Restoring Brain Metabolism and Function in Older Adult T1DM Patients Using an AP System
Phase: NA
Conditions: Type1 Diabetes Mellitus
Sponsor: Yale University

Protocol Title: Restoring brain metabolism and function in older adult T1DM 
patients using an AP system. 
Approval Date: 25 July 2022 
Clinicaltrials.gov Registration #: NCT03353792 
 

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
HRP-503B – BIOMEDICAL RESEARCH PROTOCOL
Protocol Title: Restoring brain metabolism and function in older adult T1DM 
patients using an AP system.
Principal Investigator: Raimund I. Herzog, MD 
Version Date: 13 March 2019
Clinicaltrials.gov Registration #: NCT03353792
a) Probable Duration of Project: State the expected duration of the project, including all follow-up 
and data analysis activities.
6 years
b) Does this study have a Clinical Trials Agreement (CTA)?
Yes☒
No☐
Page 1 of 58
This template is intended to help investigators prepare a protocol that includes all of the necessary 
information needed by the IRB to determine whether a study meets approval criteria. Read the 
following instructions before proceeding:
1. Use this protocol template for a PI initiated study that includes direct interactions with 
research subjects. Additional templates for other types of research protocols are available in 
the system Library.
2. If a section or question does not apply to your research study, type “Not Applicable” 
underneath.
3. Once completed, upload your protocol in the “Basic Information” screen in IRES IRB system.
INSTRUCTIONS
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
a.
If so, does it require compliance with ICH GCP (E6)?
Yes☒
No☐
c) Will this study have a billable service? Yes ☐
No☒
d) 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
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the 
HRU, the Principal Investigator and any co-investigators who are physicians or mid-level practitioners 
(includes PAs, APRNs, psychologists and speech pathologists) who may have direct patient contact with 
patients on YNHH premises must have medical staff appointment and appropriate clinical privileges at 
YNHH. If you are uncertain whether the study personnel meet the criteria, please telephone the 
Physician Services Department at 203-688-2615. By submitting this protocol as a PI, you attest that 
you and any co-investigator who may have patient contact has a medical staff appointment and 
appropriate clinical privileges at YNHH.
Page 2 of 58
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, 
would normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the 
patient or the patient’s insurer. The service may or may not be performed by the research staff on your 
study, but may be provided by professionals within either Yale-New Haven Hospital or Yale Medical 
Group (examples include x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to 
pathology). Notes: 1. There is no distinction made whether the service is paid for by the subject or their 
insurance (Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This 
generally includes new services or orders placed in EPIC for research subjects.
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department 
of Physician Services (688-2615) for prior approval before commencing with your research protocol.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
SECTION I: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
The goal of this study is to confirm the safety and effectiveness of a predictive low glucose suspend 
(PLGS) system in older patients with type 1 diabetes mellitus (T1DM) in order to reverse brain 
metabolic adaptations and restore metabolic sensitivity, hypoglycemia awareness and appropriate 
hormonal counterregulatory responses (CRR). The ultimate purpose of our study is to demonstrate the 
clinical usefulness of a technology-driven approach in older adults with T1DM to achieve tight 
glycemic control without exposing these particularly vulnerable patients to the risks of profound 
hypoglycemia.
2. Background: Describe the background information that led to the plan for this project. Provide 
references to support the expectation of obtaining useful scientific data.
a.
Counterregulatory failure and hypoglycemia unawareness in intensively treated older adult type 1 
diabetic patients.
While the complications of uncontrolled hyperglycemia in diabetic patients can be avoided via 
intensive insulin therapy [1, 2], recent studies indicate that long-term exposure to the frequent 
hypoglycemia encountered under this treatment
alters brain structure and function [3] and 
increases the fear of hypoglycemia as a severe 
complication of T1DM treatment [4-6]. 
Constrained by these two extremes, measures 
allowing intensive glucose control that preserve 
normal brain function are still needed. In non- 
diabetic individuals, hypoglycemia initiates 
counterregulatory responses (CRR) that restore 
normal 
plasma 
glucose 
levels. 
These 
mechanisms occur on several levels: pancreatic 
insulin secretion is suppressed; glucagon and 
epinephrine are released, and conscious 
measures are taken to reverse this possibly life- 
threatening state [7]. In T1DM patients, several 
of these responses may be compromised. The 
loss of endogenous insulin secretion and the 
reliance on insulin injections render rapid shut- 
off in case of hypoglycemia impossible. This 
problem is often accompanied by the loss of 
hypoglycemia induced glucagon release [8] and 
patients become particularly vulnerable to 
impairments in catecholamine secretion. This 
scenario is commonly associated with intensive 
insulin therapy and worsened with increasingly 
frequent hypoglycemic episodes and old age [9- 
12]. It is thus a functional disorder linked to 
iatrogenic hypoglycemia, since scrupulous 
avoidance of hypoglycemia can restore normal
Page 3 of 58
Figure 1: Overall Hypothesis: Improved glycemic control 
and strict avoidance of hypoglycemia via 8-week use of a 
close-loop/artificial 
pancreas 
system 
reverses 
brain 
metabolic adaptations in older adult T1DM patients (A). This 
reduces the uptake of alternate fuels into the brain and their 
contribution to brain energy metabolism. B) As a result, 
counterregulatory responses (CRR) with appropriate 
glucagon and epinephrine release are restored and patients 
regain hypoglycemia awareness. Reestablishment of brain 
energy homeostasis improves cognition, quality of life and 
overall health in older adults.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
CRR [13-15]. Finally, symptom awareness often becomes 
impaired (“hypoglycemia unawareness”) in conjunction with 
the reduced sympathoadrenal response to hypoglycemia [16] 
(also referred to as hypoglycemia associated autonomic failure 
or HAAF) [17]. As a result, many T1DM patients are reluctant 
to commit to intensive insulin therapy because their immediate 
fear of hypoglycemia exceeds their fear of future long-term 
complications. 
Because 
insulin-induced 
hypoglycemia 
remains the major limiting factor to optimal glycemic 
management in T1DM [7] it is our goal to protect these 
patients from the negative consequences of recurrent 
hypoglycemia (RH). New insulin delivery technologies like 
PLGS pumps that halt basal insulin delivery for impending 
hypoglycemia have emerged as promising new clinical tools. 
However, while they have been shown to reduce RH in 
younger patients with T1DM, their benefit in elderly patients 
has not been evaluated and the potential mechanism of their
benefit remains undefined (see Fig.1). A better grasp of the metabolic and regulatory mechanisms 
responsible for the effects of hypoglycemia, particularly in the brain, will permit tighter glycemic 
control of diabetic patients without increasing the risk of serious hypoglycemic injury.
b. Hypoglycemia in the brain.
The negative impact of hypoglycemia on brain function and development early in life is well 
established [3, 5, 18]. We have recently shown how T1DM in young patients with varying degrees of 
glycemic control results in cognitive and brain structural changes [19-21]; however, very little is 
known about this structure-function relationship in older adults with T1DM. Profound hypoglycemia 
in T1DM affects higher brain structures of the fully developed brain, with the most vulnerable cells 
located in the hippocampus and the frontal cortex [22-24]. Interestingly these are the brain regions 
responsible for higher cognitive function and memory and are specifically those involved in the 
cognitive and memory deficits affected by hypoglycemia [25] and the phenomenon of hypoglycemia 
unawareness [6]. Underscoring the importance of normal glucose homeostasis in the brain of older 
individuals, regional mitochondrial dysfunction with reduced ATP production has recently been linked 
to several neurodegenerative and psychiatric disorders [26-28] and likely also explains the higher 
association between T1DM and depression [29, 30]. Consequently, attempts to restore glucose 
homeostasis and impaired brain energy are of great clinical interest [31-34]. Similar approaches may 
be beneficial in the treatment of complications associated with T1DM; however, recent efforts remain 
limited by our lack of knowledge of the changes induced by frequent shifts in brain glucose levels. To 
overcome this barrier, we have applied state-of-the-art technology such as magnetic resonance 
spectroscopy (MRS) and hypoglycemic clamps to define brain energy metabolism and its regulation 
in the context of diabetes and frequent hypoglycemia. Using carbon-13 labeling of glucose and 
alternate energy substrates in our rodent model as well as patients with T1DM we arrived at a more 
complete understanding of brain alternate fuel metabolism in the context of hypoglycemia [35, 36]. 
However, since these observations outlined below were mostly generated in younger patients, little is 
known about their applicability to older adults. Using further advances in MRS methodology, we will 
refine our understanding of brain energy metabolism in older T1DM patients experiencing frequent 
hypoglycemia.
Page 4 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
c.
Quantifying brain energy substrate metabolism in the context of hypoglycemia.
Use of energy substrates labeled with the non-radioactive isotope carbon-13 (13C) and in vivo MRS 
allow real time measurement of their brain uptake and metabolic flux via the tricarboxylic acid (TCA) 
cycle into different amino acid and neurotransmitter pools. In what is referred to as metabolic 
compartmentalization and the glutamine-glutamate cycle, accumulation of the excitatory 
neurotransmitter glutamate in the synaptic cleft to toxic levels is prevented by its rapid uptake by 
astrocytes, where glutamine synthetase, present only in these cells, converts it to glutamine. Glutamine 
is then transported back to neurons, where glutaminase converts it to glutamate, replenishing the 
neuronal glutamate pool (see Fig.2) [37-39]. In vivo measurement of the appearance rates of 13C- 
label in the C4 carbon-positions of glutamate and glutamine, [4-13C]-Glu and [4-13C]-Gln, 
respectively, allows fitting of the data with a three-compartment blood-neuronal-astroglial metabolic 
model that our group developed to calculate relevant metabolic rates, including the relative substrate 
contributions to the astrocytic or neuronal TCA cycles [37, 38, 40-43]. With this model, we can 
determine brain metabolism under different physiological conditions and disease states. While broadly 
applicable to different brain regions in rodent models with significantly smaller brain volumes, in vivo 
MRS studies in humans were up to now technically limited to measurements of regions within the 
occipital cortex. This area is responsible for processing of visual information, however, and metabolic 
adaptations to hypoglycemia observed here may not be the same throughout the brain. Further studies 
are therefore needed to characterize metabolism in the regions associated with the cognitive deficits 
recently identified in older adult patients with longstanding T1DM and frequent hypoglycemia [44]. 
Use of MRS permits measurement of brain fuel uptake and metabolism in real time, which is 
particularly suited to characterize adaptations to hypoglycemia in T1DM patients. Technologic 
innovations presented in this proposal will allow us for the first time to conduct localized carbon-13 
MRS measurements in the frontal cortex of older adults, the region associated with higher cognitive 
function.
d. Brain alternate fuel metabolism influences CRR and hypoglycemia awareness.
In addition to glucose the brain can also utilize alternative substrates such as the monocarboxylic acids 
acetate, lactate and ketones, to maintain its energy requirements, particularly under hypoglycemia [45- 
48]. Interestingly these substrates cross the blood brain barrier (BBB) via a class of shared 
monocarboxylic acid transporters (MCTs). Once in the brain, glucose and most alternate substrates 
enter both the astrocytic and neuronal TCA cycles (see
Fig.3); however, acetate is predominantly incorporated 
into astrocytes due to the exclusive presence of 
glutaminase in these cells [40-43]. Application of these 
principles to the investigation of brain energy 
metabolism under hypoglycemia provides the basis for 
a better understanding of the characteristic changes 
distinguishing T1DM patients from healthy subjects 
[48, 49]. Our prior observation that infused acetate 
showed enhanced uptake and increased contribution to 
metabolism in the cortex of intensively treated T1DM 
patients (see Fig.4) [48] led us to perform similar 
experiments in our animal model that accurately 
reflects the salient features of the clinical symptoms 
encountered 
in 
T1DM 
patients, 
such 
as 
counterregulatory  failure  with  low  epinephrine and
Page 5 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
glucagon release under hypoglycemia [50, 51] and cognitive 
impairment [52]. We found that the uptake of acetate and lactate, was 
significantly facilitated in non-diabetic animals exposed to 
hypoglycemia, demonstrating that exposure to hypoglycemia, and not 
the overall glycemic control, is both necessary and sufficient to induce 
these adaptations [35, 36]. These exciting findings were recently 
confirmed in human studies, demonstrating enhanced lactate uptake 
into the brain of T1DM patients with frequent hypoglycemia [53], and 
thus form the scientific premise for the work presented herein. 
Intriguingly, it had been shown earlier that higher lactate levels in the 
brain region responsible for maintenance of peripheral glucose 
homeostasis, the hypothalamus, impair hormonal counterregulation to 
hypoglycemia in an animal model [54]. This makes it likely that 
impaired CRR in patients is indeed caused by higher alternate fuel 
contributions in the hypothalamus, a region currently not yet fully 
accessible to MRS metabolic measurements [55]. Since we have also 
shown in our animal model that lactate maintains neuronal firing
activity under hypoglycemia [35], it is very likely that, as was recently suggested, even small 
contributions of alternate energy substrates to brain metabolism can make glucose deficits (i.e. as 
under hypoglycemia) unnoticeable to patients, thus perpetuating hypoglycemia unawareness [56]. 
Since most studies thus far have been cross-sectional phenotypic characterizations, it is not clear 
whether this association is due to patient characteristics such as genetic predisposition and personal 
attributes or whether they stem from a reproducible sequence of adaptations like those seen in our 
rodent model. Our study, which proposes a prospective 8-10-week PLGS insulin pump intervention 
to strictly avoid hypoglycemia and combines simultaneous measurements of brain metabolism and 
CRR hormones, will be scientifically more rigorous and thus ideally suited to address this scientific 
question.
e.
Meticulous avoidance of hypoglycemia restores CRR and hypoglycemia awareness and may affect 
cognition.
Few studies to date have specifically evaluated whether reduction of hypoglycemia reverses its 
negative effect on the brain. Most were very lengthy and resource intensive [57-60] and found that 
CRR and hypoglycemia awareness were reversible in both patients with short term (<7 years duration) 
T1DM [13]), and with longstanding disease [14]. While early improvements were shown to occur after 
as little as 2 days, most studies lasted from 2 weeks to up to 4 months. To date no study has been 
conducted to determine whether older T1DM patients with several decades of disease exposure, where 
long-term adaptations may be less reversible (i.e., ‘fixed metabolic defects’), might similarly benefit 
from strict hypoglycemia avoidance. A recent case control study defining risk factors for severe 
hypoglycemia in older adults not only identified glucose variability and hypoglycemia unawareness 
as the most relevant predisposing contributors [44], but also showed that the group with more 
hypoglycemia and glycemic excursions performed worse on tests of executive function and 
psychomotor processing speed. A randomized trial investigating use of different technologies on 
restoration of hypoglycemia awareness [61] found that continuous glucose sensor use had the biggest 
impact on patients’ ability to avoid hypoglycemia during the day, however, since most severe and life 
threatening hypoglycemic episodes occur during sleep, when patients cannot take immediate action, 
the urgent need for an automated system that can eliminate hypoglycemia becomes apparent. These 
observations raise the intriguing possibility that the same metabolic adaptations that result in
Page 6 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
hypoglycemia unawareness also contribute to impairment of cognitive performance and may as such 
be reversible by strict hypoglycemia avoidance. Our specific aims will specifically address this 
question.
f.
Predictive low glucose suspend (PLGS) systems.
The current “state-of-the-art” treatment for T1DM in the US is sensor-augmented insulin pump 
therapy. Large-scale studies have demonstrated the benefit of these devices on HbA1c and a reduction 
in hypoglycemia [62-65]. Despite these improvements, human control of sensor-augmented pump 
therapy requires frequent, almost nearly continuous, surveillance of the system, and despite the use of 
audible alarms to warn of actual or impending hypoglycemia, sensors alone do not eliminate the risk 
of hypoglycemia. The true power of continuous glucose sensors can be better exploited in a “closed- 
loop” system in which sensor-detected glucose levels dynamically inform and adjust insulin delivery 
commands through the pump and even suspend basal insulin infusion in the setting of hypoglycemia. 
This so-called “low-glucose suspend” feature would by design limit hypoglycemia duration and/or 
magnitude. Due to the greater risk of severe hypoglycemia with seizures at night [66-69], and since 
most patients don’t respond to alarms when asleep [70], such automatic “threshold suspend” pumps, 
