Conditions: Diabetes Mellitus, Type 2 Glucose, High Blood Glucose Metabolism Disorders (Including Diabetes Mellitus)
Keywords: diabetes type 2 diabetes insulin resistance diazoxide MRI
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 37
Healthy volunteers: yes

Brief summary:
The goal of this study is to determine whether metabolic control centers in the brain can be activated in patients with type 2 diabetes (T2D) as compared to non-diabetic individuals. This is important since people with diabetes have inappropriately high production of glucose, which could be at least in part due to impaired activation of important brain centers.

Detailed description:
In this study investigators will use functional magnetic resonance imaging (fMRI), a safe, noninvasive method of measuring brain activity by imaging the blood flow to different parts of the brain, to assess the impact of the medication diazoxide on both diabetic and non-diabetic patients. fMRI is a technique for measuring and mapping brain activity. This technique relies on the fact that cerebral blood flow (CBF) and neuronal activity are coupled.

Previous rodent and human studies have demonstrated that diazoxide activates potassium (KATP) channels that are sensitive to ATP in the hypothalamus, inhibiting hepatic glucose production. However, these inhibitory effects of diazoxide on hepatic glucose production are curiously absent in diabetic patients, which suggests that they may have impaired activation of KATP channels and thus lowered brain activity in this area of the brain.

After screening and meeting eligibility criteria, participants will have 2 day-long study visits (one day in which the brain will be imaged before and after receiving diazoxide, and one day in which the brain will be imaged before and after placebo). Each study day will include up to 3 MRI scans per study visit and hourly blood draws.

Arms:
arm 1: Proglycem, oral suspension (4-7 mg/kg). Healthy participants will receive diazoxide between MRI scans. arm 2: Taste-matched placebo. Healthy participants will receive placebo between MRI scans. arm 3: Proglycem, oral suspension (4-7 mg/kg). Type 2 diabetic (T2D) participants will receive diazoxide between MRI scans. arm 4: Taste-matched placebo. T2D participants will receive placebo between MRI scans.

Interventions: intervention 1: Diazoxide intervention 2: Placebo
Intervention descriptions: intervention 1: Healthy and T2D participants will receive diazoxide at a dose of 4-7 mg/kg (based upon weight) between baseline MRI scan and second MRI scan. intervention 2: Healthy and T2D participants will receive placebo between baseline MRI scan and second MRI scan.

Protocol document:
Prot_SAP_000.pdf: 
Use of Functional MRI to Assess Hypothalamic Activation in 
Response to Diazoxide
IRB No: 2018-9040
NCT03566511
IRB Approval Date: 06/02/2021


