Very Low Carbohydrate Diet as an Adjunctive Therapy for Youth Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Yale University

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 1 of 26
                   
                                   
HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2017-1)
Protocol Title: A Very Low Carbohydrate Diet as an Adjunctive Therapy for Youth Type 1 Diabetes
Principal Investigator: Laura Nally, MD
Version 4 Date: November 18, 2021
Clinicaltrials.gov Registration #: NCT04082884
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 2 of 26
SECTION I: RESEARCH PLAN
1.
Statement of Purpose: This prospective, open-label pilot/feasibility study of youth with T1D is to evaluate 
glycemic and metabolic changes taking place with a very low carbohydrate diet.
2.
3.
Probable Duration of Project: The expected duration of the project is 5 years, including all follow-up and 
data analysis activities.  
4.
Background: As recently reported by the Type 1 Diabetes Exchange (T1DX)  Registry, adolescents  with type 
1 diabetes (T1D) was the age group that had the highest hemoglobin A1c (A1c) levels compared to older 
participants;  young adults aged 10-25 years were a close second (1).   While the American Diabetes 
Association (ADA) recommends youth target A1c of <7.5% and adults <7%, only 17% of youth and 21% of 
young adults in the T1DX achieved these targets despite increased penetrance of diabetes technologies into 
clinical care (1, 2).  These data suggest a need for novel approaches to improve glycemic control in 
adolescents and young adults with T1D.  
Even for compliant youth with T1D, postprandial hyperglycemia continues to pose a challenge for many 
reasons, including, delayed insulin absorption and action compared to absorption of glucose from the 
gastrointestinal tract and dysregulated glucagon secretion after mixed meals (3).  Moreover, postprandial 
glycemic changes can differ substantially depending on the macronutrient composition of the meal.  
Specifically, meals with reduced carbohydrate but increased fat and protein content will lessen immediate 
postprandial hyperglycemia (4).  For many, being able to avoid carbohydrates and adhere to a very low 
carbohydrate diet may be easier than administering varying amounts of insulin for variable amounts of 
carbohydrate intake. Although standard treatment of T!D recommends varying the  pre-meal dose of rapid-
acting insulin depending on the patient’s insulin to carbohydrate ratio, studies have shown that inaccurate 
carbohydrate counting happens frequently and contributes to increased glycemic variability (5). 
Data from the Diabetes Control and Complications Trial (DCCT) demonstrated that lowering the A1c by 
intensive insulin management to near-normal glycemic levels decreases the risk of complications related to 
diabetes (6).  However, intensive management in the DCCT was accompanied by marked increases in severe 
hypoglycemia and more recent data have implicated increased insulin doses as risk factors for 
cardiovascular disease in T1D (7).  One approach to achieve targeted glycemic control with less insulin 
exposure is through the use of a very low carbohydrate diet (VLCD), defined as limiting carbohydrate intake 
to 50 grams  per day or less (8).  In adults with T1D, these diets have been shown  to achieve exceptional 
glycemic control with physiologically normal A1c values with lower total daily insulin doses due to decreased 
mealtime insulin for low amounts of carbohydrate intake (9, 10).  
Importantly, VLCDs have not been formally studied in adolescents and young adults with T1D. Observational 
data on children using a VLCD are also conflicting.  A small case series of 6 children with T1D on a low 
carbohydrate diet showed deficits in anthropomorphic measurements and elevated lipids, though in some 
cases a caloric deficit was also reported (11).  Conversely, a recent observational study of 131 children with 
T1D on a VLCD reported no significant change in height percentile or SDS after initiating the diet (12).  Prior 
studies have explored use of low carbohydrate diets in T1D, but none have specifically monitored for 
ketosis.  In those studies, it is likely that the lack of carbohydrate intake led to lower insulin needs, thus 
increasing lipolysis and ketogenesis, and levels of ketosis while on this type of diet require further study (13).  
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 3 of 26
Since rigorous studies implementing a VLCD in youth with T1D remain to be done, the present pilot study is 
being undertaken to evaluate the glycemic and metabolic changes that accompany  initiation of a very low 
carbohydrate diet in adolescents and young adults with T1D who are receiving insulin pump therapy. 
Specifically, we will measure changes in plasma glucagon, β-hydroxybutyrate, and free fatty acid (FFA) levels, 
as well as changes in basal hepatic glucose production, glycerol turnover, lipid oxidation and plasma 
glucagon responses to arginine infusions. Continuous glucose monitoring will be used to evaluate changes in 
plasma glucose responses to meals before and after initiation of the VLCD. Insulin pump downloads will be 
employed to assess changes in basal and bolus insulin doses. 
Aims:  To examine changes in sensor glucose levels, basal and bolus insulin doses, and FFA, glucagon, and β-
hydroxybutyrate levels following implementation of a VLCD.  Sensor-derived time glucose ranges will serve 
as a surrogate marker of hemoglobin A1c given the short duration of the study.  We will also be assessing 
safety measures of the diet, including daily fasting ketone levels.  Hypothesis:  We hypothesize that use of a 
VLCD with strict monitoring of ketosis will reduce glycemic variability and increase time in target range, 
defined as 70-180 mg/dL by reducing the time in the hyperglycemic (>180 mg/dL) and hypoglycemic ranges 
(<70 mg/dL).  Decreased carbohydrate intake will lead to less postprandial hyperglycemia.  Lower insulin 
doses for meals and snacks as a result of decreased carbohydrate intake will lessen postprandial 
hypoglycemia as well.
Further, we will also measure changes in glucose and glycerol metabolic fluxes using stable isotopes and 
indirect calorimetry to measure rates of fat oxidation before and after 2 weeks of a VLCD. Arginine infusion 
will used to assess changes in plasma glucagon responses with the VLCD. Hypothesis: Glucose and glycerol 
turnover will be increased in those with T1D on a very low carbohydrate diet. Lipid oxidation will also be 
increased. We further hypothesize that the arginine-stimulated glucagon response will be increased while 
on the VLCD will, in turn, decrease the risk of late post-meal hypoglycemia during the VLCD. 
Research Plan:  This prospective feasibility study of 10 youth (ages 13 – 25) with T1D will evaluate glycemic 
and metabolic changes after 2 weeks of a high protein VLCD compared to 2 weeks on a standard 
carbohydrate diet (see Table 1).  The study will take place in 2 parts.  Part 1 will only involve the high protein 
VLCD, but part 2 will involve high protein VLCD and high fat VLCD’s.
Table 1.  Types of study diets and macronutrient content in each planned diet.  
Type of Diet
Carbohydrates
Protein
Fat
Standard 
Carbohydrate
25%+
Not specified
Not specified
High Protein VLCD
11%
54%
35%
High Fat VLCD
11%
23%
66%
Part 1:  First, to evaluate the feasibility of following a high protein VLCD,  participants will follow a standard 
carbohydrate diet for 2 weeks, followed by a 1 week transition to a VLCD, and then follow the a high protein 
VLCD for 2 weeks.  The study will consist of 3 in person or virtual visits which will take place over ~5 weeks.  
All participants will be initially studied for 2 weeks while ingesting a standard diet recommended by the 
American Diabetes Association, followed by a 1-week transition to a VLCD, and followed by 2 weeks on the 
high protein VLCD.  During the first (baseline) period fasting β-hydroxybutyrate levels will be measured 2-3 
times per week.  During  the VLCD study periods, fasting β-hydroxybutyrate levels will be measured daily in 
the morning using a blood ketone meter;  insulin doses will be collected using insulin pump downloads and 
continuous glucose monitoring (CGM) profiles will be used to assess glycemic excursions on each diet, as 
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APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 4 of 26
well as the time in hypo-, eu- and hyperglycemic ranges.  Part 1 of the study is anticipated to be complete by 
December 31, 2022.
5.
Participants: This study will enroll 10-20 participants (ages 13 to 25) with T1D.  At least 4 adults over the age 
of 18 will be enrolled.  Ten youth will be involved in Part 1, which evaluates feasibility of the diet.  If those 
youth would like to continue to Part 2 of the study they may continue, or they will be replaced by new 
participants.  To be eligible for inclusion, the participant must have T1D for at least 1 year, have an A1c 
between 6.5% to 10.0% inclusive, and BMI of at least 19 kg/m2 (or 5th percentile for those under age 18) and 
be willing to wear a CGM, which is the currently recommended standard of care for children with type 1 
diabetes and is FDA approved for use above age 2 years. They must also be willing to adhere to a VLCD, 
measure β-hydroxybutyrate levels daily and to keep a detailed food diary.  Participants who are unable to 
wear a CGM, monitor their diabetes control or maintain the VLCD will be replaced. 
Study visits: Participants will be recruited from Yale Pediatric Diabetes Center and Yale Diabetes Center 
clinics, as well as through social media.  All participants will undergo pre-screening of their electronic 
medical record (or faxed medical record from their pediatric endocrinologist or endocrinologist) to evaluate 
study eligibility by review of medical history, as well as prior physical exams and laboratory tests.  No blood 
will be collected in part 1 of the study.
Figure 1.  Timeline of visits and telephone follow ups for the duration of the study.  Visits and calls may be 
modified depending on patient availability and academic schedule.  Part 1 of the study will involve in-person 
or virtual visits (Facetime, Video Doximity Calls, Zoom, or Skype) and telephone study visits.  Part 2 of the 
study will involve in-person visits.
 