now approved by the FDA and widely available for T1DM patients, have been very effective in 
reducing the magnitude and duration of hypoglycemia by up to 30% [71, 72]. However, while these 
results are encouraging, they were not specifically tested in more vulnerable older adults with T1DM. 
In addition, the degree to which PLGS technology can reverse brain metabolic adaptations to 
hypoglycemia has not been determined. This study will, for the first time, define the effect of PLGS 
systems on reducing the impact of hypoglycemia on brain metabolism and function in older T1DM 
patients.
g. Special considerations regarding older adults with T1DM.
The dramatic reduction of microvascular complications reported by the DCCT [1] and UKPDS [2] 
have long motivated pursuit of long-term tight glycemic control as the goal of successful diabetes 
management. Recent evidence demonstrating that frequent and severe hypoglycemia contributes to 
morbidity and mortality in older, more vulnerable patients [73-76], however, suggests that these 
treatment goals should be adjusted, particularly in older adults who have already reached several 
decades of disease exposure and are at especially high risk for realization of long term complications. 
Instead of liberalizing therapy with resultant higher average glucose, which as we have shown impairs 
cognition in patients with T1DM [21], the true goal remains maintenance of euglycemia while 
avoiding hypoglycemia at all cost. While many patients can properly calculate daily insulin doses [44] 
and manage insulin pumps with high degrees of treatment satisfaction, with increasing age, 
progressive impairment of vision and particularly declining cognition, everyday diabetes self-care 
becomes more and more difficult. It is for these reasons that this patient population may especially 
benefit from automated insulin pumps that eliminate hypoglycemia while requiring minimal user 
intervention. To conduct this study we have partnered with the Yale Program on Aging, a center of 
excellence focused on maintenance of health status in older adults, to test the novel hypothesis that 
implementation of a PLGS system can positively impact cognitive performance, psychomotor function 
and treatment satisfaction.
3. Research Plan: Summarize the study design and research procedures using non-technical language 
that can be readily understood by someone outside the discipline. Be sure to distinguish between 
standard of care vs. research procedures when applicable, and include any flowcharts of visits
Page 7 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
specifying their individual times and lengths. Describe the setting in which the research will take 
place.
We hypothesize that meticulous avoidance of recurrent hypoglycemia for 8 weeks using FDA 
approved PLGS systems reverses brain metabolic adaptations and ameliorates their adverse 
consequences in older adults with longstanding T1DM. To address this hypothesis we designed a 
single-site, parallel group, randomized clinical trial. Following enrollement and CGM 
documentation of hypoglycemia during the 4-week run-in period, study participants are 
randomized to intervention and control groups. The intervention group consists of treatment with 
a PLGS-enabled insulin pump/CGM combination (Medtronic MiniMed 670G pump with 
Guardian sensor, or Tandem t:slim X2 pump with Dexcom sensor) in auto mode for Medtronic users 
and with Basal-IQ for Tandem users; subjects in the control group will use the same PLGS-enabled 
insulin pump/CGM combination but in manual mode for Medtronic users or without Basal-IQ for 
Tandem users (see Fig.5A). Patients will continue to use their own insulin as specified in their 
clinical plan, separate from the study
Auto Mode: The MiniMed 670G Insulin Pump is capable of continuous insulin delivery, at set and 
variable rates, for the management of diabetes mellitus in persons requiring insulin. When used 
with the CGM components (Guardian 3 sensor and transmitter), the pump system is capable of 
continuous or periodic monitoring of glucose levels in the interstitial fluid under the skin and 
detection of possible low or high blood glucose episodes. The pump also displays continuous 
glucose values, storing this data so that it can be retrospectively analyzed to track patterns and 
improve diabetes management. These features are similar to the commercially available Medtronic 
sensor-enabled system. The MiniMed 670G Insulin Pump also includes the closed loop algorithm 
and SmartGuard feature that may be enabled by the user. The SmartGuard feature enables insulin 
to suspend before a sensor glucose threshold is reached. The closed loop and SmartGuard feature 
will not be active at the same time. When closed loop is enabled on the MiniMed 670G insulin 
pump, the sensor glucose values received from the transmitter by the insulin pump will be used to 
automatically calculate the insulin dose. It will then deliver insulin to the patient, at five minute 
intervals, to achieve glycemic control. This is in addition to user-defined insulin boluses that 
patients will continue to require for meals. When Closed Loop is not enabled, the user may have 
the SmartGuard feature enabled. Here it will suspend basal rate delivery before the sensor glucose 
value has reached the programmed low threshold.
Manual Mode: If neither the Closed-Loop nor the SmartGuard features are enabled, the pump will 
deliver pre-programmed basal rates without modulation by the sensor. In this way, manual mode 
functions like any other insulin pump system. That is, there is no change in the level of technology 
when compared to the subject’s existing insulin pump. The only exception to this is if the 
SmartGuard feature is enabled, which will be determined by experienced study clinicians.
Basal-IQ: The Basal-IQ feature helps reduce the frequency and duration of low-glucose events by 
predicting glucose levels 30 minutes ahead and suspending insulin if the patient is expected to drop 
below 80 mg/dL or if glucose is currently below 70 mg/dl and falling. The system resumes basal 
insulin delivery once glucose values start to rise.
All participants will undergo MRS measurement of brain [2-13C]-acetate metabolism under controlled 
hypoglycemia (hyperinsulinemic hypoglycemic clamp) before and after the 8-week intervention (see 
Fig.5B). To determine the effect of strict hypoglycemia avoidance in the intervention group we will 
measure brain acetate metabolite enrichment time courses, which will be fitted with our metabolic
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 8 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
8-10 wk Study Period
4-wk Run-in Period
Figure 5: Overall Study Design. A) Following a 1 week of CGM 
screening for hypoglycemia, eligible T1DM patients will undergo 4 
weeks of CGM for run-in and then will be randomized to 8-10-week 
therapy with PLGS insulin pump in either auto or manual mode. B) 
MRS study with timeline for hyperinsulinemic-hypoglycemic clamp 
and carbon-13 tracer infusion.
AInutetorvmenotdioenCGLr/AouPp+ 
CGM
Standard insulin 
therapy + CGM
ContrCoGl Group
Manual mode CL/AP +
model to determine whether acetate contribution to brain oxidative capacity is diminished. In addition, 
we will assess how counterregulatory epinephrine and glucagon responses under hypoglycemia are 
affected by the intervention. The day before each MRS session, cognitive performance and 
hypoglycemia awareness will be also assessed. Blood Volumes collected and Schedule of Events 
Tables are included at the end of this application (see Appendix 1-2).
a) Screening visit and Run-in Period (YNHH Hospital Research Unit):
At the screening visit, study subjects will complete the informed consent form for participation in 
voluntary clinical research. Demographic and clinical data collected will be reviewed by study 
personnel to confirm eligibility.
Once consented, all subjects will be further screened with a medical history and physical 
examination, blood work (electrolytes, hematocrit, creatinine, liver function tests and HbA1c) and 
a 12-lead electrocardiogram (EKG). In subjects who do not already take advantage of continuous 
glucose monitor (CGM) systems, a CGM (iPRO monitor, Medtronic) will be applied and keep in 
position for 7 days. After 7 days, glucose CGM data will be downloaded to determine degree and 
frequency of hypoglycemia during a brief visit. In subjects already using a CGM system, glucose 
data will be downloaded and analyzed by study staff to determine degree and frequency of 
hypoglycemia. The subject will perform a preliminary cognitive test (Montreal Cognitive 
Assessment) and a questionnaire to evaluate hypoglycemia unawareness, see Appendix 3).
If the subject is eligible for the study, the subsequent sessions to complete the study will be 
scheduled. The subject will be asked to record CGM data in the 4 weeks before the first study 
session (run-in period) to collect
baseline data on glucose control. In 
the event that scheduling issues 
preclude the sequencing of scanning 
sessions as described below, certain 
modifications can be made to 
accommodate 
a 
subject. 
In 
particular, the duration of the 
intervention may vary from 8 to 10 
weeks 
and 
the 
cognitive 
assessments may be scheduled up to
1 week before the corresponding 
MRS session.
b) MRS
studies
and 
hyperinsulinemic 
hypoglycemic 
clamps 
(Magnetic 
Resonance 
Research Center)
Subjects will be asked to remain 
fasting from midnight prior to the 
study and to check their blood 
glucose at home before bed and on 
awakening to ensure that the 
glucose level is above 70mg/dl and 
below 200mg/dl. They will be
Page 9 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
instructed to call Dr. Herzog with any readings outside of this range. Upon arrival to the MRRC 
(7:30AM), their blood glucose will be checked as a safeguard, and insulin received via the insulin 
pump will be held. An IV catheter will be inserted for infusion of insulin and glucose to maintain 
normal glucose levels. A urine pregnancy test will be completed on all female subjects of child 
bearing potential. Any female testing positive will be excluded from the study. A second IV 
catheter will be inserted for arterialized venous blood sampling and then patients will be placed in 
the scanner for MRS. MRS measurement will be performed under clamped insulin-induced 
hypoglycemia as described below. At the end of the clamp procedure, a symptom questionnaire 
will be administered, asking the subjects to rate the intensity of their symptoms on a scale from 0 
to 7 (none to severe) [13] (Appendix 4). Neuroglycopenic (dizziness, tingling, blurred vision, 
difficulty in thinking, faintness) and autonomic symptoms (anxiety, palpitations, hunger, sweating, 
irritability, or tremor) are included in this assessment, which has been well validated over time. 
The visit will last no longer than 4 hours, including ~130 minutes of hypoglycemic clamp and MR 
spectroscopy.
After 8 weeks, both groups will undergo repeat MRS assessment of brain metabolism study 
according to the same procedures. They will then resume their previous out-patient care via insulin 
pump.
Hypoglycemic Clamp: To produce a controlled hypoglycemic state with a target glucose level of 
55mg/dl, we will use the hyperinsulinemic-hypoglycemic clamp method that gently lowers plasma 
glucose levels according to the protocol that was developed at Yale and is broadly used for these 
types of studies [29, 27, 28]. All subjects will receive a continuous insulin infusion (2mU/kg/min) 
and a variable infusion of 20% dextrose (see Fig.6B), which is titrated based on plasma YSI 
glucose measurements sampled every 5 minutes from a second IV line placed in the opposite arm. 
During the clamp procedure the plasma glucose level will be gently lowered from the initial level 
of 95-100mg/dl to the target of 50  3 mg/dL.
Throughout, blood is obtained for glucose, ketones, lactate, insulin, glucagon, cortisol, and 
catecholamines and will be assayed using established RIA, HPLC & ELISA methods in the YCCI 
Core Lab (see blood draw schedule below).
start 
hypo 
clamp
glucose
~55mg/dl
for ~10-15min
glucose
~55mg/dl
for ~20-25min
Timeline
-60 min
-10 min
13C-tracer
Baseline
start infusion*
+5
+10
+15
+30
+60
+90
+120
Insulin
X
X
X
X
X
X
Ketones
X
X
X
X
X
X
Lactate
X
X
X
X
X
X
X
C13 enrichment
X
X
X
X
X
X
X
X
Counterreg. 
hormones
X
X
X
X
X
X
Glucose
--------------------------------glucose every 5 min during hypo clamp---------------------------------
* blood draws timed to labeled acetate infusion
Counter-regulatory hormones = epinephrine, norepinephrine, glucagon, cortisol, growth hormone
Page 10 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
At the end of the study, insulin will be stopped and the 20% dextrose infusion increased to restore normoglycemia. 
Subjects will eat and IV cannulas will be removed. Once each subject is clinically recovered with stable blood glucose 
levels above 80 mg/dL, they can be discharged.
Magnetic Resonance Spectroscopy: During the MRS studies, subjects will lie supine in a 4T 94 
cm bore magnet. After head positioning under the coil, anatomical images will be obtained for 
localization of a circa 30ml voxel within the frontal cortex. Following power calibrations, non- 
iterative shimming and achievement of stable hypoglycemia all study subjects will receive a bolus 
of [2-13C]acetate (Isotech, Williamsburg, OH) 6 mg/kg · min administered for 5 minutes followed 
by a continuous infusion of 3 mg/kg · min for a total of 120 minutes, according to our previously 
published protocol [11, 66]. Then localized 1H-[13C]-MRS measurements with a temporal 
resolution of 5 min/ spectrum will be performed and selective POCE data acquired to the steady 
state label concentrations and fractional enrichments of acetate, and the C4 positions of glutamate 
and glutamine.
c)
Cognitive, symptom and quality of life assessment (YNHH Hospital Research Unit/MRRC/ 
Long Wharf Diabetes Research Suite (#503) at 1 Long Wharf Drive):
On a day close to each MRS study, subjects will arrive at the Long Wharf Diabetes Research Suite 
to perform a baseline assessment of cognitive performance. CGM data will be obtained. A battery 
of validated cognitive tests that were shown to be associated with severe hypoglycemia in older 
adults with T1DM will be completed, including Symbol Digit Modalities, Trail Making Test, 
Grooved Pegboard Test [77]. In addition, we will use validated questionnaires to determine the 
degree of hypoglycemia unawareness, quality of life and satisfaction of insulin therapy [78-80] 
(see Appendix 4).
d) Randomization and follow-up visits between MRS assessments (YNHH Hospital Research 
Unit/MRRC/Long Wharf Diabetes Research Suite (#503) at 1 Long Wharf Drive):
After completion of the first MRS session, subjects will randomized to either the intervention or 
control group. The intervention group consists of treatment with a PLGS-enabled insulin 
pump/CGM combination (Medtronic MiniMed 670G pump with Guardian sensor, or Tandem 
t:slim X2 pump with Dexcom sensor) in auto mode for Medtronic users and with Basal-IQ for 
Tandem users; subjects in the control group will use the same PLGS-enabled insulin pump/CGM 
combination but in manual mode for Medtronic users or without Basal-IQ for Tandem users. All 
subjects will undergo a PLGS system training session with a study nurse or nurse practitioner. 
Subjects will have weekly phone calls with study team members (physician and/or advanced 
practice nurse or registered nurse) to review blood glucose logs and insulin doses, potential adverse 
events, and other clinical or device-related issues. Subjects can also speak with a study physician, 
advanced practice nurse or registered nurse more frequently if there are any questions or concerns.
The two pump devices that will be used are: Medtronic  MiniMed™ 670G system or Tandem 
t:slim X2 with Control IQ software. For subjects who use multiple daily injections as part of their 
standard insulin therapy or for subjects who do not use the MiniMed 670G pump or t:slim X2 
pump, a loaner MiniMed 670G system will be provided. For subjects who use multiple daily 
injections as part of their standard insulin therapy, the training and support described above will 
be provided and may potentially be provided on a more frequent and/or intensive basis depending 
on the needs of the subject. A washout is not required given that regardless of method of 
administration (pump or injection), the insulin and dosages remain the same. Likewise, the risks 
remain similar. Furthermore, regardless
Page 11 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
of the method of administration that the subject uses in their usual standard of care, all subjects 
will be trained and supported as much as is necessary in order to ensure that they understand how 
to use the PLGS system, and any subject who, in the opinion of the clinical study staff, is deemed 
to not be able to safely use the system will not continue in the study.
Program on Aging field core staff will remain in close contact with study participants via phone 
to identify and eliminate any obstacles to successful study completion.
4. Genetic Testing N/A ☒
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will be 
received
iii. the types of information about the donor/individual contributors that will be entered into 
a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for future 
research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers that 
connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer identified: 
that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials
5. Subject Population: Provide a detailed description of the types of human subjects who will be 
recruited into this study.
We will enroll 30 patients aged 50-80yrs (at least 50% over the age of 65) with tightly controlled 
(HbA1c <8%), c-peptide-negative T1DM of >10 years duration. Male and female subjects of all races 
and ethnicities will be targeted for study. Additional criteria will be BMI <35 kg/m2 and a history of 
frequent hypoglycemia with unawareness (defined as 2 or more episodes of severe hypoglycemia 
within one year (requiring assistance) and 2 or more glucose values < 54 mg/dL during a week of 
CGM (iPRO monitor, Medtronic) prior to enrollment. Hypoglycemia awareness will be assessed by 
detailed interviews and answering Ryan, Gold and Clarke questionnaires [78-80] that will be compared 
to hypoglycemic episodes recorded during blinded CGM. Exclusion criteria will be any significant 
medical comorbidities, significant alcohol intake and vegetarian diet since both are known to have an 
impact on counterregulation and brain metabolism [81, 82]. All inclusion and exclusion criteria are 
listed in the section below (Inclusion/exclusion criteria).
Page 12 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
6. 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 ☒
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion?
Inclusion criteria:

