end of 24 months after initiation of 
metformin or placement of gastric band, or at the time of treatment failure (A1C >8.0% on two 
successive visits). Data for secondary analyses will be determined at other study visits. Blood 
and urine samples will be collected for planned measures and extra blood and urine samples 
will be stored for future analyses. Further details on these measures are provided below, and 
are summarized in Table 6.2. 
6.2.1 Fasting Blood and Urine Samples (see Table 6.2) 
HbA1c will be measured and fasting blood and urine samples will be collected every six months. 
Aliquots of fasting blood and urine will be stored for subsequent measurement of biomarkers. A 
blood sample for DNA will be collected at randomization. Routine chemistries will safety will be 
done at baseline and every 6 months.  
6.2.2 Oral Glucose Tolerance Test (OGTT) 
Participants will come to the clinical research testing facility in the morning following a 10-12 
hour overnight fast. They will drink 75 grams of an oral glucose solution (centrally provided 
from a single manufacturer) over ≤5 minutes. Blood samples will be obtained at -10, -5, 10, 20, 
30, 60, 90, 120, 150 and 180 min relative to glucose ingestion. OGTT procedures will be 
performed at baseline and 12 and 24 months after initiation of metformin or placement of 
gastric bands. 
Table 6.2: Testing Schedule 
 
Baseline 
2-mo 
4-mo 
6-mo 
8-mo 
10-mo 
12-mo 
15-mo 
18-mo 
21-mo 
24 mo 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OGTT 
X 
 
 
 
 
 
X 
 
 
 
X 
Hyperglycic Clamp 
X 
 
 
 
 
 
X 
 
 
 
X 
DEXA 
X 
 
 
 
 
 
X 
 
 
 
X 
MRI 
X 
 
 
 
 
 
X 
 
 
 
X 
A1C 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
Fasting/Biomarkers  
X 
 
 
X 
 
 
X 
 
X 
 
X 
Band Questionnaires 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Sleep Questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Labs-1 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Clinical Labs-2 
 
 
 
X 
 
 
X 
 
X 
 
X 
Fasting/Biomarkers are discussed in section 3.3.  Clinical Labs-1 (CBC, UA, chemistries) are for all subjects; Clinical 
Labs-2 (B vitamins, ferritin, vitamin D) are for band group only (paid by Allergan). 
 


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6.2.3 Hyperglycemic Clamp 
Hyperglycemic clamps (at approximately 200 mg/dl) will be performed after a 10-12 hour 
overnight fast at baseline and at 12 and 24 months after initiation of metformin or placement 
of gastric bands. The clamp procedure will incorporate 3 main sets of blood sampling for the 
planned outcome measurements: first phase (0-10 minutes); second phase (100-120 minutes); 
and maximal stimulated responses (from 10 minutes before until 10 minutes after arginine 
injection once plasma glucose has been raised to~450 mg/dl). A priming glucose bolus will be 
used to stimulate first phase responses, a continuous dextrose infusion will be used to create 
steady state hyperglycemia at ~200 mg/dl for second phase and then raise glucose to ~450 
mg/dl for maximum response to arginine. Arterialized venous blood samples will be obtained at 
5-min intervals throughout for measurement of plasma glucose concentration to guide the 
glucose infusion. 
For the OGTT and clamp measures, participants will be asked to refrain from vigorous exercise 
and tobacco use for 24 hours before the initiation of testing. Study medications will be withheld 
the morning of testing. 
6.2.4 DEXA Scans 
Patients lie flat for 10 min while DEXA is performed by a licensed technician using a Hologic 
Discovery A scanner. Body fat is calculated using software provided by the manufacturer. 
Results are transferred electronically to the study database to allow analysis of fat content by 
regions of interest. Bone mineral density will also be determined from the DEXAs 
 
6.2.5 MRI Scans 
Approximately 80 5mm axial slices are obtained from the top of the liver to the pelvis using a 
series of 10-15 second breath holds on USC’s research dedicated GE Healthcare 3 Tesla magnet. 
The procedure takes approximately 30 minutes.  Iterative decomposition of water and fat with 
echo asymmetry and least-squares estimation (IDEAL) is used to delineate subcutaneous and 
visceral fat depots and quantify organ fat.  SliceOmatic (Tomovision, Inc.) is used for post-image 
processing to compute subcutaneous and visceral adipose tissue volume and fractional fat 
content of liver and pancreas.  
6.2.6 Physical Measures 
Height will be measured with a stadiometer. Weight will be measured with a calibrated 
electronic scale. Waist and hip circumferences will be measured at the mid-point between the 
iliac crest and the lowest rib (waist), and at the top of the femur (hip) with the participant 
standing upright. Body fat and regional fat distribution will be measured by DEXA. Abdominal 
subcutaneous and visceral fat and hepatic and pancreatic fat will be measured by magnetic 
resonance imaging (MRI). 


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6.2.7 Questionnaires  
Participants will complete the Pittsburgh Sleep Questionnaire, Epworth Sleepiness Scale and 
Berlin Questionnaire at baseline for analysis of sleep-related measures as potential predictors 
of response to treatment. Dietary intake is assessed the Block Food Frequency Questionnaire. 
Quality of life is assessed using the RAND SF-36. Bariatric Analysis and Reporting Outcomes 
System (BAROS) is used to assess clinical outcomes related to gastric band patients. Visual 
Analog Scale is used to assess pain. 
6.2.8 Safety Measures 
Clinical labs for safety monitoring (local lab), including CBC, serum transaminase levels and 
creatinine, will be collected at baseline and every 6 months during treatment for all study 
participants. Additional measurements of vitamins B1, B6, B12; 1.25OH vitamin D; and ferritin 
will be made every six months during treatment for participants on the LAP-Band arm of the 
trial. Abnormal laboratory values that, in the estimation of the BetaFat clinician investigators, 
require medical attention will be provided to participants, who will be advised to follow-up the 
abnormal value(s) with his or her primary care provider. Additionally, the BetaFat team will 
communicate the abnormal laboratory value(s) directly to the primary provider. Adverse events 
(AE) will be surveyed at each visit using a standardized questionnaire. Pregnancy tests (local 
lab) will be performed in women with child-bearing potential before each DEXA scan and if 
indicated by symptoms and menstrual history prior to other study procedures. 
6.3 Visit Windows 
Follow-up visits are scheduled every two months after randomization during the first year and 
every three months during the second year. Each participant will have a visit calendar 
generated at the time of randomization and they will be encouraged to complete visits within 1 
week before or after the scheduled date. However, it is likely that some visits will not be 
completed within this window. To maximize the amount of on-trial information available from 
each participant, we will define visit windows as (a) first year after randomization: from two 
weeks before to six weeks after a scheduled visit; and (b) second year after randomization: 
from one month before to two months after a scheduled visit.  Visits that do not occur within 
these windows will be deemed missed.  .  
7 SAFETY / HUMAN SUBJECTS PROTECTION 
This study will be conducted in compliance with the protocol and all applicable regulatory 
requirements. The participating sites have Federal-wide Assurance with the Office for Human 
Research Protections and they follow local HIPAA regulations. Prior to study initiation, the 


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protocol and the informed consent documents will be reviewed and approved by the IRB at 
each participating site and by an independent Data and Safety Monitoring Board (DSMB). Any 
amendments to the protocol or consent materials must be approved by the DSMB and the IRBs 
before implementation. 
7.1 Data and Safety Monitoring Board (DSMB)  
A DSMB consisting of appropriately qualified and conflict-free independent experts is appointed 
by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and provides 
input to the Institute. Board members are chosen by the NIDDK without consultation with the 
study investigators. The purpose of the Board is to assure independent review as to whether 
study participants are exposed to any unreasonable risk because of study participation, and to 
monitor study progress and integrity. In addition to safety monitoring, the Board can review 
unblinded study data and make recommendations for early termination of studies for achieving 
an end point or for futility. Before any of the studies in the RISE Consortium can begin, the 
DSMB, in addition to the local IRBs, must approve the protocol. Any subsequent major changes 
to the protocol must also be approved by the DSMB and IRBs. 
Following each DSMB meeting a summary of AEs and DSMB recommendations is provided to 
the IRB of each participating clinical center and other institutional monitoring 
committees/boards as needed. 
7.2 Data and Safety Monitoring Plan  
7.2.1 Informed Consent 
The informed consent process will be conducted by qualified study personnel. All participants 
must read, sign and date a consent form prior to participation in any stage of the study. The 
informed consent will be revised and participants re-consented whenever there is new, 
clinically significant information regarding the safety of the interventions, when a relevant 
protocol amendment is approved, or when any new information becomes available that may 
affect an individual’s participation in the study. 
7.2.2 Safety Review Plan and Monitoring 
A. Justification of Sample Size: See Section 9.3. 
B. Stopping Rules: The DSMB may suggest terminating a study arm at any time for safety or 
efficacy reasons. Details of interim analysis plans and stopping rules can be found in 
Sections 9.4 and 9.5.  


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C. Safety Monitoring Committee: The RISE Consortium will appoint an internal Safety 
Monitoring Committee which review AEs or other safety-related problems sent to them 
from the field. The RISE SMC will review AEs in a blinded manner. An external Safety Review 
Officer will evaluate any serious adverse events (SAE) where the SMC is not in agreement 
about whether the event is related to study drug as well as certain specified SAEs of 
concern (e.g., pancreatitis). The Safety Review Officer will not be blinded to study 
intervention.  
D. Safety Review Plan: The DSMB will meet twice yearly to review study progress and safety as 
described in Section 7.1. 
7.2.3 Confidentiality 
A. Protection of Participant Privacy: Participants’ names are linked to study IDs only on a single 
recruitment database and only certified project personnel are authorized to have access to 
this database. Only study IDs will be used in all other study databases (e.g., for tracking and 
merging and sharing with other sites and the NIH). NIH has obtained a certificate of 
confidentiality for the entire RISE Consortium, including the BetaFat Study 
B. Database Protection: All hard-copy files are stored in locked cabinets within locked offices 
at the clinical centers. Primary electronic data are entered into and maintained on a secure 
USC server with two-level password protection against non-project personnel. The server is 
backed up daily and automatically. Data for analyses common to other studies in the RISE 
Consortium will be transmitted to a secure, password-protected website maintained by the 
RISE Coordinating Center (CoC) at George Washington University. The CoC holds no 
personal identifiers and stores the data on its enterprise server accessible only by approved 
staff.  
At the end of the study, all hard copy records will be kept in a secure locale for a period 
dictated by local IRB and Institutional policies, as well as FDA, regulations, whichever is 
longest.  
C. Confidentiality during AE Reporting: AEs and SAEs are recorded on data collection forms and 
reported to the Coordinating Center without personal identifiers. Identifiers on 
accompanying documents (such as medical records) are removed before submission to the 
Coordinating Center and any subsequent transfer to the Safety Monitoring Committee 
and/or Safety Review Officer.  