Screening & Enrollment Visit 1:  Screening will be conducted by invitation to potentially eligible subjects.  For 
the first part of the study, the study will be explained and telephone or e-consent will be obtain prior to 
conducting any study procedures.  Participants will 1) meet in person or 2)use telephone to discuss the study or 
3) Skype, Zoom, FaceTime or Doximity Dialer enabling video calls.  Scales will be provided for all participants.
Consent:  Consent will be transitioned to an online/electronic format using the YSM version of REDCap if 
consent is not obtained in person.  

Two copies of the consent form will be sent to subjects by mail, fax, or e-mail, prior to the 
consenting phone call so that subjects have time to review the consent prior to signing it and so 
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APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
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that subjects have a physical copy in hand to follow along and ask questions during the consenting 
phone call/virtual visit.

The consent will be signed and dated by the participant and returned via a self-addressed 
envelope or faxed to the research team. It will be signed and dated by the person obtaining 
consent upon receipt. 

Once the consent is signed by the research team member, it will be filed in the subject’s research 
record.

A note to file to document the consenting process took place over the phone, which explains the 
difference in dates, will be completed and stored with the signed consent forms.
After consent has been obtained, participants will review their diabetes history and answer demographic 
questions.   At this and all other study visits, participants will meet (virtually or in person for part 1) with a 
diabetes care provider (i.e., a physician, nurse practitioner, or physician assistant) who will carry out a 
comprehensive review of diabetes management and review blood glucose and ketone records. Participants will 
be asked to rate their puberty status in lieu of a physical exam for puberty.  A validated system for self-
assessment of puberty status that has been used by pediatricians will be used for this study.  Women of 
childbearing age will have a urine pregnancy test performed at the time of the screening/enrollment visit and 
the need for contraception for the entire duration of the study will be discussed. If pregnancy testing cannot be 
performed in-person, a pregnancy test will be mailed to the participant an we will ask them to securely send a 
photo of the results to the study team. The treatment regimen will be adjusted as clinically indicated.  
Individuals will be asked to wear a continuous glucose monitor (CGM) during the 2-week standard carbohydrate 
and 2-week VLCD assessment period. A CGM will be provided if the individual does not have one that they use 
as a part of routine care.  Insulin pumps and CGMs will be downloaded to assess prior glycemic control. 
Baseline data obtained at the enrollment visit will include:

Demographic characteristics, including family income, highest parental education attained, and number 
of individuals in the home.

Anthropometric measures will be reviewed from the most recent clinic visit, including height, weight, 
BMI, vital signs).  Participants will self-identify their tanner stages based on gender-specific norms. 

Current diabetes care practices (frequency of self-monitored blood glucose (SMBG), insulin dosing, 
review of blood glucose values)

Medical History: duration of diabetes, comorbidities, past medical history, social history, family history, 
medications, and allergies.

Additional diabetes history including current/past use of CGM, insulin pump, and other modes of 
diabetes technology.

Frequency of missed school days and Emergency Department visits due to decompensated diabetes 
(i.e., hyperglycemia, ketosis and DKA) over the past 6 months