Provide signed and dated informed consent form

Male or female

Age 50-80 years (at least 50% over the age of 65)

T1DM (>10 years duration)

C-peptide undetectable

HbA1c of < 8%

History of frequent hypoglycemia with unawareness (defined as 2 or more episodes of severe 
hypoglycemia within one year requiring assistance) and 2 or more glucose values < 54 mg/dL during 
the week of Continuous Glucose Monitoring (CGM) (iPRO monitor, Medtronic) prior to enrollment

BMI <35 kg/m2

Good general health as evidenced by medical history and blood screening

Willing to comply with all study procedures and be available for the duration of the study

Willing to fast for a limited time period on the morning of a clamp study
Exclusion Criteria

Significant diabetic complications (untreated proliferative retinopathy, creatinine ≥1.5 mg/dl, urinary 
albumin levels 300 mg/day, autonomic neuropathy, painful peripheral neuropathy)

Significant alcohol intake and vegetarian diet since both are known to have an impact on 
counterregulation and brain metabolism

Any contraindications for MRI scanning, including presence of metallic implants or claustrophobia.

Heavy exercise on a regular basis (i.e. marathon runners)
Page 13 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

Known allergic reactions to components of the study product(s)

Treatment with another investigational drug or other intervention

Active infection including hepatitis C, hepatitis B, HIV

Any past or current history of alcohol or substance abuse

Psychiatric or neurological disorders under active treatment

Weighing less than 110 lbs

Baseline hemoglobin < 10.5 g/dL in females, or < 12.5 g/dL in males.

Blood donation within 30 days of the study

History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose 
aspirin treatment is allowed)

Co-existing cardiac, liver, and kidney disease

Abnormal liver function tests

Women who are pregnant (as assessed by pregnancy test that will be performed on female participants 
at reproductive age), planning to become pregnant, or lactating.