Meredith A. Hawkins, MD, MS
1
#2018-9040
Use of Functional MRI to assess hypothalamic activation in response to diazoxide
OVERVIEW:
KATP channels are potassium channels sensitive to ATP/ADP ratio with their activation resulting 
in cell hyperpolarization. KATP channels have been identified on a subgroup of hypothalamic 
neurons (1) where they play a part in mediating responses of the brain to nutritional signals, while 
on pancreatic beta cells they have a critical role in regulation of insulin secretion (2).
Previous studies from our and other groups have demonstrated that central KATP channel 
activation with diazoxide inhibited hepatic glucose production in healthy control rodents and 
humans (3, 4).  Intriguingly, our subsequent studies in a diabetic rat model and in humans with 
type 2 diabetes (T2D) failed to show these inhibitory effects of diazoxide on glucose production 
(5). In vivo studies in rodents have shown that activation of mitochondrial KATP channels in 
cerebral arteries by diazoxide is reduced in diabetes (6), and hypothalamic neurons from obese 
rats demonstrated defective activation of KATP channels in response to insulin (7). Until now, no 
measure has been developed for assessment of direct pharmacologic activation of KATP channels 
within the hypothalamus and other brain areas (eg. thalamus and/or striatum) in vivo in humans, 
and specifically to examine the difference between diabetic vs. healthy individuals in their ability 
to respond to diazoxide.
Functional magnetic resonance imaging (fMRI) is a technique for measuring and mapping brain 
activity that is noninvasive and safe. This technique relies on the fact that cerebral blood flow and 
neuronal activity are coupled. To assess the effect of diazoxide on activation of hypothalamus 
and other brain areas in healthy control and T2D patients, fMRI will be performed at baseline and 
at two hour intervals following administration of diazoxide vs. placebo.  Since diazoxide can inhibit 
insulin secretion and potentially increase blood glucose levels, these will be measured at hourly 
intervals.
SPECIFIC AIMS:
Aim  1:  To  determine  whether  healthy  individuals  exhibit  an activation  of  KATP channels 
in the hypothalamus and other brain areas in response  to  diazoxide, that can be observed 
by functional magnetic resonance imaging (fMRI). Based on our previous studies, we 
hypothesize that diazoxide will activate KATP channels in healthy participants. Given the 
connection between KATP channel activation and neuronal hyperpolarization, as well as the 
connection between neuronal activity and cerebral blood flow, we predict that KATP channel 
activation will be associated with altered activity of hypothalamus and other brain areas recorded 
by fMRI.
Aim 2: To determine whether hypothalamic responses to diazoxide observed by fMRI are 
diminished in patients with type 2 diabetes (T2D).  We hypothesize that patients with T2D will 
not respond to diazoxide due to defective activation of KATP channels resulting from the metabolic 
defects of chronic diabetes, and that this will be demonstrated by a lack of effect on the activity of 
hypothalamus and other brain areas recorded by fMRI.
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
2
BACKGROUND:
One of the hallmark features of type 2 diabetes (T2D) is impaired regulation of endogenous 
glucose production (EGP) (8). While EGP is inhibited by both glucose and insulin in non-diabetic 
animals and humans, T2DM is associated with increased EGP despite elevated plasma glucose 
and insulin concentrations (9). In fact, we and others have reported direct inhibitory effects of 
hyperglycemia itself on EGP in nondiabetic subjects, independent of other hormonal or metabolic 
signals, which are markedly blunted in subjects with T2DM (10).
Animal studies indicate that the brain integrates systemic nutritional signals, such as insulin and 
glucose, and modulates EGP via vagal efferents as part of an integrated regulatory network for 
metabolic function. KATP channels (potassium channels sensitive to intracellular ATP/ADP ratio) 
have been identified on a subgroup of hypothalamic neurons (1) where they play a part in 
mediating responses of the brain to nutritional signals, while KATP channels found on pancreatic 
beta cells have a critical role in regulation of insulin secretion (2). Activation of hypothalamic KATP 
channels results in neuronal hyperpolarization and appears to be an important common 
mechanism whereby both systemic glucose and insulin suppress EGP. Indeed, activation of these 
channels may account for almost 50% of EGP suppression by both agents. Furthermore, central 
administration of diazoxide has been shown to inhibit EGP in rodents via direct pharmacologic 
activation of KATP channels in the hypothalamus, while the KATP channel inhibitor glyburide blocks 
the activation of these channels (1). We have previously shown that activation of extrapancreatic 
KATP channels by orally administered diazoxide under conditions of “pancreatic clamp” in non-
diabetic animals and humans inhibits EGP (3). However, this inhibitory effect of diazoxide on EFP 
was absent in humans and rodents with diabetes (5). Intriguingly, hypothalamic neurons from 
obese rats demonstrated defective activation of KATP channels with insulin (7). 
Studies with nasally administered insulin in non-diabetic humans have identified the insulin-
induced decrease in hypothalamic blood flow as a readout for hypothalamic insulin action, which 
correlated with the increase in glucose infusion rate from before to after the insulin nasal spray 
administration (11). Until now, no measure has been developed to assess activation of KATP 
channels within the hypothalamus in vivo in humans, and more specifically to examine the 
difference between diabetic vs. healthy individuals. To assess the effect of diazoxide on 