Questionnaires will be administered, including:
a.
Diabetes Treatment Satisfaction Questionnaire (DTSQ), which includes eight items, six of which 
form a scale (scored 0-36) in which higher scores indicate greater treatment satisfaction 
(Bradley, 1994). 
b.
Nutrition Knowledge Survey (NKS) which collects information on healthful eating, carbohydrate 
counting, blood glucose response to foods, and nutrition label reading. Higher NKS scores reflect 
greater nutrition knowledge (score range is 0–100%) (Rovner 2012). 
c.
Diabetes Distress Scale (DDS) is a 17-item scale that captures diabetes distress in 4 different 
areas, including emotional burden, regimen distress, interpersonal distress, and physician 
distress (Polonsky 2005).
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APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
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HIC#: 2000026189
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All participants will receive dietary instruction to review the dietary requirements of the study.  A handout with 
examples of the type of diet required will be provided to each participant at the time of or prior to consent.  
Participants will provide a 3-day dietary history at the enrollment visit to assess current caloric intake.  Each 
subject will be instructed on how to keep a food diary. Participants and/or parents will be asked to take photos 
of all food consumed to aid in dietary recall.   After the enrollment visit, participants will be contacted to assess 
adherence to the diet and adjust insulin doses 3 times per week (see Table 1).  During these telephone follow up 
calls, food diary will be reviewed, photos of meals will be reviewed, and pump and CGM data will be uploaded 
and reviewed.  Participants will receive a link in their email to fill out the 3 surveys using Yale Qualtrix.
Visit 2:  After 2 weeks on the standard carbohydrate diet, insulin pump and CGM data will be uploaded 
(Tidepool, Dexcom, Medtrnoic, Omnipod or Tandem site, depending on the insulin pump being used) and 
reviewed.  Dose adjustments will be made as clinically indicated.  Participants will receive a link in their email to 
fill out the 3 surveys using Qualtrix.
The dietician will look at each individuals macronutrient intake during the standard carbohydrate portion of the 
study.  Based on this information, we will instruct them to eat a certain amount of carbohydrates each day.  If 
they eat more than 200 grams per day of carbohydrates during the standard diet weeks, they will be instructed 
to eat 100-150 grams of carbohydrates per day during the transition week.  If they eat less than 200 grams per 
day of carbohydrates during the standard diet weeks, we will instruct them to eat 75-125 grams of 
carbohydrates per day during the transition week. Most people with diabetes know how to carbohydrate count, 
however we will review carbohydrate counting at the time of the transition.  Carbohydrate counting will be 
taught using the “Choose Your Foods:  Food Lists for Diabetes” written by the American Diabetes Association 
and the American Nutrition of Dietetics.
For the VLCD portion of the study, participants will be given an isocaloric diet with a goal carbohydrate intake of 
less than 20% carbohydrates per day (~100 grams per day) for adolescents and less than ~50 grams per day for 
adults at least 18 years of age.  Guidelines will be provided for meals.  Participants will also receive training on 
the treatment of hypoglycemia and be instructed to call the study team immediately in the case of severe 
hypoglycemia.
Visit 3: After at least 2 weeks on each of the very low carbohydrate study diets, participants will meet virtually 
with study staff to review isulin pump and CGM data. Insulin pump and CGM data will be uploaded (Tidepool, 
Dexcom, Medtrnoic, Omnipod or Tandem site, depending on the insulin pump being used) and reviewed 
virtually, as is commonly done in clinical practice.  Dose adjustments will be made as clinically indicated.  
Participants will receive a link in their email to fill out the 3 surveys using Qualtrix.
Part 2:  In the second part of the study, participants will once again begin on a standard carbohydrate diet for 2 
weeks and then be randomized to either a high fat VLCD or high protein VLCD.  They will transition over a 1 
week period to one of these 2 diets, and then will follow the diet for an additional 2 weeks.  As in the first part of 
the study, they will have 3 visits over 5 weeks.  At the end of each 2-week period, we will evaluate glucose and 
glycerol fluxes and fat oxidation in the Hospital Research Unit (HRU) or Church Street Research Unit (CSRU) as 
well as plasma glucagon and glucose excursions after an arginine infusion. This study will be completed after 
completion of part 1.  The total duration of the study is anticipated to be 2 years, anticipated end date 
December 31, 2023.
Screening & Enrollment Visit:  Screening will be conducted by invitation to potentially eligible subjects. Written 
informed consent will be obtained prior to conducting any study-related procedures.  After consent has been 
obtained, subjects will review their diabetes history and answer demographic questions.   At this and all other 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 7 of 26
study visits, participants will meet with a diabetes care provider (i.e., a physician, nurse practitioner, or physician 
assistant) who will carry out a comprehensive review of diabetes management and review blood glucose and 
ketone records. The treatment regimen will be adjusted as clinically indicated.  Individuals will be asked to wear 
a continuous glucose monitor (CGM) during the 2-week standard carbohydrate and 2-week VLCD assessment 
periods. A CGM will be provided if the individual does not have one that they use as a part of routine care.  
Insulin pumps and CGMs will be downloaded to assess prior glycemic control. 
Women will have a urine pregnancy test performed at the time of the screening/enrollment visit and the need 
for contraception for the entire duration of the study will be discussed.  
Baseline demographic information will be obtained, including:

Demographic characteristics, including family income, highest parental education attained, and number 
of individuals in the home.

Anthropometric measures will be measured, including height, weight, BMI, and vital signs. 

Participants will undergo a physical exam, including tanner staging.

Point of care HbA1c, obtained via fingerstick and measured by a Seimens DCA Vantage device, will be 
determined unless an A1c was measured in clinic within the past 30 days.

Current diabetes care practices (frequency of self-monitored blood glucose (SMBG), insulin dosing, 
review of blood glucose values)

Medical History: duration of diabetes, comorbidities, past medical history, social history, family history, 
medications, and allergies.

Additional diabetes history including current/past use of CGM, insulin pump, and other modes of 
diabetes technology.

Frequency of missed school days and Emergency Department visits due to decompensated diabetes 
(i.e., hyperglycemia, ketosis and DKA) over the past 6 months

Baseline laboratory assessment if it has not been done in the past year, as a part of standard of care 
(comprehensive metabolic panel with electrolytes, lipid panel, urine microalbumin).

Questionnaires will be administered, including:
a.
Diabetes Treatment Satisfaction Questionnaire (DTSQ), which includes eight items, six of which 
form a scale (scored 0-36) in which higher scores indicate greater treatment satisfaction 
(Bradley, 1994). 
b.
Nutrition Knowledge Survey (NKS) which collects information on healthful eating, carbohydrate 
counting, blood glucose response to foods, and nutrition label reading. Higher NKS scores reflect 
greater nutrition knowledge (score range is 0–100%) (Rovner 2012). 
c.
Diabetes Distress Scale (DDS) is a 17-item scale that captures diabetes distress in 4 different 
areas, including emotional burden, regimen distress, interpersonal distress, and physician 
distress (Polonsky 2005).
All participants will receive dietary instruction to review the dietary requirements of the study.  A handout 
with 2 examples of the type of diet required will be provided to each participant at the time of or prior to 
consent.  Participants will provide a 3-day dietary history at the enrollment visit to assess current caloric 
intake.  Each subject will be instructed on how to keep a food diary. Participants and/or parents will be 
asked to take photos of all food consumed to aid in dietary recall.   After the enrollment visit, participants 
will be contacted to assess adherence to the diet and adjust insulin doses 3 times per week (see Table 1).  
During these telephone follow up calls, food diary will be reviewed, photos of meals will be reviewed, and 
pump and CGM data will be uploaded and reviewed.
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HIC#: 2000026189
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Prior to the HRU/CSRU admission, we will recommend a standard diet be given and no food be eaten after 
9pm (except for in cases of hypoglycemia). Participants will be advised to limit exercise in the 3 days prior to 
study to limit acute effects of recent exercise on insulin sensitivity.
Visit 2: After at least 2 weeks on the standard carbohydrate diet, participants will be admitted to the HRU or 
CSRU for the equilibration portion of the study and arginine stimulation test.  The subject may arrive at 7:30 
a.m. the morning of the study. The study nurse will do a nursing assessment, including measuring the 
subject’s temperature, blood pressure, and pulse. A urine pregnancy test will be performed and we will 
discuss the need for contraception during the VLCD portion of the study.  Two indwelling catheters will be 
placed, one into an antecubital vein for infusion of test substances and a second catheter into a 
contralateral vein for blood sampling. 
The study will begin with a ~150 minute equilibration period during which we will aim to keep glucose levels 
stable, followed by an arginine stimulation test.  Blood draws for measurements of glucose and glycerol 
enrichment are listed in tables 2, 3, and 4.  
Subjects will be asked permission to allow the serum and information collected during this research study 
to be used for future research purposes. The serum samples may be used by our research group to run 
additional assays related to the pathophysiology of diabetes.

Fasting laboratory assessment:  Upon arrival, participants will have blood tests performed, 
including β-hydroxybutyrate, free fatty acids (FFA), glucagon, comprehensive metabolic panel, 
magnesium level.