Any medical condition or medication that, in the opinion of the investigators, will interfere with the 
safe completion of the study or study outcomes
8. How will eligibility be determined, and by whom?
Eligibility will be determined based on information collected at the screening visit after consent is 
obtained. This will include findings from physical examination, medical history, EKG, and laboratory 
testing in accordance with the inclusion and exclusion criteria listed above.
Eligibility to participate in the study will be determined by the licensed medical practitioners listed 
on this protocol (see personnel section).
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research.
i.
Intravenous catheters. The placement of intravenous catheters and/or the use of intravenous 
infusions can result in local hematoma formation or thrombophlebitis. Transient vasovagal 
symptoms including nausea, sweating, and lightheadedness may also occur during intravenous 
catheter placement.
ii.
Blood sampling. Same as above and frequent blood sampling may result in a drop in hematocrit 
levels.
iii.
Hyperinsulinemic hypoglycemic clamp technique. The hyperinsulinemic hypoglycemic clamp 
technique can result in hypoglycemia symptoms of varying severity. Subjects may experience 
autonomic symptoms including hunger, anxiety, tremor, palpitations, and/or diaphoresis. Others 
may experience fatigue, concentration difficulties, and/or mild confusion. The risk of plasma
Page 14 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
glucose levels falling below the target value of 50 ± 3 mg/dL is small but present; affected patients 
may experience exaggerated symptoms, as well as the development of dizziness, blurred vision, 
and/or confusion. All such symptoms would be rapidly reversible with an intravenous dextrose 
infusion.
iv.
Infusion of labeled acetate. Carbon-13 is a stable isotope of a naturally occurring substance. There 
are no known side effects associated with the administration of 13C-acetate, which has been safely 
used by our group here at Yale for many years.
Predictive low glucose suspend system (PLGS). The subjects enrolled in this study are T1DM 
patients at high risk of recurrent hypoglycemia who can largely benefit by a reduction in frequency, 
duration, and severity of hypoglycemia potentially achieved by using a PLGS system [83-85]. The 
main risk of the use of the PLGS pump system is a worsening of glycemic control, which could be 
an increased frequency of hyperglycemia or hypoglycemia.
v.
Magnetic resonance imaging/spectroscopy. The risks due to the magnet study are similar to clinical 
MRI. Radio frequency and magnetic fields to be used for 1H and 13C spectroscopy in this study 
present no known hazards to human subjects whose bodies do not contain any para-magnetic 
metals. Subjects will be questioned using the protocol developed by Diagnostic Imaging 
concerning heart pacemakers, metallic objects, IUDs, vascular clips, electrodes, cochlear implants, 
neurostimulators, shunts, heart valve implants, penile implants, vascular filters, rods & screws, 
post CABG pacer wires, colored contact lens, dental prostheses, limb prostheses, eye prostheses, 
shrapnel, metal in head, eye, or skin, and embolization coils. If they cannot be removed safely, the 
subject will be excluded from the study. Proton decoupling, which is used in 13 spectroscopy, 
presents the potential risk of tissue heating. However, the regional heat deposition will never 
exceed the FDA guideline of 4 watts/kg. In over 1,000 experiments to date using proton 
decoupling, we have not experienced any patient complaints about tissue heating.
vi.
Questionnaires: Some subjects may feel discomfort or distress in responding to certain items on 
the questionnaires.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
The primary risks to the subject are impact by magnetic objects accidentally brought into the 
magnet room, anxiousness, irritation due to the IV blood sampling, and hypoglycemia after the 
glucose infusion. The investigators in this protocol pioneered human infusion studies of stable 
isotope labeled metabolic substrates in MR systems and have been routinely performing these 
studies since 1988. Studies of brain metabolism using stable isotope infusion in the MRC have 
been performed since 1990. To date there have been no patient injuries during these studies and 
only minor adverse incidences (anxiety, IV irritation).
To confront the specific risks listed above:
i.
Intravenous catheters. Intravenous catheters will be placed under sterile conditions by experienced 
HRU staff members. All infused solutions will be prepared in sterile form by the YNHH pharmacy 
and will be tested for pyrogenicity and sterility prior to use. During dextrose infusions, 20%
Page 15 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
dextrose will be used to reduce the risk of thrombophlebitis normally associated with the use of 
excessively hypertonic glucose solutions.
(i) Blood sampling. No subject with a hematocrit less than 37% for males and less than 33% for 
females will be studied. Total blood loss (~515 cc) for each subject, spread over the screening visit 
and 2 study visits (8-10 weeks apart), will exceed the amount obtained during a typical blood 
donation by about 10%. People who are in good health are not usually affected by this kind of 
blood loss. To protect against adverse events, all patients with significant baseline anemia (see 
exclusion criteria) will be excluded from the study. All patients who have donated blood within 30 
days of the study will be asked to wait 6 weeks before participating in the study. Study participants 
will undergo a hematocrit check prior to the second clamp visit. Should a value of less than 37% 
for males and less than 33% for females be measured, the second clamp will be postponed by at 
least 6 weeks, to ensure adequate recovery. Patients will be advised to refrain from blood donations 
for 8 weeks after study completion. All subjects will be given a telephone number to enable 
immediate communication with the PI or one of the co-investigators, to report any delayed adverse 
effects and to receive recommendations for treatment of any adverse effects.
ii.
Hyperinsulinemic hypoglycemic clamp technique. All study procedures, including the 
hyperinsulinemic clamp, will be performed under the direct supervision of a qualified, licensed 
practitioner. To avoid excess hypoglycemia during the hyperinsulinemic clamp, plasma glucose 
will be checked every five minutes using a bedside glucose monitor. Based on these measurements, 
the plasma glucose will be adjusted via the 20% dextrose infusion.
iii.
Infusion of unlabeled acetate. Stable isotope infusions will be prepared in sterile form by the 
YNHH pharmacy and will be tested for pyrogenicity and sterility prior to use. The MRRC has 
extensive experience with stable isotope infusions including BHB, glucose and lactate (HIC # 
10605, Rothman PI; HIC#1208010648, Robert Sherwin PI)) and to date there have been no adverse 
events due to the infusion.
iv.
PLGS system. The primary risk of PLGS therapy is worsening of glycemic control, either more 
frequent hyperglycemia or hypoglycemia. Both are frequent occurrences in people with type 1 
diabetes, and by study design, the subjects enrolled will already have a history of frequent and/or 
severe hypoglycemia. Published studies of PLGS systems have not demonstrated an increased risk 
of hypo- or hyperglycemia using these devices. To minimize these risks:
iv.1
All subjects undergoing therapy with PLGS insulin therapy will have an in-depth training 
session with an experienced study nurse to adequately train the use of the system. Our study team 
has trained hundreds of subjects on the use of sensor-augmented pump therapy and over 30 
subjects on the use of the specific system used in this application. Sensors will initially be placed 
by study nurses, and subjects will be trained on how to insert and remove them. Supplemental 
training materials will be available for use for subjects at home.
iv.2
All subjects will have weekly visits (in person or on the phone) with study nurses and 
physicians to review blood glucose logs and insulin doses, potential adverse events, and other 
clinical issues. Changes will be made to diabetes management as deemed necessary by study 
physicians/nurses.
Page 16 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
iv.3
All subjects will be able to reach study physicians/nurses at all times of day or night for 
urgent issues through the use of a dedicated cell phone carried by study physicians/nurses.
iv.4
All subjects using CGM will be instructed to insert sensors using clean technique to 
minimize infection and irritations. Subjects will be instructed to assess skin sites at the item of 
sensor removal for irritation or infection and will call the study team as needed for further 
evaluation.
v.
Magnetic resonance imaging/spectroscopy. The primary risks to the subject from MRI are impact 
by magnetic objects accidentally brought into the magnet room, anxiousness, irritation due to the 
IV blood sampling, and hypoglycemia after the glucose infusion. The investigators in this protocol 
pioneered human infusion studies of stable isotope labeled metabolic substrates in MR systems 
and have been routinely performing these studies since 1988. Studies of brain metabolism using 
stable isotope infusion in the MRC have been performed since 1990. To date there have been no 
patient injuries during these studies and only minor adverse incidences (anxiety, IV irritation). To 
confront the specific risks listed above:
v.1 All potential study subjects will also be screened for MR safety using the standard MR safety 
protocol developed by Yale New Haven Hospital’s Diagnostic Imaging department. Subjects with 
claustrophobia, a history of panic attacks or with other contraindications to MR scanning will be 
excluded from the study. The MR safety screening process will be performed both during the 
screening interview and on the day of an MR study.
v.2 Study subjects will be closely followed by an experienced clinical research team, including an 
experienced nurse with ACLS training who is with a patient at all times, a licensed MD, and an 
experienced MRS technologist. All personnel involved in the study will be trained in MR safety 
procedures. The MD and technologist who are outside of the room have direct visual contact with 
the subject and nurse through a window, a TV monitor, and audio contact through a speaker 
system. Subjects who become claustrophobic in the magnet will be removed immediately from the 
magnet room. Patients who experience distress in the magnet room for any reason including 
seizures, loss of consciousness, or pain will be removed from the magnet room in accordance with 
well-established procedures developed for the Magnetic Resonance Research Center. Should an 
emergency arise, the technologist will telephone the hospital emergency operator and have an 
ambulance with personnel trained in resuscitation sent to the MR Center. The other members will 
remove the patient via the detachable patient bed from the magnet room if immediate resuscitation 
is needed the physician present during the study will perform this procedure, using a fully equipped 
crash cart which will be in the console room during the study.
vi.
Questionnaires: All subjects will be able to speak to a study physician or nurse at any time if 
responding to certain questions produces discomfort and/or distress. Subjects will be referred to 
appropriate counseling and support if deemed appropriate by study physician/nurse.
All subjects will be given a telephone number to enable immediate communication with the P.I. or one of 
the co-investigators, to report any delayed adverse effects and to receive recommendations for treatment 
of any adverse effects.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the final 
determination of the risk to subjects.)
Page 17 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
a.
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study?
Moderate
b. If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study?
N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are available here 
http://www.yale.edu/hrpp/forms-templates/biomedical.html for
i. Minimal risk
ii. Greater than minimal
The risks associated with the current study are deemed moderate for the following reasons:
We do not view the risks associated with the combined use of insulin and dextrose as minimal. Given 
our experience with the combined co-administration of insulin and dextrose, we do not view the 
proposed studies as high risk. Although PLGS systems were not specifically tested in vulnerable older 
adults with T1DM, safety data collected in other populations are reassuring.
Although we have assessed the proposed study as one of moderate 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:
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 Dr Herzog according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures. 
b.) Probable: Adverse event is likely related to investigational procedures. 
c.) Possible: Adverse event may be related to investigational procedures.
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures. 
e.) Unrelated: Adverse event is clearly not related to investigational procedures.
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
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:
1. is life-threatening
Page 18 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
2. results in in-patient hospitalization or prolongation of existing hospitalization
3. results in persistent or significant disability or incapacity
4. results in a congenital anomaly or birth defect OR
5. results in death
6. 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, or
7. adversely affects the risk/benefit ratio of the study
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 HIC or HSC is necessary.
Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse 
events occurring at a greater frequency than expected, and other unanticipated problems 
involving risks to subjects or others to the HIC or HSC.
The investigator will report the following types of adverse events to the HIC or HSC:
a) serious
AND
unanticipated
AND
possibly,
probably
or
definitely
related
events;
b) anticipated
adverse
events
occurring
with
a
greater
frequency
than
expected;
and
c) other unanticipated problems involving risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others will be reported 
to the HIC or HSC within 48 hours of it becoming known to the investigator, using the appropriate 
forms found on the website.
Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Center for Clinical
Investigation Research Subject Advocates (RSAs), Cancer Center's Quality Assurance, 
Compliance and Safety Committee (QUACS) 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):
-
All Co-Investigators listed on the protocol.
-
Yale Center for Clinical Investigation Research Subject Advocates (RSAs)
The principal investigator Dr Herzog 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.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or others be 
reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications? 
N/A
Page 19 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
10 Statistical Considerations: Describe the statistical analyses that support the study design.
To test the hypothesis that “Strict avoidance of hypoglycemia for 8 weeks reduces frontal cortex 13C- 
acetate utilization by 25%” a two-sided nonparametric Wilcoxon rank sum test will be used. SAS® 
statistical software, version 9.4, will be used to conduct data analyses.
Sample size estimation and power calculation have been conducted with PASS statistical software. [86, 
87]. Sample size estimates are based on published human acetate data, as well as our previously published 
differences between control and RH animal studies [48, 56]. These differences correspond to a decrease 
of approximately 25% or more in brain acetate utilization in the group of T1DM patients undergoing the 
PLGS intervention. We estimate that sample sizes of 12 subjects per group will achieve 80% power to 
detect this 25% reduction with estimated group standard deviations of 0.18 and 0.10 in the respective 
control and intervention groups, using a two-sided Wilcoxon rank sum test and assuming a significance 
(alpha) level of 0.05. To adjust the sample size for possible missing values, three additional study 
participants will be enrolled per treatment group; we thereby estimate that a sample size of 15 per group 
will be adequate to test the proposed primary hypothesis.
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the section.
A. RADIOTRACERS
N/A
B. DRUGS/BIOLOGICS
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):
Page 20 of 58
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes:
1) The intention of the investigation is NOT to report to the FDA as a well-controlled study in 
support of a new indication for use or to be used to support any other significant change in the 
labeling for the drug. ☒YES ☐NO
2) The drug that is undergoing investigation is lawfully marketed as a prescription drug product,
and the intention of the investigation is NOT to support a significant change in the advertising 
for the product. ☒YES
☐NO
3) The investigation does NOT involve a route of administration or dosage level or use in
populations or other factor that significantly increases the risks (or decreases the acceptability 
of the risks) associated with the use of the drug product. ☒YES
☐NO
4) The investigation will be conducted in compliance with the requirements for institutional
(HIC) review and with the requirements for informed consent of the FDA regulations (21 
CFR Part 50 and 21 CFR Part 56). ☒YES
☐NO
5) The investigation will be conducted in compliance with the requirements regarding promotion
and charging for investigational drugs. ☒YES
☐NO
Page 21 of 58
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
☐i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply):
☐Blood grouping serum
☐Reagent red blood cells
☐Anti-human globulin
☐ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and
☐iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
☐The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Exempt Category 4
☐A clinical investigation involving use of a placebo if the investigation does not otherwise require 
submission of an IND.
2.
Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might influence 
risks. If this is the first time this drug is being administered to humans, include relevant data on animal 
models.
According to our previously published protocol [11, 66], subjects will receive a bolus of [2-13C] acetate 
6 mg/kg · min administered for 5 minutes followed by a continuous infusion of 3 mg/kg · min for a total 
of 120 minutes. The MRRC has extensive experience with stable isotope infusions including BHB, 
glucose and lactate (HIC # 10605, Rothman PI; HIC#1208010648 Herzog PI) and to date there have 
been no adverse events due to the infusion. Of note, carbon-13 is a natural isotope of carbon. It is non- 
radioactive and has no side effects.
3.
Source: Identify the source of the drug or biologic to be used. 
[2-13C] acetate, Isotec, Williamsburg, OH
a)
Is the drug provided free of charge to subjects? ☒YES
☐NO
If yes, by whom?
The drug is used only for experimental purpose during the MRS sessions and will be charged on 
investigators’ funds.
4.
Storage, Preparation and Use: Describe the method of storage, preparation, stability 
information, and for parenteral products, method of sterilization and method of testing sterility 
and pyrogenicity.
Stable isotope infusions will be prepared in sterile form by the YNHH pharmacy and will be tested 
for pyrogenicity and sterility prior to use according to standard procedures.
Check applicable Investigational Drug Service utilized:
☒ YNHH IDS
☐ Yale Cancer Center
☐CMHC Pharmacy
☐ West Haven VA
☐PET Center
☐ None
☐Other:
1.   Use of Placebo:
☒Not applicable to this research project
Page 22 of 58
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.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
If use of a placebo is planned, provide a justification which addresses the following:
a) Describe the safety and efficacy of other available therapies. If there are no other available therapies, 
state this.
b) State the maximum total length of time a participant may receive placebo while on the study.
c) Address the greatest potential harm that may come to a participant as a result of receiving placebo.
d) Describe the procedures that are in place to safeguard participants receiving placebo.
Continuation of Drug Therapy After Study Closure ☒Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
☐Yes If yes, describe the conditions under which continued access to study drug(s) may apply as well 
as conditions for termination of such access.
☐NO If no, explain why this is acceptable.
C. DEVICES
1. Are there any investigational devices used or investigational procedures performed at Yale-New 
Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and Vascular 
Center)? Yes No The two pump devices that will be used 
are:          Medtronic  MiniMed™ 670G system or Tandem t:slim X2 with Control IQ 
software
2. Background Information: Provide a description of previous human use, known risks, and any other 
factors that might influence risks. If this is the first time this device is being used in humans, include 
relevant data on animal models.
GENERAL RISKS related to the MiniMed™ 670G insulin pump system may include:
If Yes, please be aware of the following requirements:
A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the Tools tab in 
the EPIC Banner, Click on Lawson, Click on “Add new” under the New Technology Request 
Summary and fill out the forms requested including the “Initial Request Form,” “Clinical 
Evidence Summary”, and attach any other pertinent documents. Then select “save and submit” to 
submit your request; AND
Your request must be reviewed and approved in writing by the appropriate YNHH committee before 
patients/subjects may be scheduled to receive the investigational device or investigational procedure.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