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7.3 Expected Side Effects 
The BetaFat Study will use two interventions: (a) metformin or (b) gastric banding with the 
LapBand system. The expected side effects are provided below.  
7.3.1 Metformin 
Known adverse effects associated with metformin are primarily gastrointestinal (diarrhea, 
nausea, vomiting, abdominal bloating, flatulence, anorexia), hematologic (reduced vitamin B12 
levels and, rarely, megaloblastic anemia), and the rare possibility of lactic acidosis. The risk of 
lactic acidosis associated with metformin use will be minimized by (1) monitoring liver 
transaminases, (2) monitoring renal function, and (3) temporary discontinuation of metformin 
before radiologic studies involving the injection of contrast dye, surgical procedures requiring 
reduced fluid intake, and serious illness that might be associated with hypoxia, dehydration, or 
shock. To monitor for clinically significant vitamin B12 deficiency, we will follow guidelines in 
the metformin package insert and perform a complete blood count annually while participants 
are taking metformin. 
 
7.3.2 Gastric Band 
A variety of risks have been reported in the literature in association with gastric banding: 
erosion into stomach (2-9%), slippage (2-18%), leakage (1-4%), tubing or port malfunctions (1-
10%), infection (1-5%), bleeding (<1%) and dyspepsia/ulceration (5-20%), and death (<0.1%). In 
Dr. Katkhouda’s program at USC, there have been no deaths, erosions or perforations in nearly 
400 operations (~200 with diabetes). The rate of slippage, leak or malfunction requiring revision 
is <3%.  
7.4 Risk Management  
7.4.1 Metformin 
To minimize the risk of gastrointestinal side effects, metformin is given with meals, started at a 
dose of 500 mg/d, and titrated to the target does of 1000 mg bid over a four-week period. If GI 
side effects develop and are mild, the patient is encouraged to remain on the study medication. 
If GI side effects are moderate or difficult to tolerate, metformin is reduced to the next lowest 
dose (for example, 1000 mg bid to 1000 mg + 500 mg; 1000 mg + 500 mg to 500 mg bid; etc.). If 
symptoms persist, metformin is reduced to the next step. If GI symptoms resolve, metformin is 
re-escalated by 500 mg per day each week until reaching the previously tolerated dose. The 
participant will continue on the maximum tolerated dose.  


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 Renal insufficiency increases the risk of lactic acidosis associated with metformin. To asses 
renal insufficiency, serum creatinine and estimated GFR (eGFR) will be calculated using the 
CKD-Epi equation (ref . Ann Intern Med. 2009;150(9):604-612.) at screening and every six 
months on therapy.  Participants must have an eGFR of 45 mL/minute/1.73 m2 or higher to be 
eligible for the BetaFat study. . Metformin will be discontinued if eGFR is below 30 
mL/minute/1.73 m2. If eGFR ≥30 and <45 mL/minute/1.73 m2 then the RISE Safety Committee 
will review the case to assess the benefits and risks of continuing treatment, and make a 
recommendation to the clinical center investigators about whether to continue the participant 
on metformin. 
Metformin will be discontinued temporarily 24 hours before, during, and for 48 hours after any 
of the following events: 1) procedure involving the injection of contrast dye; 2) surgery or other 
procedure requiring general anesthesia; 3) any illness that could be associated with hypoxia, 
circulatory failure, or dehydration; 4) hospitalization.  Serum creatinine will be rechecked no 
sooner than 48 hours after the conclusion of the event and study medication recommenced if 
appropriate.  
To monitor for clinically significant vitamin B12 deficiency, we will follow guidelines in the 
metformin package insert and perform a complete blood count annually while participants are 
taking metformin.  
7.4.2 Gastric Band 
Risks of the banding procedure will be minimized by (a) exclusion of people with standard 
clinical contraindications to the device (see list in the Appendix), (b) use of a single surgeon with 
an experienced surgical team and state-of-the art facilities; (c) pre-operative participant 
education and evaluation and careful post-operative care by a multidisciplinary team 
experienced in medical, surgical, nutritional and psychological aspects of bariatric surgery; (d) 
availability of an on-call physician to address symptoms and patient concerns; and (e) 
availability of the surgical team and an experienced radiologist to diagnose and treat potential 
complications. 
7.4.3 DEXA Scans 
Potentially fertile women have a urine pregnancy test immediately prior to DEXA, which is 
performed only if the pregnancy test is negative.  
7.4.4 MRI Scans 
Individuals with contraindications to MRI will be excluded from the study during Screening and 
enrollment. As an additional safety measure, all enrolled participants go through a safety 


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screening with the on-site MRI technician on the day of the exam to ensure that they are "MRI 
Safe". The scanner operates within FDA guidelines, particularly for RF power deposition (SAR) 
and gradient switching speed (dB/dt). During the exam, participants have intercom access to 
the operating technician. An emergency "squeeze ball" is also available to immediately stop the 
exam. The MRI procedure will be terminated immediately at the subject's wish. Participants will 
be informed that failure to complete the experiment will not result in any form of prejudice, or 
affect access to medical care. 
7.4.5 Other indications for Interruption of Discontinuation of Medication 
A. Pregnancy:  Study medications will not be administered if a participant becomes pregnant. 
The participant is referred to a high risk obstetrics clinic for further care. 
B. Lactation:  No study medication will be administered to women who are nursing a baby. 
C. Lactic acidosis:  Any study participant who experiences a bout of lactic acidosis will have 
metformin permanently discontinued.  
D. Dermatological problems:  Any study participant who experiences severe dermatological 
problems, such as urticaria, bullous rashes, exfoliative dermatitis, Stevens-Johnson 
syndrome, thought to be related to study medication will have study medication 
permanently discontinued. 
 
7.4.6 Hyperglycemia  
Participants are instructed regarding the signs and symptoms of hyperglycemia and are to call 
the clinic with any concerns. HbA1C will be measured at six-month intervals. If a value exceeds 
7%, therapy is invigorated by frequent telephone contact and/or visits to encourage optimal 
medication adherence and lifestyle choices. If a scheduled HbA1C exceeds 8.0% the test will be 
repeated one month later. If the value remains >8.0%, end-of study testing is performed and 
the participant completes participation in the study and is referred for standard care of 
diabetes. 
7.4.7 Glucose and Arginine Infusions 
Irritation of a vein resulting in phlebitis can occur with administration of concentrated glucose 
solutions. The risk will be decreased by minimizing the use of concentrated solutions and 
selecting large veins for infusion of solutions. Overdose of arginine can be fatal, especially in 
children. We will use a dose of 5 gm. in adults. This dose has been used safely in many studies.  


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7.5 HIPAA – Protection of Patient Information 
All data collected in the process of pre-screening, screening, and conducting the proposed 
research will be stored and maintained locally and centrally in compliance with HIPAA 
regulations. Access to study data will be secure with limited, password-protected access. Only 
study personnel who are IRB approved will have access to data collected as part of these 
studies. Data collected locally for the BetaFat study will be stored on a server that is maintained 
with the highest stringency of protection. Similarly, data transferred to the RISE CoC will be 
stored on a server that is maintained with the highest stringency of protection.  
8 ADVERSE EVENT REPORTING  
An adverse event is defined as any medical problem experienced by a BetaFat participant 
whether or not considered intervention-related by the clinical center staff. The timely and 
complete reporting of adverse events is a critical requirement in the conduct of this trial. This 
trial will be conducted under an IDE for participants without diabetes and will comply with all 
FDA reporting requirements. 
8.1 Definition of Serious Adverse Events 
a. The event results in an inpatient hospitalization (any overnight stay associated with an 
admission). 
b. The event results in the prolongation of a hospital stay. 
c. The event results in permanent or severe disability. 
d. The event results in death. 
e. A pregnancy results in a congenital anomaly. 
f. The event results from an overdose (either accidental or experimental) of the study 
medication. 
g. The event is life-threatening. 
h. Treatment is required to prevent a serious event, as defined above. 
8.2 Non-serious Adverse Events  
Non-serious are all AEs which do not meet the above criteria for “serious”. 
8.3 Reporting Adverse Events 
AEs will be ascertained in an unbiased manner using standard questions that are identical and 
administered identically to participants in both treatment arms. To accomplish this, AEs will be 
reported on a standard form that is completed by the study staff at each regular study visit.  
Targeted non-serious AEs (e.g., abdominal pain) are ascertained by asking questions relating to 


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specific events of import in prediabetic or diabetic participants as well as side effects that may 
be associated with any of the study treatment arms. AEs also include any significantly abnormal 
physical finding identified on examination and any significantly abnormal laboratory result 
obtained on the patient between visits or at the time of the visit. 
In order to facilitate timely reporting of SAEs, the clinical center staff who learn of an SAE must 
enter the completed RISE Consortium Serious Adverse Event Report prior to the close of the 
following business day. 
8.4  Tracking Adverse Events 
 Serious Adverse Events: SAEs will be monitored by the RISE Safety Monitoring Committee, 
which will remain blinded to treatment arm. The external DSMB will monitor SAEs by 
treatment arm. It is important to note that all serious and unexpected AEs must be reported 
to the CoC, regardless of the drug-related assessment. For example, a patient struck by 
lightning requires a report, even though this is not likely to be a drug related event. 
 Non-serious adverse events: Non-serious AEs are tabulated by the CoC in periodic reports in 
the same format as is done for the DSMB. Summaries of the AEs are provided to the Safety 
Monitoring Committee, which reviews this summary during one of its regularly scheduled 
meetings.  
 Safety Monitoring Committee: The Safety Monitoring Committee reviews AEs in a blinded 
fashion. The committee considers whether changes in the protocol (monitoring, consent 
process, etc.) are indicated based on the occurrence, frequency, or severity of AEs. The 
committee also evaluates whether there is any clustering of AEs by clinic. Any concerns on 
the part of the Safety Monitoring Committee may be referred to the Safety Review Officer 
and/or DSMB, which can review SAEs in an unblinded manner. 
 Safety Review Officer: The Safety Review Officer will review all SAEs in an unblinded fashion 
and will confirm or reject the causality determination of the SAE to study intervention. As 
deemed necessary, he/she may contact the local site PI to obtain additional information 
about the SAE. Any concerns on the part of the Safety Review Officer may be referred to the 
DSMB. 
8.5 Emergency Unmasking 
Treatments will not be masked in the BetaFat study, so emergency unmasking is not relevant to 
this study. 