Non-radioactive, Stable Isotope Tracer Infusions will be employed to assess rates of glucose and 
glycerol metabolism at the end of the ~150-minute baseline equilibration period. From -150 to 0 
min, 4.5 mg/kg of 6,6-
2H2-glucose (99% enriched; Cambridge Isotope Laboratories, Andover MA) will 
be followed by a continuous infusion at 0.06 mg/kg/min. 
2H5- glycerol will be infused at 1.6 μmol/kg 
followed by a constant infusion of 0.11 μmol/kg/min to assess glycerol turnover. During the basal 
turnover period, a variable rate insulin infusion may be utilized to maintain plasma glucose between 
~80-120 mg/dL. As results from prior participants become available, infusions of the isotopes may 
be adjusted in subsequent participants to ensure enrichment is not too low for measurement.

Metabolite Collection: Samples for measurements of glucose and glycerol enrichment, as well as 
hormones and substrates, will be obtained every ~15-30 minutes of the baseline equilibration phase 
(see Table 2). Additional blood samples at baseline will be collected and used to derive additional 
metabolic risk markers of timely interest; specific uses are to be determined but will only be 
conducted after corresponding future protocol approvals.  Biomarkers collected as part of this 
research will be stored by the YCCI core lab services.  

Measures of Oxidation: Indirect calorimetry will be utilized at each HRU/CSRU visit to evaluate rates 
of glucose and fat oxidation.

Arginine Stimulation Test (AST):  An AST will be conducted as a gold-standard assessment of islet 
hormone secretion, specifically, that of glucagon through stimulation of α cells. At time 0, arginine 
will be administered (5g of 10% solution) over ~ 1 minute.  We will measure stimulated glucagon, 
glucose, ketone, and c-peptide levels after arginine stimulation.  Blood glucose samples will be taken 
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HIC#: 2000026189
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at baseline and every ~15 min for 60 minutes, centrifuged, and measured at bedside with an 
automated glucose analyzer (YSI 2300; Yellow Springs Instruments, Yellow Springs, OH). 

Questionnaires:  Participants will be asked to complete Diabetes Treatment Satisfaction 
Questionnaire, Nutrition Knowledge Survey, and Diabetes Distress Scale.  These questionnaires 
should take no more than 10-15 minutes total to complete. 
Upon completion of the AST, participants will meet with study staff to review the requirements of the 
transition week and VLCD portion of the study.  The dietician will look at each individuals macronutrient 
intake during the standard carbohydrate portion of the study.  Based on this information, we will 
instruct them to eat a certain amount of carbohydrates each day.  If they eat more than 200 grams per 
day of carbohydrates during the standard diet weeks, they will be instructed to eat 100-150 grams of 
carbohydrates per day during the transition week.  If they eat less than 200 grams per day of 
carbohydrates during the standard diet weeks, we will instruct them to eat 75-125 grams of 
carbohydrates per day during the transition week. Most people with diabetes know how to 
carbohydrate count, however we will review carbohydrate counting at the time of the transition.  
Carbohydrate counting will be taught using the “Choose Your Foods:  Food Lists for Diabetes” written by 
the American Diabetes Association and the American Nutrition of Dietetics.
For the VLCD portion of the study, participants will be given an isocaloric diet with a goal carbohydrate 
intake of less than 20% carbohydrates per day (~100 grams per day) for adolescents and less than ~50 
grams per day for adults at least 18 years of age.  Guidelines will be provided for meals.  Participants will 
also receive training on the treatment of hypoglycemia and be instructed to call the study team 
immediately in the case of severe hypoglycemia.
Visit 3: After at least 2 weeks on the very low carbohydrate study diet, participants will be admitted to the 
HRU/CSRU and repeat the same protocol listed in Visit 2. 
Table 1.  Planned study interventions for part 2 of the study.
Measurement
Wk 0
Phone 
wk 0.5
Phone 
wk 1
Phone 
wk 1.5
Visit 
end 
wk 2
Transition 
to VLCD 
wk 2-3
Phone 
wk 3
Phone 
wk 3.5
Phone 
wk 4
Phone 
wk 4.5
Visit 
end 
wk 5
Dietary Recall, 
assessment 
for symptoms 
related to 
VLCD
X
X
X
X
X
X
X
X
X
X
X
Diabetes 
management 
review, dose 
adjustments 
as needed, 
CGM data 
analysis
X
X
X
X
X
X
X
X
X
X
X
Baseline 
laboratory 
assessment
X
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PI:  Laura M. Nally, MD
HIC#: 2000026189
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Fasting 
laboratory 
assessment
X
X
Stable isotope 
study of 
glucose and 
glycerol 
metabolism, 
indirect 
calorimetry, 
arginine 
stimulation 
test
X
X
Diabetes 
Treatment 
Satisfaction 
Questionnaire
X
X
X
Diabetes 
Treatment 
Satisfaction 
Questionnaire 
(Change)
X
Nutrition 
Knowledge 
Questionnaire
X
X
X
Diabetes 
Distress Scale
X
X
X
 
Table 2.  Planned blood tests during the baseline glucose and glycerol turnover study.
Time 
(minutes)
-150
-120
-90
-60
-30 
steady 
state
-15 
steady 
state
Glycerol 
(2mL)
X
X
X
X
X
X
Glucose
(0.5 mL)
X
X
X
X
X
X
Table 3.  Planned blood tests during arginine stimulation testing. Time 0 represents time of Arginine 
infusion.
Time 
(minutes)
-15
0
5
15
30
45
60
BOHB (0.3 -
1mL vs use 
meter)
X
X
X
X
X
X
X
Glucose
(0.5mL)
X
X
X
X
X
X
X
Glucagon
(2mL)
X
X
X
X
X
X
X
C-peptide 
(3mL)
X
X
X
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 11 of 26
Storage 
(3mL)
X
X
X
X
X
X
X
Table 4.  Blood volume collected during each HRU visit.
Weight (kg) at 
Blood Draw
Equilibration
Arginine 
stimulation 
Test
Fasting 
laboratory 
assessment
Storage 
(Serum)
Total Blood 
Volume 
Collected 
(mL)
Total Blood 
Volume 
Collected 
(mL/kg)
40 to 42
36 mL
51.5 mL
11 mL
24 mL
122.5
~3
43 to 65
36 mL
51.5 mL
11 mL
24 mL
122.5
1.9-2.8
>65
36 mL
51.5 mL
11 mL
24 mL
122.5
<1.9
6.
Genetic Testing   
N/A ☒
7.
Subject Population: 
Part 1:  10 participants ages 13 to 25 years of age with a clinical diagnosis of T1D for at least 1 year will be 
enrolled for 5-6 weeks for part 1 of the study.  Participants who reach the age of majority during the study 
will be re-consented using the adult consent form.
Part 2:  10 participants ages 13 to 25 years of age with a clinical diagnosis of T1D for at least 1 year will be 
enrolled for 5-6 weeks for part 1 of the study.  Participants who reach the age of majority during the study 
will be re-consented using the adult consent form.
8. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment 
in the research project. Will subjects who may require additional safeguards or other considerations be 
enrolled in the study? If so, identify the population of subjects requiring special safeguards and provide a 
justification for their involvement.
☒Children
☐ Healthy 
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☒ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐  No ☒ 
Rationale for studying adolescents: Effective glycemic control is needed to prevent future micro and 
macrovascular complications of T1D. Thus, it is critical to investigate ways to improve control in adolescents 
(both male and female), the population with the poorest glycemic control across all age ranges. The proposed 
study will employ a novel method that may limit acute complications of T1D, as well as improve overall 
glycemic control. Such studies can only be carried out in adolescents, due to the unique characteristics of this 
cohort.
9. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion Criteria:  
Ages 13-25 years old
BMI > 19kg/m2 for individuals at least 18 years old or greater than the 5%ile for those under age 18
Participants 18 years of age must be able to read and provide written consent
Participants under 18 years of age must be able to read and provide written assent
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 12 of 26
Participants are managed using an insulin pump or injections
Participant has or is willing to wear a CGM for the duration of the study as described above
Participant is willing to complete diet logging procedures stated above
Exclusion Criteria:
A1c < 6.5% or > 10%
Recent history of more than 1 of diabetic ketoacidosis (DKA) in the past 6 months
Treatment with glucose-lowering drugs other than insulin
Unstable psychiatric disorders, including eating disorders (DSM-V criteria)
Weight loss medications within the last 6 months
Females who are pregnant, lactating or planning to become pregnant in the next 6 months.
Another medical condition that precludes participation in the study.
10. How will eligibility be determined, and by whom? Eligibility will be determined by the PI or a co-investigator, 
and/or study team member who will verify that the parent/caregiver meets inclusion/exclusion criteria.
11. Risks: 
Risks of Very Low Carbohydrate Diet:  Previous studies have suggested that switching to a very low 
carbohydrate diet can cause symptoms including nausea, vomiting, abdominal pain, constipation, fatigue, 
and lightheadedness.  These symptoms will be screened for at follow up visits throughout the study (see 
Table 1).
Hypoglycemia/Hyperglycemia: Participants in the study will be at risk of hypoglycemia and hyperglycemia. 
For this reason, during the HRU/CSRU admission, blood glucose levels are measured frequently throughout 
the study by a reliable device (YSI 2300) so that if needed, dextrose infusion can be utilized to prevent 
hypoglycemia. The study procedures may result in elevated or low glucose values. At the end of each visit, 
the participant will receive guidance for glucose monitoring, food intake, and insulin dosing as needed.  
During the study, dose adjustments will be made according to standard of care to prevent hypoglycemia and 
hyperglycemia. 