Hypoglycemia

Hyperglycemia

Diabetic Ketoacidosis

Seizure

Coma

Death
GENERAL WARNINGS

Do not use the pump when a flammable anesthetic mixture with air, oxygen, or nitrous oxide is present. 
These environmental conditions can damage your pump and result in serious injury.

Always use the fingertip for blood samples used for calibrating the sensor while in Auto Mode. The fingertip 
was the only site studied for use with Auto Mode. Do not use blood samples from the palm to calibrate the 
sensor as this site was not studied for use with Auto Mode and the performance of the system is not known.

Do not make treatment decisions, such as determining your insulin dose for meals, using the MiniMed™ 
670G continuous glucose monitor (CGM) values, as they are not intended to be used to make such treatment 
decisions. The MiniMed™ 670G CGM does not replace a blood glucose meter. Always use the values from 
your blood glucose meter for treatment decisions. Blood glucose values may differ from sensor glucose 
values. Using the sensor glucose readings for treatment decisions could lead to high or low blood glucose.

Never rely on the pump beeps or vibrations alone to navigate through the pump screens or menus. Always 
check your pump screen as you navigate. The pump beeps and vibrations are intended to notify you of a 
condition that may require attention. Relying on the pump beeps or vibrations alone to navigate can result in 
incorrect menu selection or settings.

Do not use your pump if the screen appears broken or unreadable. In some instances, impact to the pump can 
damage the screen while the buttons continue to function. If the screen is broken or unreadable, do not press 
any buttons. Remove the pump and begin using your backup insulin plan per the direction of your healthcare 
professional. If the pump is accidentally programmed while the screen is broken or unreadable, this could 
result in high or low blood glucose levels. If your screen is damaged, contact the 24-Hour Technical Support 
to arrange for shipment of a replacement pump.

Only use rapid acting U100 insulin (Humalog® and Novolog®) that has been prescribed by your healthcare 
professional for use with an infusion pump. Do not put any other drugs or medications inside your reservoir 
for use with this pump. Other drugs or medications are not intended for use with this pump. Use of other 
drugs or medications can cause serious injury.

Always make sure the infusion set is disconnected from your body before you rewind your pump or fill the 
infusion set tubing. Never insert the reservoir into the pump while the tubing is connected to your body. 
Doing so could result in an accidental infusion of insulin.

Do not insert the reservoir in the pump if you did not rewind your pump. Doing so could result in an 
accidental infusion of insulin.

Do not use the MiniMed™ 670G insulin pump or additional system devices adjacent to other electrical 
equipment which may cause interference with the normal system operation. This includes mobile 
communication devices such as cell phones, GPS navigation systems, anti-theft systems, and any electrical 
equipment that has an output transmitter power greater than 1W. For more information about recommended 
separation distance guidelines between the insulin pump and common RF emitters, see Guidance and 
manufacturer's declaration, on page 335. The recommended separation distance between the insulin pump 
and common RF emitters is 12 inches. Other electrical equipment that may compromise normal system 
operation has been contraindicated. 

Do not unscrew or retighten the tubing connector on the reservoir while the infusion set is connected to your 
body. Doing so could result in an accidental infusion of insulin.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

Do not use standard Luer sets with the MiniMed™ 670G insulin pump. Luer sets are not compatible with the 
pump. MiniMed™ reservoirs and MiniMed™ infusion sets are specifically designed for use with the 
MiniMed™ 670G insulin pump.

Do not change or modify your MiniMed™ reservoir or MiniMed™ infusion set unless expressly approved 
by Medtronic Diabetes. Modifying the devices can cause serious injury, interfere with your ability to operate 
the device, and void your warranty.

Do not rely on preset pump alarms or reminders alone to prompt you to check your blood glucose. This can 
cause you to forget to check your blood glucose. Set additional reminders on other devices, such as your cell 
phone.

Do not change or modify the internal RF transmitter or antenna unless expressly approved by Medtronic 
Diabetes. Doing so could interfere with your ability to operate the equipment.

Do not attempt to use the MiniLink™™ transmitter (MMT-7703), the Guardian™ Link transmitter (MMT-
7763), or the Guardian™ Connect transmitter (MMT-7821) with the MiniMed™ 670G insulin pump. These 
transmitters do not communicate with this insulin pump.

If other devices that employ radio frequencies are in use, such as cell phones, cordless phones, and wireless 
networks, they may prevent communication between the transmitter and the insulin pump. This interference 
does not cause any incorrect data to be sent and does not cause any harm to your devices. Moving away 
from, or turning off, these other devices may enable communication. If you continue to experience RF 
interference, please contact the 24-Hour Technical Support.

Special Precautions regarding Electromagnetic Compatibility (EMC): This body worn device is intended to 
be operated within a reasonable residential, domestic, public or work environment, where common levels of 
radiated “E” (V/m) or “H” fields (A/m) exist; such as cellular phones, Wi-Fi®, Bluetooth®, electric can 
openers, microwave and induction ovens. This device generates, uses, and can radiate radio frequency energy 
and, if not installed and used in accordance with the provided instructions, may cause harmful interference to 
radio communications.

Portable and mobile RF communications equipment can affect Medical Electrical Equipment as well. If you 
encounter RF interference from a mobile or stationary RF transmitter, move away from the RF transmitter 
that is causing the interference.

Do not rely on glucose sensor-enabled features when Airplane Mode is on because the pump does not 
receive sensor readings from the transmitter. Glucose sensor-enabled features include CGM, SmartGuard™, 
and Auto Mode. When using Airplane Mode, always rely on your blood glucose (BG) values when making 
therapy decisions to avoid hypoglycemia or hyperglycemia.

This device can generate, use, and radiate radio frequency energy and, if not installed and used in accordance 
with the instructions, may cause harmful interference to radio communications. If the device does cause 
interference to radio or television reception, you are encouraged to try to correct the interference by one or 
more of the following measures:

Decrease the distance between the transmitter and the insulin pump to 6 feet (1.8 meters) or less.

Decrease the distance between the meter and the insulin pump to 6 feet (1.8 meters) or less. •

Increase the separation between the transmitter and the device that is receiving/emitting interference.
Note: Harmful interference is defined by the FCC as follows. Any emission, radiation or induction that 
endangers the functioning of a radio navigation service or of other safety services or seriously degrades, 
obstructs or repeatedly interrupts a radio communications service operating in accordance with FCC rules.

The safety of the MiniMed™ 670G system has not been studied in people with impaired kidney function. 
Please let your healthcare professional know if you have kidney disease so you and your healthcare 
professional can determine if the potential benefits of using the system outweigh the risks.

The safety of the MiniMed™ 670G system has not been studied in pregnant women, people with type 2 
diabetes, or in people using other antihyperglycemic therapies apart from insulin. Please let your healthcare 
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
professional know if any of these conditions apply to you so you and your healthcare professional can 
determine if the potential benefits of using the system outweigh the risks.

The safety of using Auto Mode, Suspend before low, and Suspend on low in people who have no pump 
experience is not known. Auto Mode, Suspend before low, and Suspend on low should not be used if insulin 
pump settings have not been previously established. Insulin pump settings include basal rates, insulin to carb 
ratio, or insulin sensitivity factors. Always discuss with your healthcare professional before using Auto 
Mode, Suspend before low, or Suspend on low. Reservoir and infusion sets For the most current warnings, 
see the user guide that came with your device.

Only use rapid acting U100 insulin (Humalog® and Novolog®) that has been prescribed by your healthcare 
professional for use with an infusion pump. Do not put any other drugs or medications inside your reservoir 
for use with this pump. Other drugs or medications are not intended for use with this pump, and can result in 
serious injury.

If insulin, or any liquid, gets inside the tubing connector, it can temporarily block the vents that allow the 
pump to properly prime the infusion set. This may result in the delivery of too little or too much insulin, 
which can cause hyperglycemia or hypoglycemia. If this occurs, start over with a new reservoir and infusion 
set.

Do not reinsert the introducer needle into the infusion set. Reinsertion may cause tearing of the soft cannula, 
which may result in unpredictable medication flow.

If infusing insulin, and your blood glucose level becomes unexplainably high, or an occlusion alarm occurs, 
check for clogs and/or leaks. • If in doubt, change the infusion set because the soft cannula may be dislodged, 
crimped and/or partially clogged. Should any of these problems arise, make a plan with your healthcare 
professional for rapidly replacing insulin. Test your blood glucose level to make sure the problem is 
corrected.

Reuse of the infusion set may cause damage to the cannula/needle and lead to infection, site irritation, and/or 
inaccurate medication delivery.

Dispose of transfer guard safely in sharps container.

Never prime the set or attempt to free a clogged line while the set is inserted. You may accidentally inject too 
much medication.

Do not put disinfectants, perfumes, or deodorants on the infusion set as these may affect the integrity of the 
set.

Dispose of the infusion set and introducer needle safely, in a sharps container, after a single use. Do not clean 
or re-sterilize.

Store infusion sets in a cool, dry place. Do not leave infusion sets in direct sunlight or inside a vehicle.

Only use reservoir and infusion sets manufactured or distributed by Medtronic Diabetes. The pump has 
undergone extensive testing to confirm appropriate operation when used with compatible reservoirs and 
infusion sets manufactured or distributed by Medtronic Diabetes. We cannot guarantee appropriate operation 
if the pump is used with reservoirs or infusion sets offered by third parties. We are not responsible for any 
injury or malfunctioning of the pump that may occur in association with such use.

Use aseptic techniques when temporarily disconnecting the set and consult your healthcare provider on how 
to compensate for missed medication when disconnected.

If infusing insulin, carefully monitor your blood glucose levels when disconnected and after reconnecting.

Reservoir and transfer guard are sterile, non-pyrogenic, and for single use only.

Do not clean or re-sterilize. Reuse of the reservoir may lead to insulin degradation, infection, inaccurate 
medication delivery, and/or leaks which may cause damage to the pump. • Inaccurate medication delivery, 
infection and/or site irritation may result from improper insertion and maintenance of the infusion site.

If using this infusion set for the first time, do the first set-up in the presence of your healthcare professional.

Do not leave air in the infusion set. Prime completely.

Replace the infusion set every 48 to 72 hours according to Centers for Disease Control guidelines, or per 
your healthcare professional’s instructions.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

If infusing insulin, do not change the infusion set just before bedtime unless you can check your blood 
glucose 1 to 3 hours after insertion.

Do not use if package has been opened or damaged.

Ensure sterility by checking that the sterile paper and tamper-proof seal are not damaged.

This device is sterile and non-pyrogenic unless the package has been opened or damaged. Do not use if the 
package has been opened or damaged. Do not use the infusion set if the tubing connector needle has been 
damaged.

Do not use the infusion set for more than 3 days. Insulin is not labeled for more than three days when it is 
used in an infusion set. If insulin is used in the infusion set for more than three days, it may increase the risk 
of set occlusions and cause problems with insulin absorption, which may lead to severe hyperglycemia and 
DKA.