hypothalamic activation in healthy control and T2D patients, fMRI will be performed at baseline 
and following administration of diazoxide vs. placebo. Therefore, the current proposal will address 
the mechanism of central action of diazoxide by elucidating the areas of the brain affected by 
diazoxide in healthy subjects and those with T2D, with the use of fMRI.
SIGNIFICANCE:
Increased EGP is the major cause of postabsorptive hyperglycemia in T2D which persists despite 
the presence of hyperglycemia and hyperinsulinemia. Up to one half of regulation of EGP by 
hyperglycemia is centrally mediated; hypothalamic KATP channels appear to have a key role in 
integration of central regulation of EGP by nutrients. While direct pharmacologic activation of 
central KATP channels in non-diabetic humans and animals results in significant reduction of EGP, 
this effect is lost in T2D. Therefore, it is highly plausible that there is an impairment of central 
regulation of EGP in individuals with T2D. Furthermore, it is possible that the defect of central 
regulation of EGP in these individuals is at the level of hypothalamic KATP channels. We are 
proposing to address this important question by using fMRI: a state-of-the art, non-invasive and 
safe technique to evaluate neuronal activity in response to KATP channel agonists in healthy 
individuals and compare them to patients with T2D.
EXPERIMENTAL APPROACH AND METHODS:
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
3
Subject Characteristics:
We will perform a small, non-randomized pilot study in order to optimize fMRI conditions 
including anatomical localization and software algorithms. The pilot phase of the study will 
consist of up to 10 individuals (both diabetic and non-diabetic). Once conditions have been 
optimized, we will progress to the main study and begin randomization. Pilot phase participants 
may be eligible to subsequently participate in the main study. 
The study population for the main phase of the study will consist of 15 normal, healthy, non-
diabetic individuals and 15 individuals with moderately uncontrolled T2D (please see below for 
full inclusion and exclusion criteria). 
Screening Procedures:
All subjects will be screened for eligibility prior to enrollment into the study. The purpose, nature, 
risks and benefits of the study will be explained to all subjects in the Clinical Research Center 
(CRC) prior to their enrollment in the study, and their voluntary, informed, written consent will be 
obtained. Screenings will be conducted in the GCRC suite at Albert Einstein College of Medicine. 
The screening visit will allow for the clinical evaluation of the subjects, including history, physical 
examination, blood and urine analyses, baseline EKG, and consent procedures. A blood draw 
(~35 cc/7 tsp) and urine collection will be performed and the following labs will be sent to 
accessioning for all participants: CBC, LFT, lipid profile, basic metabolic panel, HbA1c, insulin, 
PT/PTT, urinalysis, and urine drug screen. Additionally, urine microalbumin and urine creatinine 
will be measured for participants with T2D, and urine pregnancy test will be measured for all for 
women of childbearing age. If recent documentation of these lab tests is available from the 
participant’s primary care or other physician, the study doctor may decide to use these 
results, depending on when the previous labs were done in place of those listed above, 
and if participant consents to providing a copy of these for their study file.  The subject will 
be notified by phone or in writing of his/her eligibility status after his/her chart has undergone 
review by P.I. or fellow.
Randomization: For the pilot phase of this study, participants will not be randomized, and will 
receive either diazoxide or placebo as described in the study procedures below.
For the main study, participants will be randomized to receive placebo or diazoxide in a random 
order. Each subject will receive the experimental agents in random order as determined by study 
coordinator (using the envelope method). The subject will be blinded as to which agent he/she is 
receiving. 
Drug Storage: All medications received from both Weiler Pharmacy and from external 
pharmacies will be logged. Each study protocol will have its own drug binder with the medication 
log. Lot number, expiry date, and date of usage will be documented for all medications and 
additionally, date received and location of storage will be documented for medication obtained 
outside of Weiler pharmacy.
STUDY PROCEDURES:
We will perform a small, non-randomized pilot study in order to optimize fMRI conditions 
including anatomical localization and software algorithms. The pilot phase of the study will 
consist of up to 10 individuals (both diabetic and non-diabetic). Once conditions have been 
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
4
optimized, we will progress to the main study and begin randomization. Pilot phase participants 
may be eligible to subsequently participate in the main study. 
Study Visit 1
All subjects will be asked to refrain from strenuous exercise and to fast starting at 10PM (no food 
or drinks except for water) on the day prior to the study.
Subjects with type 2 diabetes will be admitted to Jack D. Weiler Hospital the evening before the 
study to acutely normalize plasma glucose levels using variable low dose insulin infusion with a 
target plasma glucose level of 100 – 120 mg/dL beginning at approximately 1AM. A physician will 
admit the patient, document the subject’s History and Physical, and place the appropriate orders 
into Epic. An inpatient nurse, familiar with our research studies will take care of the patient 
overnight, and will be provided with a detailed written protocol for overnight insulin infusion and 
contact numbers of the fellow and the P.I., in addition to verbal instructions and clarifications by 