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9 STATISTICAL CONSIDERATIONS 
All analyses will be conducted under the intention-to-treat principle using the treatment as 
assigned to each subject, and using all available data from all subjects. We will assess the 
distributional characteristics of all variables and will adjust the analysis accordingly by 
employing transformations or robust (model free) or nonparametric (distribution free) 
methods. 
9.1 Primary Outcomes and Analyses 
Two primary outcomes, each measuring ß-cell function, will be used to compare the two 
intervention groups at the end of the treatment period. ANCOVA will be the primary approach 
used for the analysis. We will employ White’s robust (information sandwich) estimate of the 
covariance matrix of the model coefficients as the basis for inferences. This approach preserves 
power and protects the type 1 error probability when the homoscedastic normal errors 
assumptions are violated. All analyses will be adjusted for the baseline value of each endpoint. 
Both primary outcomes will be analyzed separately with a total type I error probability of 0.05 
for each, i.e. without an adjustment for 2 separate outcomes. 
9.2 Secondary Outcomes and Analyses 
Comparisons of the primary study outcomes will be made for those with vs. without diabetes at 
study entry, BMI <35 kg/m2 vs. ≥35 kg/m2 at study entry, by race/ethnicity and sex, by baseline 
HbA1c and ß-cell function, and by categorical groups of various biomarkers.   
Analysis of covariance will be used to compare the metformin and gastric band groups for 
additional continuous variables of interest at both the 12-month and 24-month time points 
relative to the start of the interventions. As for the primary outcomes, all analyses will be 
adjusted for the baseline value of each endpoint. 
An important secondary analysis of this study is to determine whether ß- and -cell function 
from OGTT and fasting samples are sufficiently well correlated with more robust assessments of 
ß- and -cell function obtained from the hyperglycemic clamp to validate their use in large 
clinical trials. For these analyses, Pearson and non-parametric Spearman correlations of simple 
versus sophisticated measures of ß- and -cell function will be computed. 
 To examine biomarker associations with glucose metabolism, Pearson and non-parametric 
Spearman correlations of each biomarker with ß- and - cell function, insulin sensitivity and 
glucose tolerance measures will be determined. In addition, multiple linear regression models 


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will be developed to predict measures of glucose metabolism with the most informative 
biomarker sets. 
Other planned secondary analyses will examine relationships between exposure variables such 
as body weight and fat, insulin resistance; circulating adipokines and fat metabolites, and 
glucose levels and primary and secondary β-cell outcomes within and across treatment groups. 
9.3 Sample Size/Power Calculations 
We calculated sample size and power based on practical and statistical considerations. 
Practically, we can perform surgery on 44 subjects within the time frame and budget of the NIH 
U01 grant and associated support from Allergan. Allowing loss to follow-up rate of 10% per 
year, this will give us ~35 subjects per group to complete 24-months follow-up. Statistically, 
with 35 subjects/group, by using two-group t-test we can detect a minimum effect size of 0.68 
in difference between the two intervention groups with type I error of 0.05, 2-sided t-test, and 
80% power. Adjustment for baseline value using analysis of covariance will give us 89% power 
to detect the minimal effect size of 0.68, or give us 80% power to detect a minimal effect size of 
0.59 when the baseline and follow-up are correlated with a correlation coefficient of 0.5. 
Feasibility of observing this effect size is supported by data from diabetes prevention studies 
using weight loss, TZDs or metformin, as follows:  
 The diabetes risk reduction associated with a mean 12 lb. weight loss in the DPP was 58%, 
similar to the 55% risk reduction in TRIPOD, where we have direct measures of beta cell 
function. Those measures revealed an effect size of 0.33 for β-cell compensation between 
placebo and troglitazone at two years.  
 Given the similarity of diabetes risk reduction between TRIPOD and the DPP and assuming 
mitigation of adverse effects of obesity as a primary mechanism for diabetes prevention in 
both studies, we estimate an effect size for β-cell compensation of 0.33 for weight loss of ~12 
lbs. vs. placebo.  
 Gastric band patients at USC had an average weight loss of 35 lbs. at 24-months (Figure 1, 
above), nearly three times the average weight loss seen over the course of the DPP. Thus, we 
may see an effect size of 3 x 0.33 = 0.99 for β-cell function in gastric banding compared to no 
treatment. 
 Diabetes risk reduction with metformin in the DPP was 31%, approximately 53% of the 
reduction seen with lifestyle induced weight loss. If all of the protection were due to 
preservation of β-cell compensation, this would represent and effect size of ~0.18 vs. placebo. 
The differential in projected effect sizes between band-induced weight loss (~0.99) and 
metformin (~0.18) is ~0.80, well above the 0.68 or the 0.59 minimal effect sizes that we have 
the power to detect with our study design. 


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9.4 Interim Analysis Plans 
The DSMB will monitor trial outcomes as they emerge for futility with specific rules outlined in 
the DSMB Monitoring Plan. This trial will not be stopped for lack of efficacy, as it is a proof-of-
principle study with small numbers of participants in each treatment arm. 
9.5 Handling of Missing Data 
It is anticipated that a small number of participants may reach HbA1C >8.0% on two visits and, 
thus, have primary outcomes completed prior to 24-months. If follow-up time between 
baseline and end-of-trial differ between the two intervention groups, we will use rate of change 
(defined as (baseline-end-of-trial)/follow-up time) as the outcome in the analysis to take into 
account of differential follow-up time.  
10 DATA PROCESSING AND MANAGEMENT  
10.1 Data Management System 
We will use REDCap (http://project-redcap.org) as our primary tool for data capture. REDCap is 
a secure, web-based application that is free through the CTSA consortium. It provides: 1) an 
intuitive interface for data entry (with data validation); 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for data downloads to 
common statistical packages such as SAS; 4) procedures for importing data from external 
sources (e.g., DEXA data). REDCap has been adopted by many CTSAs across the country. All 
BetaFat study personnel at KPSC have access to REDCap through CTSA consortium. A data 
dictionary and web-based data entry system will be developed which includes data validation 
algorithms according to case report forms (CRFs). Data from non-CRFs such as laboratory and 
imaging will be merged by unique study IDs for data analyses. 
10.2 Data Transfer  
Newly entered and imported clinical center data on REDCAP are monitored and managed by 
the BetaFat data center. Those data will be transferred to George Washington University CoC 
through the CoC data management system. 
10.3 Quality Control 
Range checks, inter-item checks, cross-table checks, and double data entry verification are used 
where appropriate to ensure accurate data entry. Specific quality control procedures are run to 
check for missing, incorrect, and questionable values immediately after they are entered. 
Reports with the necessary patient identifying information and the problem values are printed 


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and sent to the clinical research coordinator for correction. When returned, corrected values 
are entered and checked again for consistency with other items. The goals are to make quality 
control a continuous process, to make the turnaround time between error detection and 
correction as short as possible, and to document any changes made to the database. 
10.4 Back-up, Data Security and Confidentiality 
To assure participant confidentiality, names are linked to study IDs only on a single recruitment 
database and only limited project personnel are authorized to have access to this database. 
Only study IDs will be used in all other study databases (e.g., for tracking and merging). All data 
are maintained on a secure USC server with two-level password protection against non-project 
personnel. Servers are automatically backed up daily. Backup procedures include: twice-weekly 
system backup, daily incremental backup, and off-site disaster recovery backup. Security 
procedures include: logon and link password protection, and for internet access, separate Web 
servers which use SSL and encryption algorithms. Virus and malware protection software is 
used on all computers and is updated on an hourly basis. All portable computers employ full 
disk encryption. Both USC and KPSC computing facilities provide support in the event of a 
disaster. Access to the server and databases is secured by use of login user accounts and 
passwords. Remote access is granted only to authorized users and is accomplished using a 
secure virtual private network (VPN). Appropriate filtering/firewall setup is used to prevent 
unauthorized access. 
10.5 Tracking Study Progress 
The purpose of tracking reports is to keep the collaborative group informed of study progress, 
and to report special problems and resolutions. Reports will be produced regularly by the 
BetaFat Data Center, as directed by the Steering Committee. These reports will be distributed 
to the study group through the study website. 
Tracking reports include the following types of information: 
 screening and enrollment (versus goal), by gender, BMI and HbA1C 
 tables describing adherence to the study protocol (attendance,  intervention compliance) 
 database inventory 
 progress of analysis and manuscripts 
10.6 Archiving and Study Close-out Including Repository 
At the end of the study, after all data have been received and edited, the database is archived 
in computer readable format, including readme documentation files, files of study documents 
(such as forms annotated with variable names, protocols, and manuals of procedures), data 


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files in the form of SAS transport files and input statements, data dictionaries, and program 
code documenting any derived variables. After the study is complete, all data will be available 
to RISE study investigators and to investigators from outside the study in a manner consistent 
with the NIDDK’s data distribution procedures. Data will be stored at a readily accessible, 
password-protected website. 
11  STUDY ADMINISTRATION  
This randomized clinical trial is one of three studies conducted by the RISE Study consortium. 
RISE is a collaborative study group funded by the NIDDK of the National Institutes of Health 
(NIH) under a cooperative agreement mechanism. The goal of the RISE Study is to test different 
interventions to preserve ß-cell function in separate trials, while allowing for the ability to 
compare data across studies and combine data from individual studies by harmonizing study 
outcomes and data collection. The RISE Study investigators will be conducting three separate 
clinical trials. The investigators for each trial are responsible for recruiting participants and 
implementing their respective protocols. In addition, the RISE Study investigators participate in 
consortia activities, as described below. 
11.1 Organization (Including Sponsors) 
The major organizational components and their responsibilities are described: 
 The RISE Steering Committee, composed of the principal investigators of the clinical centers, 
the coordinating center, and the NIDDK project office, is the primary decision making body 
for the RISE Consortium with overall responsibility for the design and conduct of the 
common elements of the three study protocols. 
 The NIDDK project office participates in all decision-making activities and selects and 
oversees the activities of the DSMB. 
 The BetaFat Data Center, located at Kaiser Permanente Southern California has 
responsibility for coordinating the BetaFat study, including production and distribution of 
materials and documents, set-up and administration of the data management system, 
maintenance of the local study database, analysis of primary study results, and distribution 
of final study data to the Coordinating Center.  
 The Coordinating Center located at the George Washington University Biostatistics Center is 
responsible for maintenance of the central database and website, for preparing reports for 
the monitoring committees and NIDDK, and for reporting of results in collaboration with the 
other studies in the RISE Consortium, and for transmission of study data to the NIDDK 
repository. 


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 The Central Blood Laboratory (CBL) operates under subcontract to the Seattle Institute for 
Biomedical and Clinical Research. The CBL is responsible for providing procedures for the 
handling, storage, and shipment of blood specimens, for performing specified tests and 
assays common to the three RISE Consortium studies, for performing quality control, for 
providing patient-level reports to clinical centers, and for transferring results to the 
coordinating center. 
 The DSMB is composed of outside experts in the design and conduct of clinical trials, and in 
type 2 diabetes. The board is responsible for reviewing the study documents, monitoring 
study progress, and monitoring patient safety.  
 Working committees include Outcomes, Recruitment and Retention, Safety and Monitoring, 
Publications and Presentations, Ancillary Studies, Lab Quality Control, and Program 
Coordinators. Committees can be discontinued and additional committees can be created 
as required. 
 Allergan Corporation provides funding but has no other role in the study. 
11.2 Central Laboratories and Reading Centers 
In collaboration with the coordinating center and study investigators, central laboratories and 
reading centers perform the following tasks: 
1. Establish procedures and standards for training staff involved in the measurement, 
collection, preparation, handling, transfer, and all other procedures and processes. 
2. Conduct training sessions and contribute training materials to the study manuals of 
procedures. 
3. Provide or facilitate the acquisition of equipment and materials, including specifying brands, 
sizes, and suppliers as applicable.  
4. Establish procedures for data entry and transfer of data to CoC. 
5. Develop procedures for the internal as well as external quality control, and provide periodic 
reports on the quality control surveillance. 
6. Provide long-term storage of reserve specimens or materials as directed by the Steering 
Committee for use in ancillary or future studies. 
Each director represents the laboratory or center at RISE Steering Committee meetings, on 
Steering Committee conference calls, and on other conference calls where the director’s 
participation is deemed necessary. 