Before insertion, clean the insertion site with isopropyl alcohol.

Check frequently to make sure the soft cannula remains firmly in place as you may not feel pain if it pulls 
out. The soft cannula must always be completely inserted to receive the full amount of medication.

Release the tubing with caution as a hard pull of the tubing can result in damage to the infusion 
set/introducer needle. Ensure that the infusion set is properly in place when the tubing is fully released.

If the infusion site becomes inflamed, replace the set, and use a new site until the first site has healed. 
Replace the infusion set if the tape becomes loose, or if the soft cannula becomes fully or partially dislodged 
from the skin.

Failure to remove trapped air from reservoir may result in inaccurate delivery of medication

Never point a loaded insertion device towards the body part, where insertion is not desired.

Remove the needle guard before inserting the infusion set.
Page 23 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
3. Source:
a) Identify the source of the device to be used.
b) Is the device provided free of charge to subjects? ☒Yes ☐No
4. Investigational device accountability: State how the PI, or named designee, ensures that an 
investigational device is used only in accordance with the research protocol approved by the HIC, and 
maintains control of the investigational device as follows:
a) Maintains appropriate records, including receipt of shipment, inventory at the site, dispensation 
or use by each participant, and final disposition and/or the return of the investigational device (or 
other disposal if applicable):
Device shipments will be verified against the packing slip and logged in the study regulatory 
binder. The dispensing and return of the study devices to the subjects will be recorded in the 
study regulatory binder.
b) Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number):
c) Lot and/or serial numbers are recorded on the packing list sent with equipment shipments
d) Study equipment will be stored according to manufacturer’s instructions in locked areas of the 
research office as appropriate for the required storage conditions. Ensures that the device is 
stored in a secure area with limited access in accordance with applicable regulatory 
requirements:
Study equipment will be stored according to manufacturer’s instructions in locked areas of the 
research office as appropriate for the required storage conditions.
e) Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
Equipment will only be distributed to subjects who have signed an approved consent and have 
met all eligibility criteria for study participation.
1. Targeted Enrollment: Give the number of subjects:
a.
Targeted for enrollment at Yale for this protocol: 30
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
Posters
Mass E-mail Solicitation
Letter
Departmental/Center Website
Medical Record Review*
Departmental/Center Research Boards 
Departmental/Center Newsletters
Web-Based Clinical Trial Registries
Radio 
Telephone 
Television 
Newspaper
YCCI Recruitment database
Clinicaltrials.gov Registry (do not send materials to HIC)
Page 24 of 58
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
 Other (describe): Yalestudies.org and yalestudies social media Facebook and Twitter
* 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.
Some subjects will be identified through their previous participation in HIC #1009007394: “Effect of a long- 
term Medium Chain Triglyceride diet on cognitive function and brain activation.”, HIC #0505000079: 
“Effect of Medium Chain Fatty Acids in cognitive function during acute hypoglycemia in patients with type 
1 diabetes.” And HIC#1208010648 “Impact of Hypoglycemia on Brain Ketone and Neurotransmitter 
Metabolism in Type 1 DM”.
In addition, we will collaborate closely with the YNHH JDAT group to identify subjects that match our 
specific inclusion and exclusion criteria.
b. Describe how potential subjects are contacted.
Possible study participants will be approached by their caregivers or study staff at the different locations 
where Type 1 Diabetic patients are seen at Yale SOM, YNHH and YMG. These sites include the Adult 
Endocrine clinic (Yale Diabetes Center, YNHH), Veterans Affairs Hospital, West Haven, community 
clinics and Yale University Health. We will also accept referrals from outpatient clinics in the community. 
Flyers will be put up on notice boards at and around Yale University and Yale New Haven Hospital. Study 
volunteer listings will be requested from the YCCI volunteer database (HIC#0805003779) to assist with 
recruitment of subjects. Brief screenings will take place either over the telephone or email and subjects 
will then be invited to a full screening at the HRU (see Appendix 6 – Phone script for recruitment).
Epic MyChart will identify and notify potential candidates for a study. Patients who have an Epic MyChart 
account and meet basic inclusion /exclusion criteria will be notified of the study through a MyChart 
message (see Appendix 7 – MyChart message). The notification will provide an overview of the study 
and a phone number for additional information. Within MyChart, patients can indicate whether or not they 
are interested in the study. If a patient is interested, research coordinators may contact the patient for 
eligibility screening. If a patient selects no- they are not interested in the study, they will not receive any 
additional messages about the study within Epic, and their information will not be shared with the research 
coordinator.
c. Who is recruiting potential subjects?
Caregivers or study staff.
The text to appear on yalestudies.org is as follows:
Purpose (healthcare version): The goal of this proposal is to implement a Predictive Low Glucose 
Suspend (PLGS) system in older patients with type 1 diabetes mellitus (T1DM) in order to reverse brain 
metabolic adaptations and restore metabolic sensitivity, hypoglycemia awareness and appropriate
Page 25 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
hormonal counterregulatory responses (CRR). For purposes of this study we are looking to enroll aged 
T1DM subjects.
Purpose (subject friendly version): We are trying to demonstrate that a new insulin pump system can 
prevent low glucose episodes and improve brain function in aged T1DM subjects.
Inclusion Criteria:
1. Type 1 Diabetes Mellitus >10 years duration
2. HbA1c <8%
3. Age 50 years and older
4. Male or female
5. A person in good health
Exclusion Criteria:
1. Significant Systemic Disease or diabetic complications
2. Pregnancy
3. Significant Anemia
4. Excessive Exercise
5. Vegetarian Diet
6. Excessive Alcohol Use
7. Substance Abuse
Compensation offered:
Up to $800
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.
Subjects with type 1 diabetes will be recruited from the surrounding area. Therefore it is possible that 
some patients may be under the care of the principle investigator, Dr Herzog, in the setting of the Yale 
Diabetes Center or Dr Weinzimer in the Pediatric Diabetes Clinic.
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.
Page 26 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data:
We are requesting a waiver of HIPPA Authorization in order to utilize the YNHH admission lists that 
would indicate patients we may not be able to contact prior to their discharge from the hospital. Such 
cases may be admissions that are over the weekends and holidays that may meet our criteria for 
inclusion. We would like to be able to identify Type 1 diabetic potential subjects that may be 
interested in participating, but were discharged prior to being able to discuss the study in person. We 
will contact the clinician that the patient is scheduled to see for follow up care and ask that they assist 
with referring the potential subject to contact us, or will allow us to speak to the subject at their next 
visit directly if the subject agrees when asked by their clinician.
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:
By signing this protocol application, 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.
6. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be 
obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.
The study will be described to the subject in detail, including the purpose and potential risks associated 
with the study. This will be explained by the physician, including the intervention and process for the 
study day. The subject will be required to read and sign the consent form approved by the HIC, and the 
patient will retain a copy of this consent to review. Additionally, the patient will sufficient time to ask 
questions during the screening and will be encouraged to contact investigators with further questions 
or concerns.
7. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.
Page 27 of 58
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.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
In this study, we are not using vulnerable subjects. Subjects will be asked open-ended questions in 
order to evaluate their understanding of the research protocol and the risks involved.
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.
N/A
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 ☒
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
☐Entire Study (Note that an information sheet may be required.)
Page 28 of 58
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.
If using a short form without a translated HIPAA Research Authorization Form, please request a 
HIPAA waiver in the section above.
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
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
☐Entire Study
For a waiver of consent, please address 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?
Confidentiality & Security of Data:
What protected health information (medical information along with the HIPAA identifiers) about subjects 
will be collected and used for the research?
Protected health information will include all blood work, urine pregnancy in women, medical history, 
physical examination, cognitive test and questionnaire results.
b. How will the research data be collected, recorded and stored?
Page 29 of 58
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
To comply with HIPAA standards, patient identification will be kept confidential. Subjects will be 
identified by code number, not by name during the data analysis. This data will be stored in computer files 
by code number, and their names will appear only on the initial form. Data that links the subject’s number 
to the subject will be kept in password protected documents and kept on a secured server. Any data that 
contains patient’s identifying information will be released only with written consent from the patient.
All subjects who enroll in studies conducted at the HRU, such as this study, will have a medical record 
created for them at YNHH. In addition, the researchers and HRU staff will have access to records of any 
prior admissions to YNHH, including the details of those admissions.
c. How will the digital data be stored?
CD
DVD
Flash Drive
Portable Hard
Drive 
server.
Secured Server
Laptop Computer
Desktop Computer
Other: ITS maintained secure
d. 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 documents will be password protected and held on a secured server which will only be available to 
the principle investigator and the co-investigators.
e.
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.
Individual’s names will appear only on the initial forms and these will be kept under on a secured server. 
All data files that could link a code number to an individual study subject will be password protected. 
Once the study is completed zeroing will be used to remove any identifiable subject information.
f. Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified data)
Principle investigators, co-investigators , and the Food and Drug Administration (FDA).
g. If appropriate, has a Certificate of Confidentiality been obtained?
N/A
Page 30 of 58
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
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
h. Are any of the study procedures likely to yield information subject to mandatory reporting 
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents of child 
abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported.
N/A
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.)
Study subjects will derive no direct medical benefits from the study. However, the potential benefits of 
this study to older T1DM population are substantial in that the knowledge gained from this work should 
provide important information concerning the effects of recurrent, antecedent hypoglycemia on CNS 
responses to hypoglycemia and the potential benefit provided by PLGS system.
1. Alternatives: What other alternatives are available to the study subjects outside of the research?
Standard insulin pump therapy.
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.
For completion of this entire study subjects will receive up to $800, as follows: 
Screening visit: $50
1st Questionnaire and PLGS training session: $100 
1st Hypoglycemic session: $250
2nd Questionnaire session: $50 
2nd Hypoglycemic session: $350
Payment will be issued in the form of a Bank of America pre-paid debit card using the Yale electronic 
payment service. The subject’s name, address, and telephone number will be shared with Bank of America 
for ePayments. After the first payment milestone (the screening visit) the subject will receive a card in the 
mail which he/she will need to activate over the phone. Completion of subsequent study visits will 
automatically add additional funds to the card. Participants may also be reimbursed for incidental expenses 
for parking.
3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.
Page 31 of 58
SECTION V: POTENTIAL BENEFITS
SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Subjects will not be responsible for any costs associated with the study or the screening portion prior to 
the study, including blood work, history and physical examination, or urine pregnancy test. We believe 
that given the length and number of procedures performed, the remuneration is fair and is not an excessive 
inducement for people to volunteer for 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?
b. Where and from whom may treatment be obtained?
c.
Are there any limits to the treatment being provided?
d. Who will pay for this treatment?
e.
How will the medical treatment be accessed by subjects?
If injury were to occur, we will provide any care or treatment required. Our study has no provision for 
additional compensation.
Page 32 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
References
1.
DCCT, The effect of intensive treatment of diabetes on the development and progression of long- 
term complications in insulin-dependent diabetes mellitus. The Diabetes Control and 
Complications Trial Research Group. N Engl J Med, 1993. 329(14): p. 977-86.
2.
UKPDS, Intensive blood-glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK 
Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 837-53.
3.
Ho, M.S., et al., Prevalence of structural central nervous system abnormalities in early-onset type 