Stable isotopes: Despite the theoretical risk of infection with infusion of stable isotopes, our team has been 
using isotopes during studies for 15 years in children and adolescents and have not experienced any adverse 
events.  

Risk of Indirect Calorimetry:  The air under the hood may become warm and stuffy, which some subjects find 
uncomfortable. Rarely, subjects may feel nauseated and/or claustrophobic while under the hood.

Risk of indwelling catheter: There are potential complications associated with indwelling catheters, including 
hematomas, discomfort, and rarely infection, thrombophlebitis, or bleeding at the catheter insertion site.

Anemia: The risk of anemia exists in studies with frequent blood draws. In our many years of performing 
studies we have not known any participants to experience this complication. The volume of blood draw at 
each visit will vary depending on the participant’s age and weight.  However, for children <18 years the 
maximum blood volume will not exceed 5 cc/kg body weight over a 1-month period.  The exact blood 
volumes collected may vary according to local IRB regulations.  The maximum blood volume collected from 
adults >18 years will not exceed 250cc over a 1-month period.

Risk of loss of confidentiality: As in any study, there is the potential for loss of confidentiality. Female 
subjects of childbearing potential will require urine pregnancy testing prior to enrollment in the protocol, 
and results of this testing have potential to result in loss of confidentiality. 

Risk of glycemic deterioration: It is possible that changing dietary requirements or insulin doses may result in 
glycemic deterioration.  Likewise, adolescents may have glycemic deterioration due to non-compliance. 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 13 of 26

Risk of CGM: Participants have the option of using FDA approved CGM as part of clinical care in our clinics. 
There is a low risk of developing a local skin infection at the site of the sensor needle placement. Itchiness, 
redness, mild bleeding, and or bruising may occur at the insertion site. Subjects may develop localized 
reactions to adhesive used to secure the sensor. 

Risk of study questionnaires:  Participants may experience some distress when discussing factors important 
to diabetes, diabetes management, and psychosocial stressors

Arginine Stimulation Test:  Intravenous infusion of glucose may cause venous irritation (phlebitis) or less 
commonly infiltration of the surrounding tissues, both which may be discomforting. Intravenously 
administered arginine may cause a transient metallic taste in the mouth, and less often a transient 
sensation of warmth or nausea; allergy is rare.  
Minimizing Risks:

Risks of Very Low Carbohydrate Diet:  In order to minimize the symptoms associated with transitioning 
to a low carbohydrate diet abruptly, participants will be slowly transitioned over 1 week to help them 
acclimate and avoid unwanted symptoms.

Hypoglycemia/Hyperglycemia: Participants will be contacted frequently during the course of the study.  
Blood draws will be done frequently during the HRU or CSRU admission to minimize hypoglycemia and 
hyperglycemia.  Intravenous glucose will be available in case hypoglycemia occurs.  All infusates 
containing insulin are prepared under a filtration cabinet (Laminated HLDA filter) by a qualified member 
of the research team using sterile disposable materials.

Participants will be encouraged to monitor closely for signs of glycemic deterioration and will be able to 
contact our diabetes staff at any time if concerns arise.  

At the end of each visit, the participant will receive guidance for glucose monitoring, food intake, and 
insulin dosing as needed.  

During the study, insulin doses will be adjusted regularly (2-3 times per week as needed) to prevent 
hypoglycemia.  Participants will use a real-time CGM that will provide alerts at the time of hypoglycemia 
and allow for early detection of hypoglycemia as well.  Participants will be trained on treatment of 
hypoglycemia and to contact the study team immediately in any case of severe hypoglycemia.

If any subject has 2 episodes of severe hypoglycemia, they will be transitioned to a regular diet after the 
2nd episode of severe hypoglycemia.

Stable isotopes: Isotopes will be carefully monitored, administered and will be prepared in the 
investigational pharmacy to ensure proper technique.  As noted in previous protocols using this stable 
isotope, the pyrogenicity and sterility of the isotopes are documented by Cambridge Isotopes before 
they are shipped to YNHH IDS.  Methods to Ensure Compound Sterility and Pyrogenicity:  All stable 
isotopes are purchased from Cambridge Isotopes (Boston, MA) and are sent to us sterile and pyrogen-
free as specified in the certification form of analysis that is attached to each order.  In addition, all 
infusates containing the isotope that will be used in the study are prepared by the Yale Investigational 
Drug Service (IDS) by using specific filters (0.22µ).  Furthermore, we also use microfilters at the end of 
each syringe as another safety precaution.  All stable isotopes are stored by the Yale IDS and are sent to 
the YCCI the morning of the study.  

Risk of Indirect Calorimetry:  Potential feelings related to wearing the “hood” will be discussed with 
participants ahead of time, if participants become uncomfortable while wearing the hood it will be 
removed.

Arginine Stimulation Test: Intravenously administered arginine may cause a transient metallic taste in 
the mouth, and less often a transient sensation of warmth or nausea; allergy is rare.  