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11.3 Training and Certification  
During the start-up period, clinic staff will receive central training and certification at a training 
workshop or other mechanisms held by the study group. The CoC staff and selected staff from 
other study components will provide instruction in all aspects of the study. The purpose of the 
training workshops and other training venues is to provide training for study staff in order to 
insure that the study is conducted in a standardized manner across all participating centers. The 
training, based on the study manual of procedures, includes review of study design, focus on 
eligibility criteria, subject follow-up schedule and assessments, metabolic and physical 
measurements, processing and shipment of specimens, use of data entry software and 
electronic forms, transferring data to the CoC, maintaining patient and data confidentiality, and 
patient treatment guidelines. 
Prior to being allowed to recruit participants, each clinical center must pass certification 
criteria, including satisfactory participation in training as above, supplying the coordinating 
center with an IRB approval letter and stamped informed consent forms, and completion of 
conflict of interest policy by all investigators. 
Throughout the study, new staff will be trained at the appropriate clinical center and by CoC 
staff where appropriate. Clinic staff will re-certify annually on identified procedures. Records of 
certifications and training will be maintained at the clinical sites. 
11.4  Site Visits  
The Steering Committee will be responsible for ongoing remote monitoring of the performance 
of study components. 
There are two types of site visits that can be conducted: (1) scheduled monitoring and (2) as 
needed to address specific problems. The RISE Consortium does not anticipate scheduled 
monitoring site visits. If necessary, site visits will be conducted to address specific problems at a 
clinical center. Depending on the specific issues, site visits will be attended by the study chair or 
designee, the NIDDK project office, the CoC, clinical center coordinators, and others as needed. 
Each visit will follow a predetermined format and site visitors will complete a checklist to record 
findings. The site visit team will review study procedures and compare data collection records 
to listings from the central database. A formal site visit report will be provided to the clinical 
center and to the RISE Executive Committee to aid in correcting any issues found.  A follow up 
report from the clinical center should go to the CoC and executive committee reporting on the 
steps taken to rectify any significant problems identified.   A follow-up site visit will be 
conducted if necessary.  


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11.5 Study Website  
The CoC maintains the study website, which is a secure site requiring a user ID and password 
combination for access. The web server utilizes the Secure Socket Layer (SSL) protocol that 
encrypts all traffic to and from the server. Investigators, coordinators, consultants, and other 
study staff who would benefit from access to the information on the website are each given a 
unique user ID and password, which identifies the user to the web server and can be used to 
restrict access to particular web pages if desired. 
The website contains study documents such as the protocol, manual of procedures, and forms, 
study calendar, directory, meeting and conference call information, links to other sites, tracking 
reports, minutes, and agendas. 
11.6 Conflict of Interest Policy 
The RISE Consortium investigators have adopted a conflict of interest policy similar to that used 
by other NIDDK collaborative groups. On an annual basis or whenever there is a significant 
change in status, RISE collaborators are required to disclose any financial or related interest 
that could present an actual conflict of interest or be perceived to present a conflict of interest. 
Disclosure is required to protect each individual’s reputation and career from potentially 
embarrassing or harmful allegations of inappropriate behavior, and to protect the integrity of 
RISE Study research. Conflict of interest forms are kept on file at the CoC, and all conflicts are 
declared at each study group meeting. 
The RISE Ethics Committee (NIDDK Project Scientist and NIDDK Project Officer) determine (1) if 
the disclosed interests could directly and significantly affect the performance of study 
responsibilities and (2) the actions needed for management, reduction, or elimination of the 
conflict. In addition to complying with the RISE conflict of interest policies, collaborators must 
certify to the Ethics Committee that they have complied with all of their local and institutional 
requirements regarding conflict of interest and disclosure. This is accomplished by supplying 
the CoC with copies of the local IRB letter of approval and stamped informed consent form(s). 
Should an institution make a determination regarding an investigator’s potential conflict of 
interest that could affect participation in RISE, the local clinic should report this to the RISE 
Ethics Committee. 
11.7 Publications and Presentations Policy  
The Publications and Presentations Subcommittee (PPS) will coordinate, monitor, review, and 
assume responsibility for overseeing the preparation of all study-wide communications (press 
releases, interviews, presentations (oral and posters), and publications) relating to the scientific 


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aspects of the study. There will be no publication or presentation of study-wide plans or results, 
including ancillary studies, which have not been reviewed and approved by a majority of the 
PPS, and for some types of communications, a majority of the Steering Committee.  
With respect to publications and presentations from the RISE Study consortium, the goals of 
the PPS are to: 
1. Ensure accurate, uniform, timely, and high quality reporting of RISE activities and 
results; 
2. Preserve the scientific integrity of the study; 
3. Safeguard the rights and confidentiality of participants; 
4. Assure that the timing of publications and presentations serves the right of the public 
to know the results of the program without jeopardizing its conduct; and 
5. Ensure that appropriate credit is acknowledged for people responsible for RISE and 
the data being reported and for the funding organizations. 
Detailed policies are found in the Manual of Operations. 
11.8 Ancillary Studies Policy  
The Ancillary Studies Subcommittee will evaluate all proposals for studies that involve RISE 
participants and/or data that are not a part of the protocol. These studies may be done in all 
RISE participants or only on a subset of participants in RISE. Ancillary studies may make use of 
data and/or samples already collected from RISE participants or may involve the collection of 
new data and/or samples. The RISE Ancillary Studies Subcommittee must review all proposed 
ancillary studies and these must receive final approval by both the Steering Committee and 
DSMB before initiation. Major factors in consideration of ancillary studies will include: 
 Clinical importance and scientific validity; 
 Compatibility of goals with those of RISE; and 
 Amount of burden on study subjects and staff, including those at the Coordinating 
Center 
Approved ancillary studies will be reviewed by the DSMB. Detailed policies are found in the 
Manual of Operations. Ancillary studies will have to obtain funding from outside the RISE study. 


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11.9 Protocol Amendments 
Adoption of protocol amendments for elements that are shared between BetaFat and other 
studies in the RISE Consortium requires two-thirds majority approval by voting members of the 
RISE Steering Committee and approval by the DSMB. Amendments that involve protocol 
elements specific to BetaFat require only approval of the local BetaFat investigators and the 
DSMB. The amended protocol is resubmitted to the local IRB, and the participant consent is 
revised appropriately. 
11.10 Repository for Storage and Distribution of Data and Samples  
At the end of the study, de-identified research data and samples of blood will be provided to 
the NIDDK Central Repositories, a research resource supported by the National Institutes of 
Health. The Repository collects, stores, and distributes biological samples and associated data 
from people with many kinds of disorders, from unaffected family members, and from other 
healthy people. The purpose of this collection is to make samples available for use in research 
for the study of obesity and diabetes and related complications after the RISE Study is 
completed. Sending samples to the Repository may give scientists valuable research material 
that can help them to develop new diagnostic tests, new treatments, and new ways to prevent 
obesity and/or diabetes.  
All participants will be asked to provide specific informed consent for release of data and 
samples to the NIDDK Repositories. Before the RISE Study investigators send data or samples to 
the Repository, each sample and data record will be given a code number and the data will be 
de-identified according to HIPAA requirements. Participants may choose to participate in RISE 
but not provide consent to have their samples and/or data transferred to the NIDDK 
Repository. 
12  STUDY TIMELINE  
The study timeline appears Figure 12.1. Recruitment will commence after IRB and DMSB 
approvals have been obtained, central study training has been performed, and all study 
medications and supplies have been procured. Screening and enrollment will begin with people 
with diabetes, for which an IDE/IND is not required. Recruitment of people with pre-diabetes 
will begin when FDA approval is obtained. Recruitment and screening are projected to occur 
over 27 months in years 1-3. On-trial visits are projected to occur over 42 months in years 1-4. 
Final testing is projected to occur over 24 months in years 3-5. Primary data analysis is 
projected to occur in year 5. Presentations and publications are projected to occur throughout 
the period of the study.  


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CONFIDENTIAL 
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dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin 
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 2.  Buchanan TA, Xiang AH: Gestational diabetes mellitus. J Clin Invest 115:485-491, 2005 
 3.  Xiang AH, Wang C, Peters RK, Trigo E, Kjos SL, Buchanan TA: Coordinate changes in 
plasma glucose and pancreatic beta cell function in Latino women at high risk for type 2 
diabetes. Diabetes 55:1074-1079, 2006 
 4.  Poitout V, Robertson RP: Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endo 
Rev 29:351-366, 2008 
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Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic 
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1996 
 6.  Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC: 
Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid 
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 7.  Scheuner D, Kaufman RJ: The unfolded protein response: a pathway that links insulin 
demand with beta cell failure and diabetes. Endo Rev 29:317-333, 2008 
 8.  Drews G, Krippeit-Drews P, Düfer M: Oxidative stress and beta-cell dysfunction. Pfügluers 
Arch 460:703-718, 2010 
 9.  Xiang AH, Kawakubo M, Trigo E, Kjos SL, Buchanan TA: Declining beta-cell 
compensation for insulin resistance in Hispanic women with recent gestational diabetes 
mellitus: association with changes in weight, adiponectin, and C-reactive protein. Diabetes 
Care 33:396-401, 2010 
 10.  Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, 
Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Saliminen V, and Uusitupa 
M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with 
impaired glucose tolerance. N Engl J Med 344:1343-1350, 2001 
 11.  Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 
diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002 
 12.  Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, 
Berkowitz K, Hodis HN, Azen SP: Preservation of pancreatic B-cell function and 
prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-
risk Hispanic women. Diabetes 51:2796-2803, 2002 


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TA: Effect of pioglitazone on pancreatic beta cell function and diabetes risk in Hispanic 
women with prior gestational diabetes. Diabetes 55:517-522, 2006 
 14.  DREAM Trial Investigators: Effect of rosiglitazone on the frequency of diabetes in patients 
with impaired glucose tolerance or impaired fasting glucose: randomised controlled trial. 
Lancet 368:1096-1105, 2006 
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Henry RR, Hodis HN, Kitabchi AE, Mack WJ, Mudaliar S, Ratner RE, Williams K, Stentz 
FB, Musi N, Reaven PD: Pioglitazone for diabetes prevention in impaired glucose 
tolerance. N Engl J Med 364:1104-1115, 2011 
 16.  Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin 
JM, O'Neill MC, Zinman B, Viberti Giancarlo, ADOPT Study Group: Glycemic durability of 
rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427-2443, 2006 
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Acad Sci 1212:41-58, 2010 
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DM, Taskinen MR, Smith U, Yki-Jarvinen H, Heine RJ: One-year treatment with exenatide 
improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 
diabetic patients: a randomized, controlled trial. Diabetes Care 32:762-768, 2009 