1 diabetes mellitus. J Pediatr, 2008. 153(3): p. 385-90.
4.
DCCT, Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and 
Complications Trial Research Group. Diabetes, 1997. 46(2): p. 271-86.
5.
Flykanaka-Gantenbein, C., Hypoglycemia in childhood: long-term effects. Pediatr Endocrinol Rev, 
2004. 1 Suppl 3: p. 530-6.
6.
Kodl, C.T. and E.R. Seaquist, Cognitive dysfunction and diabetes mellitus. Endocr Rev, 2008.
29(4): p. 494-511.
7.
Cryer, P.E., Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM.
Diabetes, 1994. 43(11): p. 1378-89.
8.
Gerich, J.E., et al., Lack of glucagon response to hypoglycemia in diabetes: evidence for an 
intrinsic pancreatic alpha cell defect. Science, 1973. 182(108): p. 171-3.
9.
Dagogo-Jack, S.E., S. Craft, and P.E. Cryer, Hypoglycemia-associated autonomic failure in 
insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic 
responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest, 1993. 
91(3): p. 819-28.
10.
Amiel, S.A., et al., Defective glucose counterregulation after strict glycemic control of insulin- 
dependent diabetes mellitus. N Engl J Med, 1987. 316(22): p. 1376-83.
11.
Amiel, S.A., et al., Effect of intensive insulin therapy on glycemic thresholds for counterregulatory 
hormone release. Diabetes, 1988. 37(7): p. 901-7.
12.
Simonson, D.C., et al., Intensive insulin therapy reduces counterregulatory hormone responses to 
hypoglycemia in patients with type I diabetes. Ann Intern Med, 1985. 103(2): p. 184-90.
13.
Fanelli, C.G., et al., Meticulous prevention of hypoglycemia normalizes the glycemic thresholds 
and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during 
hypoglycemia in intensively treated patients with short-term IDDM. Diabetes, 1993. 42(11): p. 
1683-9.
14.
Cranston, I., et al., Restoration of hypoglycaemia awareness in patients with long-duration insulin- 
dependent diabetes. Lancet, 1994. 344(8918): p. 283-7.
15.
Little, S.A., et al., Recovery of Hypoglycemia Awareness in Long-Standing Type 1 Diabetes: A 
Multicenter 2 x 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple 
Daily Injections and Continuous With Conventional Glucose Self-Monitoring (HypoCOMPaSS). 
Diabetes Care, 2014.
16.
Gerich, J.E., et al., Hypoglycemia unawareness. Endocr Rev, 1991. 12(4): p. 356-71.
17.
Cryer, P.E., Hypoglycemia in type 1 diabetes mellitus. Endocrinol Metab Clin North Am, 2010.
39(3): p. 641-54.
18.
Seaquist, E.R., et al., Hypoglycemia and diabetes: a report of a workgroup of the american 
diabetes association and the endocrine society. Diabetes Care, 2013. 36(5): p. 1384-95.
Page 33 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
19.
Barnea-Goraly, N., et al., Alterations in White Matter Structure in Young Children With Type 1 
Diabetes. Diabetes Care, 2013.
20.
Mazaika, P.K., et al., Variations in Brain Volume and Growth in Young Children With Type 1 
Diabetes. Diabetes, 2016. 65(2): p. 476-85.
21.
Mauras, N., et al., Longitudinal assessment of neuroanatomical and cognitive differences in young 
children with type 1 diabetes: association with hyperglycemia. Diabetes, 2015. 64(5): p. 1770-9.
22.
Bree, A.J., et al., Diabetes increases brain damage caused by severe hypoglycemia. Am J Physiol 
Endocrinol Metab, 2009. 297(1): p. E194-201.
23.
Auer, R.N., Hypoglycemic brain damage. Metab Brain Dis, 2004. 19(3-4): p. 169-75.
24.
Reno, C.M., et al., Defective counterregulation and hypoglycemia unawareness in diabetes: 
mechanisms and emerging treatments. Endocrinol Metab Clin North Am, 2013. 42(1): p. 15-38.
25.
Page, K.A., et al., Medium Chain Fatty Acids Improve Cognitive Function in Intensively Treated 
Type 1 Diabetic Patients and Support in vitro Synaptic Transmission During Acute Hypoglycemia. 
Diabetes, 2009.
26.
Lee, J., J.H. Boo, and H. Ryu, The failure of mitochondria leads to neurodegeneration: Do 
mitochondria need a jump start? Adv Drug Deliv Rev, 2009. 61(14): p. 1316-23.
27.
Calabrese, V., et al., Oxidative stress, mitochondrial dysfunction and cellular stress response in 
Friedreich's ataxia. J Neurol Sci, 2005. 233(1-2): p. 145-62.
28.
Moreira, P.I., et al., Insulin protects against amyloid beta-peptide toxicity in brain mitochondria 
of diabetic rats. Neurobiol Dis, 2005. 18(3): p. 628-37.
29.
Baskaran, A., R. Milev, and R.S. McIntyre, A review of electroencephalographic changes in 
diabetes mellitus in relation to major depressive disorder. Neuropsychiatr Dis Treat, 2013. 9: p. 
143-50.
30.
Lyoo, I.K., et al., Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and 
relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus. Arch 
Gen Psychiatry, 2009. 66(8): p. 878-87.
31.
Massieu, L., et al., Acetoacetate protects hippocampal neurons against glutamate-mediated 
neuronal damage during glycolysis inhibition. Neuroscience, 2003. 120(2): p. 365-78.
32.
Haces, M.L., et al., Antioxidant capacity contributes to protection of ketone bodies against 
oxidative damage induced during hypoglycemic conditions. Exp Neurol, 2008. 211(1): p. 85-96.
33.
Lund, T.M., et al., Availability of neurotransmitter glutamate is diminished when beta- 
hydroxybutyrate replaces glucose in cultured neurons. J Neurochem, 2009. 110(1): p. 80-91.
34.
Henderson, S.T., et al., Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's 
disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond), 
2009. 6: p. 31.
35.
Herzog, R.I., et al., Lactate preserves neuronal metabolism and function following antecedent 
recurrent hypoglycemia. J Clin Invest, 2013. 123(5): p. 1988-98.
36.
Jiang, L., et al., Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.
Diabetes, 2009. 58(6): p. 1266-74.
37.
Rothman, D.L., et al., 13C MRS studies of neuroenergetics and neurotransmitter cycling in 
humans. NMR Biomed, 2011. 24(8): p. 943-57.
38.
de Graaf, R.A., D.L. Rothman, and K.L. Behar, State of the art direct 13C and indirect 1H-[13C] 
NMR spectroscopy in vivo. A practical guide. NMR Biomed, 2011. 24(8): p. 958-72.
39.
Mason, G.F. and D.L. Rothman, Basic principles of metabolic modeling of NMR (13)C isotopic 
turnover to determine rates of brain metabolism in vivo. Metab Eng, 2004. 6(1): p. 75-84.
Page 34 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
40.
Lebon, V., et al., Astroglial contribution to brain energy metabolism in humans revealed by 13C 
nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for 
neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. J 
Neurosci, 2002. 22(5): p. 1523-31.
41.
Cerdan, S., B. Kunnecke, and J. Seelig, Cerebral metabolism of [1,2-13C2]acetate as detected by 
in vivo and in vitro 13C NMR. J Biol Chem, 1990. 265(22): p. 12916-26.
42.
Melo, T.M., A. Nehlig, and U. Sonnewald, Metabolism is normal in astrocytes in chronically 
epileptic rats: a (13)C NMR study of neuronal-glial interactions in a model of temporal lobe 
epilepsy. J Cereb Blood Flow Metab, 2005. 25(10): p. 1254-64.
43.
Sibson, N.R., et al., In vivo (13)C NMR measurement of neurotransmitter glutamate cycling, 
anaplerosis and TCA cycle flux in rat brain during [2-13C]glucose infusion. J Neurochem, 2001. 
76(4): p. 975-89.
44.
Weinstock, R.S., et al., Risk Factors Associated With Severe Hypoglycemia in Older Adults With 
Type 1 Diabetes. Diabetes Care, 2015.
45.
Hasselbalch, S.G., et al., Brain metabolism during short-term starvation in humans. J Cereb Blood 
Flow Metab, 1994. 14(1): p. 125-31.
46.
Maran, A., et al., Protection by lactate of cerebral function during hypoglycaemia. Lancet, 1994.
343(8888): p. 16-20.
47.
Pan, J.W., et al., [2,4-13 C2 ]-beta-Hydroxybutyrate metabolism in human brain. J Cereb Blood 
Flow Metab, 2002. 22(7): p. 890-8.
48.
Mason, G.F., et al., Increased brain monocarboxylic Acid transport and utilization in type 1 
diabetes. Diabetes, 2006. 55(4): p. 929-34.
49.
Mason, G.F., et al., Measurements of the anaplerotic rate in the human cerebral cortex using 13C 
magnetic resonance spectroscopy and [1-13C] and [2-13C] glucose. J Neurochem, 2007. 100(1): 
p. 73-86.
50.
Cryer, P.E., Mechanisms of hypoglycemia-associated autonomic failure and its component 
syndromes in diabetes. Diabetes, 2005. 54(12): p. 3592-601.
51.
Chan, O., et al., Increased GABAergic tone in the ventromedial hypothalamus contributes to 
suppression of counterregulatory responses after antecedent hypoglycemia. Diabetes, 2008. 57(5): 
p. 1363-70.
52.
McNay, E.C. and R.S. Sherwin, Effect of recurrent hypoglycemia on spatial cognition and 
cognitive metabolism in normal and diabetic rats. Diabetes, 2004. 53(2): p. 418-25.
53.
De Feyter, H.M., et al., Increased brain lactate concentrations without increased lactate oxidation 
during hypoglycemia in type 1 diabetic individuals. Diabetes, 2013. 62(9): p. 3075-80.
54.
Borg, M.A., et al., Local lactate perfusion of the ventromedial hypothalamus suppresses 
hypoglycemic counterregulation. Diabetes, 2003. 52(3): p. 663-6.
55.
Moheet, A., et al., Initial experience with seven tesla magnetic resonance spectroscopy of 
hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans. 
Magn Reson Med, 2014. 71(1): p. 12-8.
56.
Gulanski, B.I., et al., Increased Brain Transport and Metabolism of Acetate in Hypoglycemia 
Unawareness. J Clin Endocrinol Metab, 2013.
57.
Hopkins, D., et al., Improved biomedical and psychological outcomes 1 year after structured 
education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience. 
Diabetes Care, 2012. 35(8): p. 1638-42.
58.
Cox, D., et al., A multicenter evaluation of blood glucose awareness training-II. Diabetes Care, 
1995. 18(4): p. 523-8.
Page 35 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
59.
Hermanns, N., et al., Long-term effect of an education program (HyPOS) on the incidence of severe 
hypoglycemia in patients with type 1 diabetes. Diabetes Care, 2010. 33(3): p. e36.
60.
Leelarathna, L., et al., Restoration of self-awareness of hypoglycemia in adults with long-standing 
type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS 
trial. Diabetes Care, 2013. 36(12): p. 4063-70.
61.
Little, S.A., et al., Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a 
multicenter 2 x 2 factorial randomized controlled trial comparing insulin pump with multiple daily 
injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes 
Care, 2014. 37(8): p. 2114-22.
62.
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study, G., et al., 
Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med, 2008. 
359(14): p. 1464-76.
63.
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study, G., et al., The 
effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care, 2009. 
32(8): p. 1378-83.
64.
Bergenstal, R.M., et al., Effectiveness of sensor-augmented insulin-pump therapy in type 1 
diabetes. N Engl J Med, 2010. 363(4): p. 311-20.
65.
Slover, R.H., et al., Effectiveness of sensor-augmented pump therapy in children and adolescents 
with type 1 diabetes in the STAR 3 study. Pediatr Diabetes, 2012. 13(1): p. 6-11.
66.
Effect of intensive diabetes treatment on the development and progression of long-term 
complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and 
Complications Trial. Diabetes Control and Complications Trial Research Group. J Pediatr, 1994. 
125(2): p. 177-88.
67.
Jones, T.W., et al., Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med, 
1998. 338(23): p. 1657-62.
68.
Porter, P.A., et al., Incidence and predictive criteria of nocturnal hypoglycemia in young children 
with insulin-dependent diabetes mellitus. J Pediatr, 1997. 130(3): p. 366-72.
69.
Buckingham, B., et al., Duration of nocturnal hypoglycemia before seizures. Diabetes Care, 2008.
31(11): p. 2110-2.
70.
Buckingham, B., et al., Response to nocturnal alarms using a real-time glucose sensor. Diabetes 
Technol Ther, 2005. 7(3): p. 440-7.
71.
Garg, S., et al., Reduction in duration of hypoglycemia by automatic suspension of insulin delivery: 
the in-clinic ASPIRE study. Diabetes Technol Ther, 2012. 14(3): p. 205-9.
72.
Bergenstal,
R.M.,
et
al.,
Threshold-based
insulin-pump
interruption
for
reduction
of 
hypoglycemia. N Engl J Med, 2013. 369(3): p. 224-32.
73.
Duckworth, W., et al., Glucose control and vascular complications in veterans with type 2 
diabetes. N Engl J Med, 2009. 360(2): p. 129-39.
74.
Brown, A.F., et al., Guidelines for improving the care of the older person with diabetes mellitus.
J Am Geriatr Soc, 2003. 51(5 Suppl Guidelines): p. S265-80.
75.
Cayea, D., C. Boyd, and S.C. Durso, Individualising therapy for older adults with diabetes 
mellitus. Drugs Aging, 2007. 24(10): p. 851-63.
76.
American Geriatrics Society Expert Panel on Care of Older Adults with Diabetes, M., et al., 
Guidelines abstracted from the American Geriatrics Society Guidelines for Improving the Care of 
Older Adults with Diabetes Mellitus: 2013 update. J Am Geriatr Soc, 2013. 61(11): p. 2020-6.
77.
Weinstock, R.S., et al., Risk Factors Associated With Severe Hypoglycemia in Older Adults With 
Type 1 Diabetes. Diabetes Care, 2016. 39(4): p. 603-10.
Page 36 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
78.
Ryan, E.A., et al., Assessment of the severity of hypoglycemia and glycemic lability in type 1 
diabetic subjects undergoing islet transplantation. Diabetes, 2004. 53(4): p. 955-62.
79.
Gold, A.E., K.M. MacLeod, and B.M. Frier, Frequency of severe hypoglycemia in patients with 
type I diabetes with impaired awareness of hypoglycemia. Diabetes Care, 1994. 17(7): p. 697-703.
80.
Clarke, W.L., et al., Reduced awareness of hypoglycemia in adults with IDDM. A prospective study 
of hypoglycemic frequency and associated symptoms. Diabetes Care, 1995. 18(4): p. 517-22.
81.
Nicholas, P.C., et al., 1H NMR-based metabolomic analysis of liver, serum, and brain following 
ethanol administration in rats. Chem Res Toxicol, 2008. 21(2): p. 408-20.
82.
Kerr, D., et al., Influence of acute alcohol ingestion on the hormonal responses to modest 
hypoglycaemia in patients with Type 1 diabetes. Diabet Med, 2007. 24(3): p. 312-6.
83.
Buckingham, B., et al., Prevention of nocturnal hypoglycemia using predictive alarm algorithms 
and insulin pump suspension. Diabetes Care, 2010. 33(5): p. 1013-7.
84.
Maahs, D.M., et al., A randomized trial of a home system to reduce nocturnal hypoglycemia in 
type 1 diabetes. Diabetes Care, 2014. 37(7): p. 1885-91.
85.
Buckingham, B.A., et al., Predictive Low-Glucose Insulin Suspension Reduces Duration of 
Nocturnal Hypoglycemia in Children Without Increasing Ketosis. Diabetes Care, 2015. 38(7): p. 
1197-204.
86.
Hintze, J., PASS 2011. 2011, Kaysville, UT: Number Cruncher Statistical Systems.
87.
Cary, N., SAS/STAT 14.1 User’s Guide. 2015: SAS Institute, Inc.
Page 37 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 1
TIMELINE and Blood Drawing Schedule for Hypoglycemic clamp study and recovery
Time
Real 
Time
Lab 
el
Gluco 
se
0.5cc 
q5 
min 
YSI
Insuli 
n
2cc 
LTT
Glucag 
on
2cc 
Spec. 
tube
Catecho 
l’s
3cc 
Spec. 
epi 
tube: 
RTT
Acetate 
Enrichm 
ent
3cc 
GTT
Lactat 
e,  
Keton 
es, 
Cortis 
ol, GH 
3cc 
LTT
Cells/ 
Plasm 
a
10cc 
Na 
Hepar 
in 
GTT
Meta
-
bolite 
s
3cc 
Citra 
te 
BTT
Blood 
volu 
me
ALL 
TUBE 
S ON 
ICE
Notes
A.1. 
Baseli 
ne
1.00
0
X
X
X
X
X
X
X
X
26
B.1. 
Start 
insulin
/   
start 
clock
2.00
0
Gluco 
se is 
checke 
d   
every 
5
minute 
s
X
X
X
X
10
Enter 
scanner
B.2. 
  