Risk of indwelling catheter: IV insertion will be performed by trained research nurses on the HRU/CSRU. 
Trained nurses will use aseptic technique to insert the IV catheters. We will minimize the risk of pain by 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 14 of 26
offering an option of topical anesthetic to the patient prior to IV insertion. Participants will be advised to 
contact the study team immediately if they become aware of a late adverse effect.

Anemia: Samples will be obtained with the minimum necessary blood volume. The point of care YSI 
glucose determinations require only 0.3ml of blood. We will ensure that blood volume obtained does 
not exceed a maximum of 5mL/kg in pediatric participants and 250 mL in adult participants.  

Risk of loss of confidentiality: All study staff are HIPPA certified. Participant names and study records will 
be kept confidential. The IRB may inspect study records at any given time. All efforts will be made to 
maintain the participants’ privacy. Each participant will be assigned a study ID code and data will be 
linked by this study ID rather than by names, initials, social security numbers, or other personal 
identifiers. Paper documents will be stored in locked areas accessible only to authorized staff. All 
electronic data files will be protected by passwords limiting access to the files only to those with a 
legitimate responsibility for data entry or management. This ensures that, in the unlikely event that any 
primary data sources from this study are lost or misplaced, it will not be possible to identify the study 
participant. Copies of informed consent/assent forms and families' contact information will be stored 
separately from the other study data, which will not contain names or other identifying information. 
Identifiable study information will be maintained for 10 years after the research is complete. After that 
time, it will be destroyed or de-identified. The principal investigator will keep a link that identifies 
subjects to coded information, but this link will be kept secure and available only to the PI or selected 
members of the research team.  

Risk of CGM: Risks of glucose sensor insertion will be minimized because participants will be instructed 
to cleanse skin aseptically prior to insertion.  Participants will receive training on sensor use if they have 
not used the sensor previously.

Risk of study questionnaires:  Study staff and social work will be contacted to support families as 
needed.   
12. Data and Safety Monitoring Plan:
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Greater than minimal risk, but presenting the prospect of direct benefit to 
individual subjects
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? Greater than minimal risk, but presenting the prospect 
of direct benefit to individual subjects
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety-
monitoring-plans-templates for
i.
Greater than minimal
Greater Than Minimal Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency, which must be conducted at a minimum of 
every 6 months (including when reapproval of the protocol is sought).  During the review process, the 
principal investigator (monitor) will evaluate whether the study should continue unchanged, require 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 15 of 26
modification/amendment, or close to enrollment. Either the principal investigator, the IRB or [enter the 
names of other oversight bodies that have this authority, e.g., Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC)] have the authority to stop or suspend the study or require 
modifications.
2. The risks associated with the current study are deemed greater than minimal for the following 
reasons: (choose those that apply)
1. We do not view the risks associated with the arginine infusion as minimal risks.
2. Given the now established safety and validity of the current isotope infusions and arginine 
stimulation tests in our prior work, we do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists 
for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible 
to predict with certainty the absolute risk in any given individual or in advance of first-hand experience 
with the proposed study methods. Therefore, we provide a plan for monitoring the data and safety of the 
proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the principal investigator (Insert Investigator Name) according to the following 
categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets the 
criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it results in any of 
the following outcomes:
1. Death;
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 16 of 26
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event.  
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE.  It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol 
and informed consent document and (b) the characteristics of the subject population being 
studied; AND 
2. Is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non-
medical in nature, and include – but are not limited to – serious, unexpected, and related adverse 
events and unanticipated adverse device effects.  Please note that adverse events are reportable to the 
IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the prompt 
reporting requirements described in IRB Policy 710 should be reported to the IRB in summary form at 
the time of continuing review. If appropriate, such summary may be a simple brief statement that events 
have occurred at the expected frequency and level of severity as previously documented.  In lieu of a 
summary of external events, a current DSMB report can be submitted for research studies that are 
subject to oversight by a DSMB (or other monitoring entity that is monitoring the study on behalf of an 
industry sponsor).
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 17 of 26
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and 
regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified 
(choose those that apply):
X All Co-Investigators listed on the protocol.
X National Institutes of Health
The principal investigator (Laura Nally) will conduct a review of all adverse events upon completion of 
every study subject. The principal investigator will evaluate the frequency and severity of the adverse 
events and determine if modifications to the protocol or consent form are required.
Please note: For any study that may be considered high risk, the IRB will be more focused on the safety 
requirements for the study and a DSMB will likely be required. 
d.
For multi-site studies for which the Yale PI serves as the lead investigator: N/A
13. Statistical Considerations: 

For part 1 and part 2, descriptive statistics of sensor glucose values, including average glucose, standard 
deviation, and coefficient of variation

For part 1 and part 2 of the study, paired t-tests will be used to evaluate differences between the two 
dietary interventions with respect to
o
Percent time in range for sensor glucose values (70-180mg/dl)
o
Sensor-derived average glucose
o
% Time severe hypoglycemia (<55 mg/dL)
o
% Time hypoglycemia (<70mg/dL)
o
% Time hyperglycemia (>180mg/dl)
o
% Time severe hyperglycemia (>250 mg/dL)

With respect to assessment of glycerol and glucose metabolism, we will use non-parametric paired t-
test for comparison using a convenience sample for this pilot feasibility study.

Descriptive differences between fasting ketone levels, insulin to carbohydrate ratios, insulin to protein 
ratios, insulin sensitivity factors, total daily insulin dose will also be reported.

Glucagon, glucose, and beta-hydroxybutyrate response to arginine stimulation

Questionnaires will evaluate changes in diabetes treatment satisfaction, nutritional knowledge, and 
diabetes distress over time.  These analyses will help determine satisfaction with the study diet when 
compared to a standard diet. Due to the pilot nature of the study, these analyses will be exploratory, 
and we will not adjust for the number of comparisons. 

Meal content will be determined by using the ASA24 program (https://asa24.nci.nih.gov).  
Macronutrient content of each diet will be reported.