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Nessel L, Selby J, Strom BL: Risk of bladder cancer among diabetic patients treated with 
pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 34:916-922, 2011 
 20.  ORIGIN Trial Investigators: Basal insulin and cardiovascular and other outcomes in 
dysglycemia. N Engl J Med NEJMoaJune 11, 2012 (10.1056/1203858): 2012 
 21.  Dixon JB, O'Brien PE, Playfair J, Chapman L, Schachter LM:, Skinner S, Proietto J, Bailey 
M, Anderson M: Adjustabel gastric banding and conventional thearpy for type 2 diabetes: 
a randomized controlled trial. JAMA 299:316-323, 2008 
 22.  Kashyap SR, ,DS, ,KK, Gastaldelli A, Win H, Brethauer S, Kirwan JP, ,SP: Acute effects of 
gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic 
hormones in severely obese patients with type 2 diabetes. Int J Obes 34:462-471, 2010 
 23.  Nathan D, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, 
American Diabetes Association, European Association for the Study of Diabetes: Medical 
management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation 
and adjustment of therapy: a consensus statement of the American Diabetes Association 
and the European Association for the Study of Diabetes. Diabtes Care 32:193-203, 2009 
 24.  Nathan D, Davidson M, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B: 
Impaired fasting glucose and impaired glucose tolerance. Diabetes Care 30:753-759, 2007 


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 25.  Mitrakou A, Vuorinen-Markkola H, Raptis G, et.al.: Simultaneous assessment of insulin 
secretion and insulin sensitivity using a hyperglycemia clamp. J Clin Endocrinol Metab379-382, 
1992 
 26.  Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, Porte D Jr: 
Relationships between fasting plasma glucose levels and insulin secretion during 
intravenous glucose tolerance tests. J Clin Endocrinol Metab 42:222-229, 1976 
 27.  Larsen MO, Rolin B, Sturis J, Wilken M, Carr RD, Porksen N, Gottfredsen CF: 
Measurements of insulin responses as predictive markers of pancreatic beta-cell mass in 
normal and beta-cell-reduced lean and obese Göttingen minipigs in vivo. Am J Physiol 
290:E670-E677, 2005 
 28.  Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA: Beta-cell 
function in subjects spanning the range from normal glucose tolerance to overt diabetes: a 
new analysis. J Clin Endocrinol Metab 90:493-500, 2005 
 29.  Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, 
Ward WK, Beard JC, Palmer JP, Porte D Jr.: Quantification of the relationship between 
insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. 
Diabetes 42:1663-1672, 1993 
 30.  Buchanan TA, Xiang AH, Peters RK, Kjos SL, Berkowitz K, Marroquin A, Goico J, Ochoa 
C, Azen SP: Response of pancreatic B-cells to improved insulin sensitivity in women at 
high risk for type 2 diabetes. Diabetes 49:782-788, 2000 


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 31.  Buchanan TA, Xiang AH, Kjos SL, Watanabe RM: What is gestational diabetes? Diabetes 
Care 30(suppl 2):S105-S111, 2007 
 32.  Ward,WK, Bolgiano,DC, McKnight,B, Halter,JB, Porte,D, Jr.: Diminished b cell secretory 
capacity in patients with noninsulin- dependent diabetes mellitus. J Clin Invest 74:1318-
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 33.  Johnston,C, Raghu,P, McCulloch,DK, Beard,JC, Ward,WK, Klaff,LJ, McKnight,B, 
Bergman,RN, Palmer,JP: -cell function and insulin sensitivity in nondiabetic HLA-identical 
siblings of insulin-dependent diabetics. Diabetes 36:829-837, 1987 
 34.  Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn SE, Crandall J, 
Marcovina S, Goldstein B, Goldberg R, Diabetes Prevention Program: Adiponectin, 
change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. 
Diabetes 57:980-986, 2008 
 35.  Li S, Shin HJ, Ding EL, van Dam RM: Adiponectin levels and risk of type 2 diabetes: a 
systematic review and meta-analysis. JAMA 302:179-188, 2009 
 36.  Salomaa V, Havulinna A, Saarela O, et al.: Thirty-one novel biomarkers as predictors for 
clinically incident diabetes. PLoS One 5:e10100, 2010 
 37.  Kolberg JA, Jorgensen T, Gerwein RW, et al: Development of a type 2 diabetes risk model 
from a panel of serum biomarkers from the Inter99 cohort. Diabetes Care 32:1207-1212, 
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CONFIDENTIAL 
 38.  Akirav EM, Lebastchi J, Galvan EM, et al: Detection of â cell death in diabetes using 
differentially methylated circulating DNA. Proc Nat Acad Sci 108:19018-19023, 2011 
 39.  Karnik SK, Chen H, McClean GW, et al: Menin controls growth of pancreatic beta-cells in 
pregnant mice and promotes gestational diabetes mellitus. Science 318:806-809, 2007 
 40.  Park S, Kim da S, Daily JW, Kim SH: Serum prolactin concentrations determine whether 
they improve or impair â-cell function and insulin sensitivity in diabetic rats. Diabetes 
Metab Res Rev 27:564-574, 2011 
 41.  Marina AL, Utzschneider KM, Wright LA, Montgomery BK, Markovina SM, Kahn SE: 
Colesevelam improves oral but not intravenous glucose tolerance by a mechanism 
independent of insulin sensitivity and â-cell function. Diabetes Care 35:1119-1125, 2012 
 42.  Ota A, Wang Y: Cdc37/Hsp90 protein-mediated regulation of IRE1á protein activity in 
endoplasmic reticulum stress response and insulin synthesis in INS-1 cells. J Biol Chem 
287:6266-6274, 2012 
 
 


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CONFIDENTIAL 
Appendix 1: Contraindications to Gastric Banding and MRI 
1. Contraindications to Gastric Banding 
 
Inflammatory bowel disease 
 
Cardiac and/or pulmonary disease that imparts increased surgical risk: Angina pectoris, 
prior myocardial infarction or revascularization procedure, congestive heart failure, 
chronic bronchitis or emphysema 
 
Conditions associated with risk of gastrointestinal bleeding, including cirrhosis with portal 
hypertension, peptic ulcer disease, espohagitis, esophageal or gastric telangiectasia or 
arterio-venous malformation 
 
Conditions associated with narrowed esophagus, such and congenital narrowing or 
scarring 
 
Conditions associated with portal hypertension, including cirrhosis 
 
Congenital or acquired GI tract stenosis or atresia 
 
Prior intra-operative gastric injury, such as a gastric perforation at or near the location of 
the intended band placement  
 
Chronic pancreatitis.  
 
Drug or alcohol addiction 
 
Active infection anywhere in the body that could contaminate the surgical area 
 
Current or recently completed (within three months) glucocorticoid treatment at 
supraphysiological doses 
 
Inability or unwillingness to comply with the required dietary restrictions 
 
Allergy to the materials in the LapBand 
 
Personal or family history of an autoimmune connective tissue disease such as systemic 
lupus erythematosus or scleroderma  
 Pregnancy 
 
 
 
 
 

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Beta Cell Restoration through Fat 
Mitigation 
The BetaFat Study 
 
A Participating Study in the 
The Restoring Insulin Secretion (RISE) Consortium 
 
NCT Number: 01763346 
 
Consent Form 
 
Date: April 5, 2018 
 
 
CONFIDENTIAL


IRB #: HS-11-00703 
 
 
 
 
Version –04-05-18 
Page 2 of 18 
Study Title: Beta Cell Restoration through Fat Mitigation: The BetaFat Study 
 
Principal Investigator: Thomas A. Buchanan, M.D. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
You have been asked to participate as a subject in a medical experiment. Before you decide 
whether you want to participate in the experimental procedure, you have a right to the following 
information: 
 
CALIFORNIA LAW REQUIRES THAT YOU MUST BE INFORMED ABOUT: 
 
 
1. 
The nature and purpose of the study. 
 
2. 
The procedures in the study and any drug or device to be used. 
 
3. 
Discomforts and risks reasonably to be expected from the study. 
 
4. 
Benefits reasonably to be expected from the study. 
 
5. 
Alternative procedures, drugs, or devices that might be helpful and their 
risks and benefits. 
 
6. 
Availability of medical treatment should complications occur. 
 
7. 
The opportunity to ask questions about the study or the procedure. 
 
8. 
The ability to withdraw from the study at any time and discontinue 
participation without affecting your future care at this institution. 
 
9. 
Be given a copy of the signed and dated written consent form for the 
study. 
 
10. 
The opportunity to consent freely to the study without the use of coercion. 
 
I have carefully read the information contained above and I understand fully my rights as a 
potential subject in this study. 
 
 
Date: ___________________ Time: ________________ 
 
 
Signature: _______________________________________ 
(Research Participant) 
 
 
 


IRB #: HS-11-00703 
 
 
 
 
Version –04-05-18 
Page 3 of 18 
INFORMED CONSENT 
University of Southern California, Keck School of Medicine 
 
Title of Project: Beta Cell Restoration through Fat Mitigation 
 
Principal Investigator: Thomas Buchanan, M.D. 
 
24-hour Telephone Number: (323) 479-4319 (cell) 
 
We invite you to take part in a research study. We are providing you the following information in 
order to help you make an informed decision whether or not to participate in this study.  Please 
take as much time as you need to read the consent form. You may also decide to discuss it with 
your family, friends, or your doctor. You may find some of the language difficult to understand. 
If so, please ask questions. If you decide to participate, you will be asked to sign this form.  
 
This research study is sponsored by Allergan, the company that makes the device (the LAP-
BAND) being used in this study, Apollo Endosurgery, the company that supplies the device for 
this study, and by the National Institutes of Health (NIH). They provide funding to cover the 
costs of conducting this research study.  
 
WHY IS THIS STUDY BEING DONE 
You are invited to participate in a study to evaluate two different approaches for restoring the 
body’s ability to make insulin. Type 2 diabetes and pre-diabetes are caused by a progressive loss 
of the body’s ability to make insulin, the main hormone that controls blood sugar levels. In this 
study, we will compare two approaches to see which one may result in improving the body’s 
ability to make insulin. 
 
One approach is a medication, metformin, which is commonly used to treat diabetes. Metformin 
is approved by the Food and Drug Administration (FDA) to treat diabetes. The other approach is 
a surgery, called gastric banding. Gastric banding is an operation that places a plastic ring around 
the stomach to help a person to eat less and lose weight. Gastric banding is approved by the FDA 
to treat obesity in people with diabetes. The use of metformin and gastric banding is not 
approved by the FDA for people with pre-diabetes and their use in pre-diabetics is experimental.  
This study will compare the two approaches to see which one is better at stopping or reversing 
the loss of insulin that causes pre-diabetes to worsen to type 2 diabetes and that causes type 2 
diabetes to worsen over time. 
 
You are being asked to participate in this study because you because you are moderately obese 
(you have a body mass index (BMI) of 30 to 40 kg/m2) and you have either pre-diabetes (glucose 
levels above normal, but not yet diagnosed with diabetes) or mild type 2 diabetes.  Eighty-eight 
participants will take part in this study at USC. 
 