B.1
+30
2.01
5
X
X
X
X
X
X
13
B.3. 
  
B.1
+60
2.03
0
X
X
X
X
X
X
20
B.4. 
  
B.1
+90
2.04
5
X
X
X
X
X
10
C.1. 
   
Acetate 
baseline
Start 
Acetat 
e    
infusio 
n
3.00
0
Gluco 
se is 
checke 
d q5 
min
X
X
X
X
X
X
X
26
Target 
glucose
~55mg/dl
C.2. 
  
C.1 +5
3.01
5
↓
X
X
6
C.3. 
  
C.1
+10
3.03
0
↓
X
X
X
16
C.4. 
  
C.1
+15
3.04
5
↓
X
X
6
C.5. 
  
C.1
+30
3.06
0
↓
X
X
X
X
X
X
X
26
C.6. 
  
C.1
+60
3.07
5
↓
X
X
X
X
X
X
16
C.7. 
  
C.1
+90
3.09
0
↓
X
X
X
X
X
X
X
26
C.8. 
  
C.1
+120
3.10
5
Gluco 
se 
check
X
X
X
X
X
X
X
26
End clamp
TOTAL VOLUME
18 cc
227cc
∑250cc
Page 38 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 2 
Schedule of Events
Screening 
Visit
Cognitive 
assessment 1
MRS scan 1
Cognitive 
assessment 2
MRS scan 2
Informed Consent
X
Medical History
X
Physical Exam
X
EKG
X
Hematocrit (3 mLs)
X (3mLs)
Creatinine (2 mLs)
X (2mLs)
Liver Function Tests (3mLs)
X (3mLs)
HbA1c (3mLs)
X (3mLs)
Inclusion/Exclusion Check list
X
Record Blood Sugar Levels 5x 
daily *
X
CGM reading
X
X
Schedule two MR sessions
X
Urine Pregnancy (females)
X
X
IV Placement
X
X
Hypoglycemic Clamp
X
X
Cognitive battery (screening)
X
Cognitive battery (test)
X
X
MRS scan
X
X
Hypoglycemia questionnaires
X
X
X
X
X
Satisfaction questionnaires
X
X
Blood Volume per visit
11 ml
none
< 250ml
none
< 250ml
Page 39 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 3
Page 40 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 41 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 42 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 43 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 4 - Hypoglycemia symptom questionnaires
Hypoglycemic symptoms during the hypoglycemic clamp
Please rank your experience of the following SYMPTOMS on a scale from 1 to 7 where “1” means that 
you do not experience the symptom at all, while “7” means that you experience the symptom a great 
deal. Please place an “X” in ONLY ONE of the 7 boxes for each symptom.
SYMPTOM 
INTENSITY
Not at all
→
→
Moderate
→
→
A great 
deal
Inability to 
Concentrate
1
2
3
4
5
6
7
Blurry 
Vision
1
2
3
4
5
6
7
Anxiety
1
2
3
4
5
6
7
Confusion
1
2
3
4
5
6
7
Difficulty 
Speaking
1
2
3
4
5
6
7
Double 
Vision
1
2
3
4
5
6
7
Drowsiness
1
2
3
4
5
6
7
Tiredness
1
2
3
4
5
6
7
Hunger
1
2
3
4
5
6
7
Weakness
1
2
3
4
5
6
7
Sweating
1
2
3
4
5
6
7
Trembling
1
2
3
4
5
6
7
Warmness
1
2
3
4
5
6
7
Heart 
Racing
1
2
3
4
5
6
7
Page 44 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 5 - Hypoglycemia questionnaires
Page 45 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 46 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 47 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 48 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 49 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 50 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 51 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 52 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 53 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 54 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Page 55 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 6 – Phone script for recruitment
HIC #2000020059
Phone script for recruitment for Counterregulatory failure and hypoglycemia unawareness in 
intensively treated older adult type 1 diabetic patients.
This is XXX calling from the Yale Diabetes Center about a research study opportunity. I was looking at 
your pre-screen questionnaire through the Yale Center for Clinical Investigation database you had agreed 
to participate in. I would like to tell you about our current research to see if you might be interested in 
participating.
This research study is designed to demonstrate that a new closed loop insulin pump system can prevent 
low glucose episodes and enhance brain function in older patients with type 1 diabetes mellitus. We are 
looking for participants with Type1 Diabetes Mellitus, or T1DM, and who are over the age of 50, who 
have a history of frequent and/or severe episodes of low glucose values. Based on your pre-screen/screen 
information, you may be eligible.
Here is a little bit of a background information: As of right now, the best current treatment for T1DM is a 
sensor-augmented insulin pump therapy (so called “predictive low glucose suspend”; PLGS), which 
consists of an insulin pump that can “talk” with a continuous glucose monitor and can stop insulin injection 
in the presence of low glucose values. This feature limits duration and extent of hypoglycemic episodes 
that can frequently occur with traditional systems of insulin delivery.
In this study we will focus on the potential benefits of 2 FDA approved PLGS systems (Medtronic 
Minimed 670G and Tandem t:slim X2). These systems have been shown to effectively prevent 
hypoglycemia in the general patient population. Our hypothesis is that it would be safe and effective in 
reducing low glucose episodes specifically in older diabetic people.
To demonstrate this hypothesis, we will compare two groups of T1DM subjects for 8-10 weeks. As needed 
in this kind of scientific investigations, you will have the same probability to be assigned in one group or 
another and this decision will be independent from your or our determination. The intervention group 
consists of treatment with a PLGS-enabled insulin pump/CGM combination (Medtronic MiniMed 670G 
pump with Guardian sensor, or Tandem t:slim X2 pump with Dexcom sensor) in auto mode for Medtronic 
users and with Basal-IQ for Tandem users; subjects in the control group will use the same PLGS-enabled 
insulin pump/CGM combination but in manual mode for Medtronic users or without Basal-IQ for Tandem 
users. For subjects who use multiple daily injections as part of their standard insulin therapy or for subjects 
who do not use the MiniMed 670G pump or t:slim X2 pump, a loaner MiniMed 670G system will be 
provided.
To become a volunteer in this study, we’ll first have to schedule a 1-hour screening visit at the Yale New 
Haven Hospital Research unit. As part of this visit, we’ll go over the consent form with more details about
Page 56 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
the study; you will have a blood draw, an EKG, a brief physical and a short cognitive test for our baseline 
information. If you qualify for the study, we’ll be able to schedule your trial days at that point.
The trial itself consists of several sessions, of which two are 2 “questionnaire sessions”, each 8 weeks 
apart, where you will be asked to complete a battery of tests to measure your cognitive abilities, quality 
of life and satisfaction of current insulin therapy. These take 2.5 hours each. Then there are 2 
“hypoglycemic sessions” in an MRI machine, each 8-10 weeks apart and 2 days immediately after the 2 
questionnaire sessions. There will be 7 brief weekly visits in between, either by phone or in person if 
needed, to check your glucose values and to ascertain that everything is going well.
The hypoglycemic sessions will take place in the early morning and you’ll be asked to arrive fasting. The 
visit will last no longer than 4 hours and the time in the MRI scanner will be no longer than 130min. At 
the end of first of the 2 sessions you may be asked to continue your standard insulin pump therapy or to 
receive the new AC/AP pump for 8-10 weeks. You will be discharged home during the early afternoon.
For completion of this entire study you may receive up to $800. If you complete the screening visit, you 
will receive $50 as a reimbursement for your time and possible parking fee.
Do you have any questions at this point? I would be happy to go ahead and look at possible days for you 
to come in for the screening.
Thank you, I’ll send you a confirmation along with this information to your Email.
Page 57 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022

APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022
Appendix 7 – MyChart message
You are receiving this MyChart message because you were diagnosed with Type 1 Diabetes and you have 
a history of frequent and/or severe episodes of low glucose values. You may be eligible to participate in a 
Type 1 Diabetes research study conducted by Yale University investigators to demonstrate that new 
insulin pump systems (so called “closed loop” or “artificial pancreas” systems) can prevent low glucose 
episodes and enhance brain function.
Study Information:
HIC Study #: 2000020059
Title: Restoring brain metabolism and function in older adult T1DM patients using an artificial pancreas 
system.
PI: Raimund Herzog, MD
What the study involves:
Study participants will be asked to:

Have a brief screening visit to obtain detailed health information.

Wear a PLGS system for 8-10 weeks

Wear a continuous glucose monitor and have brief weekly visits for 12 weeks to assess glucose 
control and number of low glucose episodes

Have two visits in which a battery of tests and questionnaires will be completed to measure brain 
abilities (such as attention and memory), quality of life and satisfaction of current insulin therapy 
(8-10 weeks apart).

Have two visits in which blood samples and brain images will be taken during a controlled 
hypoglycemic event (8-10 weeks apart)
The study pays up to $800 as applicable as compensation for your participation.
This message is automatically generated by the electronic medical record system Epic and no one on the 
research team has been notified, nor has your name or personal information been shared with any 
investigator. To opt-out of research, including opting out of receiving future messages about research 
studies, please email optout@yale.edu or call 1-877-978-8348 and select option #3.
If you are interested in learning more about this study, please call us at (203)-737-4777 to speak to a 
study coordinator. You can also contact us by email at diabetes.research@yale.edu.
Future research opportunities:
You may also create a volunteer profile through the Research Tab in MyChart.
Page 58 of 58
APPROVED BY THE YALE UNIVERSITY IRB 7/25/2022