Safety Analysis: Frequency of diabetic ketoacidosis and severe hypoglycaemia events will be assessed in 
all participants, including those whose data do not meet evaluability criteria.  
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 18 of 26
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A.  RADIOTRACERS
☒N/A
B.  DRUGS/BIOLOGICS    ☐N/A
1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the category that 
applies (and delete the inapplicable categories): N/A
2. Background Information: All substances are non-radioactive and have been extensively used in 
pediatric research in the last 15 years by our team with no side effects or adverse effects. Recent 
studies involving minors using glucose and glycerol isotopes performed by members of our research 
team are listed below. 
HIC #
Age group
Isotope
Dosage
Isotope
Dosage
0102012241
8 years-adult
6,6-D2-glucose*
0.4 g/m2 bolus
D5-glycerol
0.6 mol/m2
4 mol/m2·min
1604017607
12-30 years 
6,6D2-glucose* 
0.4 g/m2 bolus
D5-glycerol 
0.6 mol/m2
4 mol/m2·min 
1306012200
> 12 to < 20 yrs
Type 1 Diabetes
6,6-2H2-glucose
4.5 mg/kg bolus 
0.03 mg/kg/min
2H5-glycerol
1.6mol/kg,
0.11 mol /kg/min
1509016531
12-35 years
Type 1 Diabetes
6,6-2H2-glucose
3.5 mg/kg bolus
0.04 mg kg/min
2000023149
12-16 years
18-24 years
6,6-2H2-glucose
4.5 mg/kg bolus 
0.06 mg/kg/min
2H5-glycerol
1.6mol/kg,
0.11 mol /kg/min
*Stable phases will use 20% glucose infusion containing 6,6,-D2-glucose at an enrichment of approximately 3%
PMID
Age group
Isotope
Dosage
Isotope
Dosage
30020457
14-17 years
Type 1 Diabetes
6,6-2H2-glucose
4.5 mg/kg
0.03 mg/kg/min 
2H5-glycerol
1.6mol/kg,
0.11 mol /kg/min
3. 
Source:  There is no study drug (treatment) for this protocol. However, isotopes will be obtained from 
Cambridge Isotopes, Cambridge, MA), which is routinely audited internally by its QA department and 
externally by customers, notified bodies, and regulatory agencies (e.g. FDA). Isotopes will be stored in 
the Investigational Pharmacy and will be prepared before the subjects undergo tests.
a)
Is the drug provided free of charge to subjects? ☒YES 
☐NO 
If yes, by whom? Funding for the study
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 19 of 26
1.
Storage, Preparation and Use:  The glycerol isotope will be kept with Yale-New Haven Hospital 
Investigational Drug Service, which will keep all documentation. The IDS will prepare preparations of 
isotopes before each study and store it in the med room in the YCCI. Pyrogen and sterility are tested and 
documented by Cambridge Isotopes before shipping to us.
Check applicable Investigational Drug Service utilized:
    ☒  YNHH IDS                                                        ☐  CMHC Pharmacy                                           ☐ West Haven VA
    ☐  PET Center                                                      ☐    None      
    ☐  Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation.  
2.
Use of Placebo: 
☒Not applicable to this research project
3.
Continuation of Drug Therapy After Study Closure   ☒Not applicable to this project
 B.  DEVICES
 ☒N/A
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 
a.
Targeted for enrollment at Yale for this protocol: 10-20 youth will be studied, which includes at least 4 
adults over the age of 18. 
b.
If this is a multi-site study, give the total number of subjects targeted across all sites: N/A
2.
Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
☒Flyers
☐ Internet/web postings
☐ Radio
☐ Posters
☐ Mass email solicitation
☐ Telephone
☐ Letter
☐ Departmental/Center website
☐ Television
☒ Medical record review* 
☐ Departmental/Center research boards
☐ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☒ Clinicaltrails.gov 
☐ YCCI Recruitment database
☒ Social Media (Twitter/Facebook): 
Twitter, Facebook, Instagram
☒ Other: Yale Children’s Diabetes 
Program
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified. Eligible participants will be identified through the Yale 
Children's Diabetes Program and Yale Diabetes Clinics by review of medical records and recommendation 
of clinicians. Eligible participants will also be recruited through social media and through JDAT.
b. Describe how potential subjects are contacted. The participant will be informed of the study by their usual 
diabetes healthcare team, or by a HIPAA-compliant e-mail, or phone call if there is a clinical relationship 
with a member of the research team
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 20 of 26
c. Who is recruiting potential subjects? Laura Nally, MD, William Tamborlane, MD, Amy Steffen, RN, Kate 
Weyman, APRN, Jennifer Sherr, MD, Elaine Tichy, PA, Michelle van Name, MD, Nicola Santoro, MD, PhD, 
Stephan Seibel, MD, PhD.
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship with any 
potential subject? 
☐Yes, all subjects
☒Yes, some of the subjects
☐No
If yes, describe the nature of this relationship. Participants will be recruited from the Yale Children’s Diabetes 
Program and the research team will have an existing clinical relationship with these subjects.
Recruitment process outline for clinic patients:
i.
The medical records of patients in our clinic are reviewed to determine eligibility
ii.
The medical provider of the patient will be contacted whenever possible to determine whether 
contact from the study team is appropriate.
iii.
Eligible patients are contacted in person whenever possible, or via phone or email to inform them 
of potential participation. Alternatively, potential participants are informed of the study during a 
clinic visit.
iv.
Potential participants who respond with interest in learning more will be provided potential study 
dates, consent forms to review, and contacted via phone to discuss the study in more detail
v.
Potential participants/family will then have an in-person meeting with a study team member 
(approved for consenting), to review the consent/assent forms in detail. If the potential 
participant/family wish to proceed, the forms are signed. 
vi.
Potential participants will be recruited through social media (Twitter, Facebook, Instagram).
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☒ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of 
this data: To determine whether patients will be eligible for this study and thus consent 
procedures, the study team will review the medical records. 
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: Some potential subjects may call or 
email after learning about the trial by word of mouth. We can ask some basic screening questions 
about age, date of diagnosis etc. before scheduling an enrollment visit to do further screening to 
determine study eligibility.
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
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The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, 
except as required by law, for authorized oversight of this research study, or as specifically approved for use 
in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6.
Process of Consent/Assent:  Potential participants who express interest in the study will be given a copy of 
the Consent Form/Parent Permission/Assent Form, asked to review, and then given the opportunity to 
discuss the study with the investigators in detail. For part 1 of the study, consent will be performed over the 
phone or virtually.  This will be done either via RedCap or by emailing/mailing the consent form and having 
the participant email/mail the signed consent form back to the researcher.  For part 2 of the study, consent 
will take place in person.  The investigator will comply with all applicable regulatory and legal requirements, 
ICH GCP guidelines and the Declaration of Helsinki in obtaining and documenting the informed consent. It 
will of course be stressed that participation is voluntary, and non-participation will not affect continuing care 
at the Yale Children’s Diabetes Program. The participant will have the right to refuse to participate or to 
withdraw at any time.
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Subjects will have a face-to-face 
meeting (part 1 will be in person or virtually over the phone or via Skype, Zoom, FaceTime or Doximity 
Dialer enabling video calls) with an Investigator and/or Study Personnel to address questions about the 
study rationale, procedures, risks and benefits. In order to identify and clarify any misconceptions, subjects 
will be encouraged to describe the research procedures and their associated risks in their own words, 
followed by correction of any errors by an Investigator or Study Personnel.
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent 
materials must be submitted for approval prior to use. 
Write here
As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation 
of the long form is not possible prior to intended enrollment?  YES ☒  NO ☐
Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject.   Please review the guidance and presentation on use of 
the short form available on the HRPP website.
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 22 of 26
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA waiver 
in the section above. 
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full 
waiver of consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed 
consent for this study, complete the appropriate section below.  
☐Not Requesting any consent waivers 
☒Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study (Note that an information sheet may be required.)
 For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research?  YES ☒  NO ☐ 
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒  NO ☐
 
OR
Does the research pose greater than minimal risk? YES ☐    NO☐ 
Does the research include any activities that would require signed consent in a non-research context? YES ☐   
NO ☐
 ☐ Requesting a waiver of consent:
☐ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study 
 
For a full waiver of consent, please address all of the following:

Does the research pose greater than minimal risk to subjects?  
☐ Yes If you answered yes, stop. A waiver cannot be granted.  
☐ No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐    NO☐

Why would the research be impracticable to conduct without the waiver? 