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WHAT IS INVOLVED IN THE STUDY? 
If you decide to take part, this is what will happen: 
 
Screening Visit: 
You will come to the Clinical Trials Unit (CTU) or the DORI (Diabetes and Obesity Research 
Institute) to have a screening visit. The CTU is located in the Keck Hospital of USC, the USC 
DORI is located in the CSC (Clinical Sciences Building). Both places are on the USC Health 
Sciences Campus. You must not eat or drink anything except water after 10 pm the night before 
the visit. The screening visit will include a medical history, physical exam including height, 
weight and vital signs measured and the following laboratory tests: 
• Blood tests to measure your blood cells, body chemistries, fasting glucose level, and liver, 
kidney and thyroid function 
• A urine sample for urinalysis and, if you are a woman of reproductive age, a pregnancy test 
• Hemoglobin A1c (a blood tests that reflects your average blood sugar for past three months) 
• 2-hour glucose level. You will drink about a cup of a sugary drink that tastes like sweetened 
soda. Two hours later a blood sample will be collected to test your glucose level. This test 
will tell us whether you have pre-diabetes or mild diabetes. 
 
The total amount of blood that will be taken for these tests is about 3 tablespoons. 
 
Your labs will be reviewed and your eligibility for the study will be determined. If you are 
eligible for the study and willing to participate, you will be invited to return to the CTU to have 
two baseline visits described next.  This screening visit will take about 3 hours. 
 
First Baseline Visit: 
On this visit you will have the following tests: 
Oral Glucose Tolerance Test (OGTT): You must not eat or drink anything except water after 
10 pm the night before the visit.  The next morning, between 7:00-9:00 am, you will come to the 
CTU.  You will put on a hospital gown. Next, you will lie down in a bed and an intravenous 
catheter (a small plastic tube) will be placed in a vein in one of your arms. If you are not allergic 
to lidocaine (numbing medication), we will inject a small amount of that medication under your 
skin to reduce the pain when the needle is inserted.  Approximately 30 minutes later, we will 
take a blood sample, about 4 tablespoons and five minutes after that you will drink 
approximately seven ounces (about 1 cup) of a glucose (sugar) drink that tastes like sweetened 
soda.  You will have seven additional blood samples drawn, each about one to two tablespoons, 
from the intravenous catheter during the three hours after you drink the glucose solution.  At the 
end of the test, we will remove the intravenous catheter from your arm and you will be able to 
eat lunch.  
Blood for DNA: At the beginning of the OGTT, a blood sample will be obtained for DNA. DNA 
contains your genes, the "blue print" for inherited traits (such as eye color and height).  
Differences in DNA may determine why some people are predisposed to certain diseases or why 
they respond differently to treatment than other people. After we complete the study, your DNA 
may be analyzed to look for genes that contribute to diabetes, obesity and their complications, 
and responses to study treatment. These analyses would be genetic research. At this time, the 


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results of genetic research cannot provide meaningful information about your health. The results 
of genetic research analyses will not be given to you or your personal health care provider. 
Diet and Quality of Life Questionnaires: While you are having your OGTT, a member of the 
research team will help you fill two questionnaires. One will tell us the kinds of food you usually 
eat, how often you eat those foods, how much you eat. The other will tell us about the quality of life 
you are experiencing, including bodily pain, physical functioning, limitations due to health 
problems, general health, vitality, social functioning, limitations due to emotional problems, and 
general mental health. 
This visit will take about 5 hours. 
 
Second Baseline Visit: 
Between 3 to 14 days later, you will return for the second baseline visit.  You must not eat or 
drink anything except water after 10:00 pm the night before the visit.  Between 7:00-9:00 am the 
next morning, you will return to the CTU and have the following tests: 
Hyperglycemic Clamp: This test will tell us how well your body makes insulin and how that 
insulin affects your blood sugar. You will put on a hospital gown and lie down in a bed.  We will 
place an intravenous catheter in one of your arms. If you are not allergic to lidocaine (numbing 
medication), we will inject a small amount of that medication under your skin to reduce the pain 
when the needle is inserted. We will place a second catheter in a vein in the opposite hand.  The 
hand will be kept warm with a heating pad.  Approximately 30 minutes after the catheters are in 
place, you will have two blood samples drawn, each about a teaspoon, from the hand catheter.   
You will then be given an injection of glucose through the arm catheter. This will be followed by 
an infusion of glucose for approximately 3½ hours. During this time, we will draw small blood 
samples from the hand vein catheter every 5-10 minutes and adjust the glucose infusion rate. For 
the first two and a half hours, we will keep your glucose level at about 200 mg/dl. This level is 
commonly found in people with mild diabetes after they eat. It will help us learn how much 
insulin your body makes in response to moderately high glucose levels. For the final hour, we 
will raise your glucose level to about 450 mg/dl and then inject a naturally occurring amino acid, 
arginine, into the arm vein. The combination of high glucose and arginine will help us determine 
the maximum amount of insulin your body can make.  
At the end of the 3½ hour infusion period, you will be given lunch and we will observe you for 
one hour to be sure that you do not develop low blood sugar levels. If you do, we will give you 
orange juice and continue to observe you until your symptoms have gone. Then we will remove 
your intravenous catheters and send you for a DEXA scan, which is described next. 
This visit will take between 5 and 5½ hours. 
 
Abdominal Fat Measurements by MRI 
The MRI (Magnetic Resonance Imaging) will measure how much fat is in a specific part of your 
belly and liver. A machine called an MRI will be used for this measurement. You will be asked 
to lie on your back inside the machine. The machine has a large magnet inside and will take 
pictures of the fat near your belly button and liver. The test takes about 30 minutes. It will be 
done at one of your baseline visits or at a separate visit. 
 


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Total Body Fat Measurement by DEXA Scan 
The DEXA scan will tell us how much fat you have in your body and where that fat is located. It 
is important for us to know this information because the amount and location of body fat may 
change the body’s ability to make insulin or use sugar as energy. You will lie on a padded table 
for approximately 10 minutes. The DEXA machine will administer an X-ray that is like a standard 
dental X-ray. If you are a woman who can still become pregnant, we will do a pregnancy test on 
your urine and we will perform the DEXA only if the pregnancy test is negative. It will be done at 
one of your baseline visits. 
 
Study Group Randomization 
At the end of the second baseline visit, you will be “randomized” 1:1 into one of the study 
groups described below.  “Randomized” means that you are placed into a group by chance (like 
the flip of a coin).  Neither you nor the study doctor can choose the treatment you receive.  You 
will have a 50% chance of receiving any one of the two treatments. 
Metformin Study Group:  
If you are assigned to the Metformin Group, you will be assigned to take the study medication, 
metformin every day for two years. Metformin will be provided in 1000 mg tablets, scored 
(notched) so they can easily be broken in half. During the first week, you will be asked to take 
one half of a tablet each morning, with breakfast. During the second week, you will be asked to 
take one half of a tablet with breakfast and one half of a tablet with dinner. During the third 
week, you will take one full tablet with breakfast and one half of a tablet with dinner. During the 
fourth week and for the rest of the study you will be asked to take one full tablet with breakfast 
and one full tablet with dinner each day. Your dose might be reduced if you have problems with 
side effects. This is described below in the section titled “What are the Possible Risks and 
Discomforts”. 
We will provide the metformin to you at each study visit. You will bring any unused pills back to 
us at each study visit.  It is very important that you take only the number of pills that are 
prescribed to you by the study team.  You will continue to take the study drug until you complete 
all clinic visits or if you end your participation in the study. 
LAP-BAND Study Group:  
If you are in the Lap-BAND group, you will have a pre-operative evaluation which includes a 
psychological evaluation, a heart evaluation with an electrocardiogram and a stress test, 
evaluation by an anesthesiologist, a chest X-ray, and blood tests. In addition, if you are female in 
the reproductive age, you will have a pregnancy test. You will also meet with a nutritionist for 
education on dietary restrictions that will apply once the LAP-BAND is in place. If you are a 
smoker, you will have to stop smoking for two months before the operation. If you are taking 
blood thinners (for example Coumadin or Plavix) you will have to stop taking them before 
surgery according to the instructions of your personal medical doctor or cardiologist. 
 


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If you qualify for the LAP-BAND on the basis of the pre-operative evaluation, your surgery will 
be performed by Dr. Namir Katkhouda at Keck Hospital of USC. You will be on a light liquid 
diet 48 hours before surgery. You must not eat or drink anything after 10 pm the night before the 
surgery. On the morning of surgery, you will come to the hospital early in the morning. You will 
be taken to the preoperative area where you will be prepared for surgery. You will be taken to 
the operating room, where you will have general anesthesia to put you to sleep for the operation.  
Surgical Procedure: This operation 
involves placing a band around the 
upper part of your stomach. The band 
contains a balloon that is adjusted to 
create a small stomach pouch. It is 
designed to restrict the amount of 
food you eat. The stomach pouch will 
fill with a small amount of food, 
creating a feeling of fullness.  
 
The band will be placed using a laparoscope. Laparoscopic surgery is done using a scope and 
hollow tube(s) called ports, which are inserted through small cuts in the abdomen. A scope is a 
thin, lighted instrument with a camera attached. It lets the surgeon see inside the abdomen. The 
surgeon can pass tools through the ports, or see tools inserted through other ports. Carbon 
dioxide gas is pumped into the abdomen. This helps the surgeon see inside the abdomen. It also 
gives him more room to work. The surgeon may not be able to complete the procedure using a 
scope or robotics. If the surgery is not done with a scope, it may be done through a larger cut. 
The surgeon will make several cuts in your abdomen. The surgeon will place the gastric band 
around the upper part of your stomach. The band will be connected to a port that the surgeon will 
place under your skin on your abdomen. To help you understand where the LAP-BAND will be 
in your body, we provide two pictures shown above. The one on the left shows how the LAP-
BAND fits on the stomach. The structure labeled “Gastric Band” is the ring that is placed around 
the stomach. The structure labeled “Port” is the port that is placed under the skin. It is connected 
to the LAP-BAND by a long tube which allows fluid to move from the port to the gastric band. 
The picture on the right shows the stomach is in the body with a LAP-BAND and port in place.  
When the procedure is complete, the cuts will be closed. A dressing will be applied. The surgeon 
may stop the procedure if he discovers severe liver disease or for any other safety reasons. 
 
A doctor from the research team will adjust the band after you have recovered from surgery. This 
is done by filling the balloon inside the band with a salt water solution. The doctor will insert a 
needle through your skin to inject salt water that will inflate the band around your stomach. The 
initial inflation will be done approximately four to six weeks after your operation. At each of the 
follow-up visits described in the next section, a member of the study team will ask you questions 
about how hungry you are and how easily you get full when you eat. Based on your answers, 
fluid will be added to or taken out of your band.  
 


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If at any time during the study you decide you no longer want to have the band in place, it can be 
removed. Removal would require an operation almost identical to the operation for placing the 
band.   
 
Follow-up Visits: You will be asked to return for follow-up visits at approximately15 days and 
45 days and then 2, 4, 6, 8, 10, 15, 18 and 21 months after your surgery (if you are in the gastric 
banding group) or 2, 4, 6, 8, 10, 15, 18 and 21 months after the first day of metformin (if you are 
in the metformin group). You must not eat or drink anything except water after 10:00 pm the 
night before each visit.  Between 7:00-9:00 am the next morning, you will come to the CTU 
where you will have a short medical history and a physical exam to record your weight and to 
look for signs and symptoms related to the lap band or metformin.  You will also have blood 
tests done at the, 6-, 12-, and 18-month visits to evaluate your response to your treatment. At the 
six-month visit you will be asked to complete the same diet and quality of life questionnaires that 
you completed at the baseline visit. In general, these visits will take 1½ to two hours each.  A 
hemoglobin A1C blood test will be done at the 4, 6, 10, 12, 18 and month visit. The results of 
this test reflect your average blood sugar levels over the prior three months. If the result indicates 
that your blood sugars are high enough to need additional treatment (that is, greater than 8.0%) 
on two successive visits, you will complete your participation in the study. We will perform your 
end-of-study tests and refer you for care of your diabetes. 
 
Some of these follow-up visits will be done at the USC DORI (Diabetes and Obesity Research 
Institute) and they might be also done at your home if convenient for you. 
 
Mid-study and End of the Study Visits 
 
Mid Study Visit: After 12 months on your assigned study treatment, you will have two visits like 
the ones you had at baseline. The first visit will be for an OGTT and MRI and the second visit 
will be for a hyperglycemic clamp. You will also have MRI and DEXA scans at the time of these 
visits. These are called mid-study visits. The OGTT, DEXA, hyperglycemic clamp and MRI at 
the mid-study visit will be performed just like the same tests at your baseline visit 
 
End of Study Visit: At the end of the two years on your study treatment, you will again have two 
visits. One will be for an OGTT, the other will be for a hyperglycemic clamp.  You will also 
have MRI and DEXA scans at the time of these visits.  These are called end-of-study visits. The 
OGTT, DEXA, hyperglycemic clamp and MRI at the end-of-study visit will be performed just 
like the same tests at your baseline visit. 
 
Post-Study Care: After you complete your participation in the study, you will return to your 
regular health care provider for ongoing medical care. If you are assigned to metformin, we will 
stop the metformin at the time of your final study visits. If you are assigned to LAP-BAND, the 
band will remain in place and you will need to be followed by a provider who is experienced in 
management of patients with LAP-BAND in place. We can offer referral to such a physician if 
you need one.  
 


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WHAT ABOUT PREGNANCY?  
You cannot participate in this study if you are pregnant or planning to become pregnant because 
some of the study procedures might hurt an unborn baby. We ask that you use effective 
contraception throughout the study. We will discuss contraceptive options that you can use, but 
those must be prescribed by your personal medical doctor.  If you think you might be pregnant 
now or at any time during the study, tell us immediately and we will do a pregnancy test to find 
out for sure. If you are a woman who could become pregnant, you will have a urine pregnancy 
test done prior to your DEXA scan. You will have the DEXA scan only if the pregnancy test is 
negative. 
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
Possible risks and discomforts you could experience during this study include: 
 
LAP-BAND 
Placement of the LAP-BAND is major surgery and the LAP-BAND is intended for very long-
term use. The risks associated with surgery to place the LAB-BAND are: 
• Death, which has occurred in fewer than 1/1000 patients  
• Damage to the liver, spleen, intestine and other organs near the stomach has occurred in 
fewer than 5/1000 patients 
• Risk of general anesthesia, which are death and damage to heart or lungs with pre-
existing risk factors such as heart disease, smoking or emphysema 
• Bleeding or infection, which occur in fewer than 1/1000 patients 
• Blood clots, which are rare 
Following surgery, some pain and discomfort at the site of the surgical incisions may be 
experienced. You will be able to eat only small amounts of food after surgery. Most of the 
information on long-term complications of the LAB-BAND is from people with severe obesity 
(BMI more than 40 kg/m2, who will not be included in this study). The following additional 
complications were reported in such severely obese people who received the LAP-BAND:  
• 51% had nausea and vomiting  
• 34% had reflux of stomach acid and/or food into the esophagus and throat 
• 27% had stomach pain  
• 24% had the band slip out of position 
• 14% had blockage of the stomach 
• 9% had constipation 
• 9% had difficulty swallowing 
• 9% had pain at the site of the fluid port under the skin 
• 8% had weakness 
• 8% had problems with healing of the surgical incision  
• 8% had some degree of hair loss 
• 7% had an infection 
• 7% had diarrhea 
• 6% had fever 


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• 5% had pain in the chest 
• 5% had chronic pain at the incision site 
• 2% had dilation (enlargement) of the esophagus 
• 2% had gallstones 
• 2% had leakage from the fluid port used to inflate the LAP-BAND 
• 1% had erosion of the LAP-BAND into the stomach 
• 1% had dehydration 
• 1% had a hernia develop between the stomach and esophagus 
• 1% had a blood clot 
• Fewer than 1% had bleeding from the stomach  
• Fewer than 1% had stomach ulcers or erosions or perforation 
 
Many of these complications can be treated medically. However, approximately 9% of severely 
obese patients required a new operation to correct serious problems such as band slippage, 
dilation (enlargement) of the stomach, obstruction of the stomach, and poor location of the band.  
 
There is less information on complication rates in people who are not as obese as the patients 
listed above. For example, in people with BMI between 30-40 kg/m2 (the range that will be 
included in this study), complication rates in the first year after surgery were: 
• 29% had vomiting 
• 22% had trouble swallowing 
• 19% had pain 
• 15% had reflux of food from the stomach to the esophagus 
• 5% had stomach pain or pain at the site of the port used to fill the LAP-BAND 
• 5% had nausea 
• 5% had indigestion 
• 3% had constipation 
• 2% had shoulder pain 
• 2% had malfunction of the LAP-BAND 
 
Approximately 5% of patients with BMI 30-40 kg/m2 required a new operation to correct serious 
problems such as band slippage, dilation of the stomach, obstruction of the stomach, and poor 
location of the band 
 
Your operation will be performed at USC by Dr. Katkhouda and his experienced surgical team. 
They have done more than 200 gastric banding operations. No patients have died during the surgery 
or had stomach erosions or stomach perforations. The rate of slippage, leak or malfunction requiring 
a second operation is less than 5%. If you do require another operation, it will be done as described 
above for your initial operation. Infection of the port occurred rarely. Blood clots have occurred 
very rarely and damage to the liver or surrounding organs are also rare. The rate of hernia at the site 
of incision has been less than 0.5%.   
 


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Metformin 
There are three main risks associated with taking metformin: 
 
Stomach problems: The most common risks are stomach problems like nausea, bloating and 
diarrhea. In general, these occur in 15-25% of people when starting metformin. The frequency will 
be minimized by having you take metformin with meals and by having you take the medication in 
slowly increasing doses during the first four weeks of the study. If you develop stomach problems 
when taking the full dose of metformin, you will have the option of reducing the dose. If you still 
have symptoms on the lowest possible dose (one pill per day) you may decide to stop taking the 
medication.   
Lactic acidosis: The second and most serious risk is development of a condition called lactic 
acidosis. This very rare condition results from the buildup of lactic acid in the blood which can 
cause tiredness and weakness. Lactic acidosis only occurs in about one person in every 1 out of 
every 33,000 people who take metformin. Usually it occurs in people who have kidney problems or 
congestive heart failure. We will examine you at baseline and during the study to be sure you don’t 
have kidney problems or heart failure. If you do, we may stop your metformin.  
Low Vitamin B12: The third risk associated with metformin is a small lowering of vitamin B12 
levels in the body. In other studies, this has happened in about7% of people who took metformin. 
Those people did not develop any signs or symptoms from low B12 levels.  We will measure your 
blood count every year to be sure you are not developing an important lowering of you B12 level. 
 
Oral glucose tolerance test (OGTT) 
Placement of Intravenous Catheter: There will be some pain during the placement of the 
intravenous needle and catheter.  Some bruising and soreness at the site for 1-2 days after the test 
will probably occur.  If you are allergic to lidocaine, please notify the research team and we will 
instead attempt to numb your skin with ethyl chloride, a cold spray.  It is less effective than 
lidocaine, but does not cause a lidocaine allergy.  There is a small (less than 1 in 1000) chance of 
infection at the site where the catheter is placed. 
 
Sweetened Sugar Drink: Some people experience nausea or upset stomach immediately after 
drinking the sweetened sugar drink.  If you become nauseous and do not wish to complete the 
test, we will stop the procedure. 
 
Blood Collection: The risks of the blood draw include pain, bruising, and rarely infection. 
 


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Hyperglycemic Clamp 
Placement of Intravenous Catheters:  The risks of the intravenous catheter are the same as for the 
OGTT. A flushing sensation, which lasts for less than a minute, may be experienced when we first 
inject the glucose.  There is a risk of low blood sugar in the hour after the glucose infusion is 
stopped.  You will be fed right after we stop the glucose and we will observe you for an hour for 
any symptoms of low blood sugar. If they occur, we will give you orange juice and observe. Muscle 
cramps have been reported rarely (fewer than 1 per 300 clamps). If they occur and do not resolve, 
we may have to stop the clamp and ask you to return to repeat it at a later date.  
 
Blood Collection: The risks of the blood draw include pain, bruising, and rarely infection. The 
Hyperglycemic Clamp will be done at a different time if your blood count is too low. 
 
DEXA Scan 
The DEXA scan will expose you to a very small amount of radiation, much less than most routine 
X-ray procedures.  Exposure to radiation can increase the risk of getting cancer.  The amount of 
radiation to which you will be exposed during a DEXA scan is so small that the precise risk is 
unknown.  
 
MRI  
There are no known risks associated with the magnetic field exposure during the MRI scans. 
Since the machine is shaped like a large tube and there is limited space inside the tube, some 
people may feel nervous and uncomfortable in this enclosed area or when they hear the loud 
tapping noise the machine makes. To help minimize this, you will be given earplugs to block the 
noise or headphones to listen to music. If for some reason you are unable to do this test at the 
time of your visit, you may be rescheduled and will still be able to participate.  
 
Diet and Quality of Life Questionnaires 
Some of the questions included in the diet and quality of life questionnaires may make you feel 
uneasy or embarrassed. You can choose not to answer such questions. 
 
Genetic Research 
There have been concerns about the possibility of discrimination based on genetic analysis. 
Despite these concerns, this has not been a problem to date. Federal and State laws provide some 
protection against employment or health insurance discrimination based on genetic findings. 
These protections do not extend to life insurance, disability insurance, or long-term care 
insurance. We will use our best efforts to keep the genetic findings in this study as confidential 
as possible. 
 