Where appropriate, how will pertinent information be returned to, or shared with subjects at a later date? 
N/A
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research?   Protected health information that will be collected and used for 
the research will include the research study records, medical records, blood sugars, services provided in 
connection with this study, the entire research record and any medical records held by Yale New Haven 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
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Hospital and the Yale School of Medicine, medical history of diabetes and other conditions that may affect 
eligibility for study participation.
2.
How will the research data be collected, recorded and stored? Clinical research forms will be created to allow 
for collection of data from schools and for study visits. Our study team is very experienced in collecting data 
and maintaining study databases, as we regularly conduct clinical trials. Study records will be maintained 
in Microsoft Excel databases, on university computers which are encrypted and served by a regular back up 
service. All study staff, office, and computers are HIPPA compliant.  
3.
How will the digital data be stored? ☐CD  ☐DVD  ☐Flash Drive  ☐Portable Hard Drive   ☒Secured Server  ☒
Laptop Computer  ☐Desktop Computer  ☐Other
4.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study? 
The list of names of the study subjects and their assigned code numbers will be kept in a locked file cabinet 
or password-protected computer file by study team members.  Individual patient medical information 
obtained as a result of this study is considered confidential and disclosure to third parties other than those 
noted below is prohibited.  Such medical information may be given to the patient’s personal physician or 
to other appropriate medical personnel responsible for the patient’s welfare. All individuals involved in the 
conduct of this study will be trained on HIPAA privacy regulations and will receive human subject protection 
training. The principal investigator will periodically monitor the methods and procedures described herein 
to ensure proper use and that continued protections are in place and being followed.
All portable devices must contain encryption software, per University Policy 5100.  If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and 
Compliance Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
5.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data 
and/or identifiers will be secured. It is likely that data from this study will be published in scientific and 
medical journals and presented at scientific and medical conferences. In all such cases, project data will be 
presented in such a way that no participant could possibly be identified. Data will be de-identified at end 
of study prior to study termination.
6.
If appropriate, has a Certificate of Confidentiality been obtained? N/A
SECTION V: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.) 
Participants may experience improved glycemic control by participating in the study.  
Long-term benefits of this research are a generalizable understanding of the changes of insulin resistance 
related to obesity and puberty in youth with T1D, which will help to inform future treatment strategies. 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 24 of 26
         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
The alternative to participating in this study is non-participation. Subjects who choose not to participate 
may continue their normal care in the Yale Pediatric Diabetes Program. There are no risks of non-
participation.
2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to 
subjects, the amount and schedule of payments, and the conditions for receiving this compensation.
Part 1:  Participants will receive a total of $75 total for participating in the full study.
Part 2:  To help offset the cost of the subjects’ participation in the study, they will receive $50 for 
each of the HRU/CSRU visits.  For each day that the participants take photos of their food and 
speak with study staff regarding dietary recall, they will receive $5. The total compensation a 
subject could potentially earn is $160.  
3.
Costs for Participation (Economic Considerations): The costs of all study-specific equipment, such as the 
blood ketone meter and ketone test strips, will be covered by the study. Since continuous glucose monitors, 
glucometers and glucose test strips are part of routine diabetes care, these will be prescribed.  Clinical lab 
HbA1c is standard of care and will be billed through the participant’s insurance and will not be covered by 
the study. 
 
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? Yes
b.
Where and from whom may treatment be obtained? Research staff or YNHH staff if necessary
a.
Are there any limits to the treatment being provided? Injuries caused directly by 
participation in the study. There will be no payment for lost wages and/or direct or 
indirect losses.
a.
Who will pay for this treatment? Subjects will be responsible for the costs of such medical 
care that is not covered by their own health insurance.
a.
How will the medical treatment be accessed by subjects? By notifying Research Team 
members
If injury should occur during any of the procedures, the overseeing physician and the study nurse 
will attend to the immediate needs of the patient. Should any acute care visit (i.e. emergency 
room or outpatient clinic), hospital admission or chronic care be necessary, the subject’s medical 
insurance will be responsible for covering any incurred charges. 
IMPORTANT REMINDERS
Will this study have a billable service?  Yes ☐ 
 No☒
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 25 of 26
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated 
entities?  Yes ☒  No ☐ 
If Yes, please answer questions a through c and note instructions below.  
a. Does your YNHH privilege delineation currently include the specific procedure that you will perform? Yes ☒  
No ☐
b. Will you be using any new equipment or equipment that you have not used in the past for this procedure? 
Yes ☐  No ☒
c. Will a novel approach using existing equipment be applied? Yes ☐  No ☒
 
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021

APPROVED BY THE YALE UNIVERSITY IRB 11/18/2021
PI:  Laura M. Nally, MD
HIC#: 2000026189
Page 26 of 26
References
1.
Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, et al. State of Type 1 
Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Diabetes technology & 
therapeutics. 2019;21(2):66-72.
2.
6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 
1):S61-s70.
3.
Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV, et al. Evolution of 
abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the 
first 2 years after diagnosis. Diabetes Care. 2014;37(6):1741-4.
4.
Bell KJ, Smart CE, Steil GM, Brand-Miller JC, King B, Wolpert HA. Impact of fat, protein, and 
glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes 
management in the continuous glucose monitoring era. Diabetes Care. 2015;38(6):1008-15.
5.
Tascini G, Berioli MG, Cerquiglini L, Santi E, Mancini G, Rogari F, et al. Carbohydrate Counting in 
Children and Adolescents with Type 1 Diabetes. Nutrients. 2018;10(1).
6.
Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in insulin-
dependent diabetes mellitus. The New England journal of medicine. 1993;329(14):977-86.
7.
Braffett BH, Dagogo-Jack S, Bebu I, Sivitz WI, Larkin M, Kolterman O, et al. Association of Insulin 
Dose, Cardiometabolic Risk Factors, and Cardiovascular Disease in Type 1 Diabetes During 30 Years of 
Follow-up in the DCCT/EDIC Study. Diabetes Care. 2019;42(4):657-64.
8.
Turton JL, Raab R, Rooney KB. Low-carbohydrate diets for type 1 diabetes mellitus: A systematic 
review. PloS one. 2018;13(3):e0194987.
9.
Gannon MC, Hoover H, Nuttall FQ. Further decrease in glycated hemoglobin following ingestion 
of a LoBAG30 diet for 10 weeks compared to 5 weeks in people with untreated type 2 diabetes. 
Nutrition & metabolism. 2010;7:64.
10.
Gannon MC, Nuttall FQ. Control of blood glucose in type 2 diabetes without weight loss by 
modification of diet composition. Nutrition & metabolism. 2006;3:16.
11.
de Bock M, Lobley K, Anderson D, Davis E, Donaghue K, Pappas M, et al. Endocrine and 
metabolic consequences due to restrictive carbohydrate diets in children with type 1 diabetes: An 
illustrative case series. Pediatric diabetes. 2018;19(1):129-37.
12.
Lennerz BS, Barton A, Bernstein RK, Dikeman RD, Diulus C, Hallberg S, et al. Management of 
Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics. 2018;141(6).
13.
Fery F, Bourdoux P, Christophe J, Balasse EO. Hormonal and metabolic changes induced by an 
isocaloric isoproteinic ketogenic diet in healthy subjects. Diabete & metabolisme. 1982;8(4):299-305.
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