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WILL YOUR INFORMATION BE KEPT PRIVATE? 
Officials of the Food and Drug Administration (FDA) and officials of the study sponsor, the 
National Institutes of Health (NIH), Allergan Corporation, and Apollo Endosurgery may look at 
your research records and medical records related to the study. The University of Southern 
California’s Institutional Review Board (IRB) may review your records. The IRB is a research 
review board that is made up of professionals and community members who review and monitor 
research studies to protect the rights and welfare of research participants. Other people who 
provide medical care or who handle billing and payment at USC may review your research 
records and medical records, if necessary to conduct the research. All personal information from 
this study will be stored in password-protected computerized databases.  All paper forms will be 
stored in secured file cabinets.  Only personnel directly associated with this study are intended to 
have access to this information.  Your personal information will not be provided to anyone 
outside this study. We may publish the information from this study in journals and we may 
present it at meetings.  If we do, we will not use your name or any unique personal identifying 
information. 
 
We have obtained a Certificate of Confidentiality from the National Institutes of Health to help 
protect your privacy. This certificate means that the researchers cannot be forced to tell people 
who are not connected with the study, including the court system, about your participation in this 
study. 
 
There are some exceptions to the privacy protection offered by the Certificate of Confidentiality. 
• If you ask us to give someone your information, we will. The Certificate of 
Confidentiality does not prevent you or a member of your family from 
voluntarily giving out information about you or your participation in this study. 
• If the study staff learns of possible abuse, neglect, or a risk of harm to yourself 
or others, we are required to tell the proper authorities. 
• If government agencies need to perform audits or evaluate a study that is funded 
by the Federal Government, including evaluations performed by the Federal 
Food and Drug Administration (FDA), we are required to share information 
about the study. 
 
This Certificate of Confidentiality does not mean the government approves of this research. If 
you enter the study after the Certificate of Confidentiality has expired, the researcher will tell 
you this and can no longer rely on the Certificate to protect your confidentiality. 
 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 


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WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART IN THIS STUDY? 
You may not receive any benefit from participating in this study.  If you are assigned to the Lap-
Band, you may lose weight which could improve your general health and lower your blood sugar 
levels. If you are assigned to metformin, your blood sugar may be lowered to a safer level.  Your 
participation in this study may help diabetic patients in the future.  
 
WHAT OTHER OPTIONS ARE THERE? 
An alternative would be not to take part in this study and continue with your current care. 
Metformin is an approved treatment for Type 2 diabetes. The LAPBAND is approved for obesity 
(BMI>30 kg/m2) in people with diabetes. Other treatments include lifestyle changes and 
medications other than metformin to lower your blood sugar levels.  
 
ARE THERE ANY PAYMENTS TO YOU FOR TAKING PART IN THE STUDY? 
As reimbursement for your time and any out of pocket expenses that result from your 
participation in the study, you will receive the following payments at the end of each visit: 
Screening Visit:  
            $50 
OGTT+MRI Visit: 
            $75 
Clamp+DEXA Visit:  
$125 
Follow Up Visits:   
 
$ 25/visit 
 
You will still be compensated for each visit that you attend even if you do not complete all of the 
study procedures. 
 
If you receive more than $600 per year for taking part in one or more research studies, including 
this study, you may be required to pay taxes on that money. This does not include any payments 
you receive to pay you back for expenses like parking fees.  You may receive an Internal 
Revenue Service (IRS) Form 1099 if you receive more than $600 in one year for taking part in 
one or more research studies.   
 
WHAT ARE THE COSTS? 
All research tests and procedures provided to you for this study are being paid for by the sponsor. 
Neither you and/or your health plan/insurance company will be charged for the cost of any 
research tests or procedures that are being done for this study. If you require any routine tests or 
procedures to treat your illness that are not related to this study (meaning you would normally 
receive them if you were not participating in this study), you and/or your health plan/insurance 
company will be billed for the costs of the routine tests and procedures in the same way as if you 
were not in a study. You will also be responsible for any co-payments and deductibles that are 
standard for your health plan/insurance coverage. Some health plans will not pay these costs for 
people taking part in studies. Check with your health plan or insurance company to find out what 
they will pay for. If you have any questions about which tests or procedures will be billed to you 
and/or your health plan/insurance company, ask the study doctor. 
 


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WHAT HAPPENS IF YOU GET INJURED OR NEED EMERGENCY CARE? 
You are participating in this study under the supervision of Dr. Thomas Buchanan, and his co-
investigators, Drs. Elizabeth Beale and Namur Katkhouda.  Some or all of the study procedures 
will be performed on the USC Clinical Trials Unit (CTU) or by staff of the CTU.  If you get hurt 
or sick from participating in the study, you will be offered treatment for the injury. Who will pay 
for the treatment depends on how and where it occurs.  If the injury is from the procedures 
performed or directed by Dr. Buchanan or a member(s) of his research team, you will be offered 
medical treatment. You and/or your health plan/insurance company/government must pay for the 
treatment. If you get hurt from a procedure performed by one of the CTU staff that was not part 
of the BetaFat research team, the CTU will review your case and decide payment.  
 
WILL YOU RECEIVE NEW INFORMATION ABOUT THIS STUDY? 
During the study, we may learn new things about the risks or benefits of being in the study. If we 
do, we will share this information with you. You might change your mind about being in the 
study based on this information.  
 
WHAT ARE YOUR RIGHTS AS A PARTICIPANT, AND WHAT WILL HAPPEN IF 
YOU DECIDE NOT TO PARTICIPATE? 
Your participation in this study is voluntary. Your decision whether or not to take part will not 
affect your current or future care at this institution.  You are not waiving any legal claims or 
rights.  If you do decide to take part in this study, you are free to change your mind and stop 
being in the study at any time. If you are removed from the study, you will be referred to your 
care provider for follow-up. 
 
CAN YOU BE REMOVED FROM THE STUDY? 
You may be removed from this study without your consent for any of the following reasons: you 
do not follow the instructions of the research team, the study doctor decides to remove you from 
the study, or the study is closed for any reason. If you are removed from the study, you will be 
referred to your primary care provider for follow-up.  
 


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WHOM DO YOU CALL IF YOU HAVE QUESTIONS OR CONCERNS? 
You may contact any one of the following individuals with questions, concerns, or complaints 
about the research or your participation in this study: 
Thomas Buchanan, M.D. ............ 323-479-4319 Cell 
Elizabeth Beale M.D……………626-232-5348 Cell, 213-287-0123 Pager 
Namir Katkhouda M.D. ...................... 323-442-5709 
Enrique Trigo ...................................... 323-313-2741 
 
If you feel that taking part in this study has hurt you, please contact Thomas Buchanan, MD at 
the work number listed above or at the 24 hour number (323) 479-4319.  If you have questions, 
concerns, or complaints about the research and are unable to contact the research team, , contact 
the Institutional Review Board (IRB) Office at 323-223-2340 between the hours of 8:00 AM and 
4:00 PM. (Fax: 323-224-8389 or email at irb@usc.edu).  
 
If you have any questions about your rights as a research participant or want to talk to someone 
independent of the research team, you may contact the Institutional Review Board Office at the  
numbers above or write to the Institutional Review Board at the LAC+USC Medical Center, 
General Hospital, Suite 4700, 1200 North State Street, Los Angeles, CA 90033.  You will get a 
copy of this consent form. 
 
Future Analysis of Your Blood Samples:  
Please mark yes or no for each question below about how your blood samples may be used for 
research outside this study. 
 
a) My blood samples may be kept for use in future research on diabetes and related diseases 
 
 
 
Yes ______ 
No _______ Initials ______    
 
b) My blood samples may be kept for use in any future medical research. 
 
 
 
Yes ______ 
No _______ Initials ______  
 
c) I agree to have my blood samples shared with other researchers. 
 
 
 
Yes ______ 
No _______ Initials ______ 
 
d) We would like you to agree to have your research data and a part of your blood, urine and 
DNA samples stored in the Central Repository of the National Institute of Diabetes, 
Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). The 
Central Repository collects, stores, and distributes biological samples and associated data 
from people with many kinds of disorders and from healthy people. If you agree to provide 
your data and samples, the Repository would make them available for future research about 
diabetes, obesity and related disorders after the BetaFat Study is over. Your data and samples 
could be valuable research material that could help researchers develop new diagnostic tests, 
treatments, and preventive measures. 


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If you agree to place you data and samples in the Repository, the Repository will take 
measures to protect your privacy, although it cannot absolutely guarantee confidentiality. 
Before researchers in the BetaFat Study send your samples to the Repository, we would give 
each sample a code number and remove your name or other personal identifying information 
such as address, social security number, or date of birth. Therefore, the Repository would not 
be able to give out this personal information to any scientists who receive your samples. 
However, the Repository would have and could share some information, such as your age, 
sex, diagnosis, race, and outcomes of the BetaFat Study. 
 
You will not receive any direct benefit or payment for allowing your data and samples to be 
placed in the Central Repository. Neither you nor your physician will get the eventual results 
of studies that might be performed using your samples. It is possible that data resulting from 
use of your samples may be used in a research publication. In that event, your name or other 
identifying information will not be included. There is a small chance that some research may 
yield results that may indirectly have a negative impact on insurability, employability, and/or 
family relationships of some individuals or groups of people. If research conducted using 
your samples in the Central Repository leads to findings or inventions that have value if they 
are made or sold. These findings or inventions may be patented or licensed, which could give 
a company the sole right to make and sell products or offer testing based on the discovery. 
Some of the profits from this may be paid back to the researchers and the organizations doing 
this study, but you will not receive any financial benefits. 
 
Your decision whether or not to allow your data and samples to be placed in the Central 
Repository is voluntary and will not affect your other participation in the BetaFat Study. If 
you choose not to participate there will be no penalty or loss of benefits to which you are 
otherwise entitled. If you agree to have your data and samples stored in the Repository, you 
can change your mind up until the end of the BetaFat Study. When study researchers receive 
written instructions from you, they will destroy your sample and all information that 
identifies you. After the BetaFat Study ends, you will not be able to withdraw your sample 
because the Repository will not know which one is yours.  The sample will stay in the 
Repository indefinitely. 
 
I agree to have my data and parts of my blood, urine and DNA samples stored in the Central 
Repository of the NIDDK at NIH. 
 
Yes ______ 
No _______ Initials ______ 
 
 
The results of our research testing will not be provided to you or to your health care provider 
because no one knows how to apply these results to your medical care. 
 


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AGREEMENT: 
I have read (or someone has read to me) the information provided above. I have been given a 
chance to ask questions. All my questions have been answered. By signing this form, I am 
agreeing to take part in this study. 
 
 
 
Name of Research Participant 
Signature 
Date Signed 
 
I have personally explained the research to the research participant and answered all questions. I 
believe that he/she understands the information described in this informed consent and freely 
consents to participate.  
 
 
 
 
Name of Investigator/Person Obtaining 
Informed Consent 
 
Signature 
Date Signed 
 
A witness is required when: (1) the participant cannot see, read, write, or physically sign the 
consent form, or (2) the Short Form method is used to obtain consent.  If no witness is needed, 
leave this signature line blank. 
 
 
 
 
Name of Witness  
Signature 
Date Signed