the fellow (See Appendix 1: diazoxide nursing protocol). An IV catheter (18 – 20 gauge) line will 
be placed in one arm of the subject for infusion of insulin. Another catheter may be placed in the 
other arm for blood sampling. Subjects’ blood glucose will be checked every hour throughout the 
night, either by drawing blood from an IV catheter or by the finger stick method. The expected 
volume of blood drawn from these tests will not exceed approximately 10 cc. In order to prevent 
hypokalemia due to insulin infusion, all subjects receiving insulin will receive an oral dose of 
potassium chloride (20mEq powder packets dissolved in water) at the time of the initiation of 
insulin infusion. Most subjects will receive up to 40mEq potassium chloride, not to exceed 80mEq 
in one day. The infusion will be stopped prior to the first MRI scan. 
T2D subjects will be asked to withhold their oral diabetes medication for 2-8 days prior to the 
study visit (8 days for patients on pioglitazone and 2 days for all other diabetes medications) in 
order to wash out any medications that could affect study results. In the subjects who use insulin, 
long acting insulin will be discontinued 24 hours prior to the anticipated start of insulin infusion 
and intermediate/short acting insulin will be discontinued 12 hours prior to the anticipated start of 
insulin infusion. The subjects will be instructed to monitor their blood glucose four times daily in 
this period and to inform the study doctor of any significant episodes of hyperglycemia (blood 
glucose >300 mg/dl). Any incidents of hyperglycemia (>300 mg/dL) will be evaluated on a case-
by-case basis by the P.I., who is an Endocrinologist. The assessment will therefore include a 
careful history of food intake and activity, timing of blood glucose readings, and symptoms of 
hyperglycemia. Please note that most patients will be on metformin and/or insulin and hence the 
entire period of washout will be no more than 2 days, and therefore marked elevations in blood 
glucose are unlikely to occur. In the unusual case of severe hyperglycemia, the subject will be 
advised to immediately resume their usual medications and the study will be rescheduled 
accordingly. 
Justification for medication washout: This short-term medication withdrawal is considered 
standard procedure in the literature and in our studies since 1996, and is carefully explained to 
all subjects prior to their participation. This is documented in our previous publications. Please 
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IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
5
see:  Hawkins et al, Diabetes 2002; 51:2179-89, in which scientific justification is provided for the 
following: sulfonylureas and metformin discontinued 48 h before the study, thiazolidinediones 
(which have longer acting metabolites and prolonged adipose effects) withheld for 8 days, and 
long-acting insulin was withheld the evening before the study. Specifically, the “wash-out periods” 
for each medication reflect the amount of time required for drug effects to abate (so that their 
presence will not affect study results), while avoiding an undue increase in glucose due to a 
prolonged period off medication. Therefore, this is not considered to put subjects at risk for 
hyperglycemia significantly above a subject’s usual blood glucose range.
Healthy non-diabetic subjects will not require an overnight admission. 
All subjects will be drug-tested on arrival to the CRC utilizing an instant result drug panel (Alere 
iCup Dx14). If the test is positive, the subject will be withdrawn from the study and will receive 
$50 for his/her time (see below under Compensation).
On the day of the experiment, all subjects will be requested to report to the GCRC Study Room 
at 0800h, after an overnight fast of 10 hours. An 18- or 20- gauge intravenous catheter will be 
inserted in the subject’s arm for hourly blood sampling. 
fMRI studies will be conducted in the 3T human MRI scanner in the Gruss Magnetic Resonance 
Research Center (MRRC) of the Albert Einstein College of Medicine. When placed in the scanner, 
the subjects will lay supine on the scanner bed, and position within the head coil and advance 
into the magnetic resonance (MR) scanner until their head is aligned with the magnet isocenter. 
Each subject will undergo up to three fMRI sessions over the course of the study day. The first 
fMRI session will be performed to establish a baseline measurement, while the following two will 
be performed after administration of either diazoxide or placebo. The number of scans the subject 
receives will be determined by initial pilot data. The subject will be informed about the number of 
scans they will receive at the time of scheduling the study. The fMRI sessions will be spaced 
approximately 2 hours apart and each will last approximately 30 minutes. The subjects will rest in 
the CRC Study Room between the fMRI sessions. We will be monitoring blood glucose hourly 
between fMRI scans. If blood glucose exceeds 200 mg/dL, we will resume intravenous insulin 
infusion using the same insulin infusion protocol during the 2-hr breaks between scans. In the 
event that the subject’s blood glucose level exceeds 300 mg/dL, we will resume insulin infusion 
and stop the study. The subject will subsequently be monitored until blood glucose reaches the 
patient’s baseline and discharged after with the advice to resume home diabetes medication(s).   
During the approximately 30 min baseline period, the MR system calibrations, adjustments, and 
anatomical MRI will be performed as per standard procedures (12). While in the MRI, pseudo-
continuous arterial spin labeling (pCASL) fMRI whole brain images will be acquired to localize 
brain activation. 
After the baseline MRI session has been completed, an oral dose of diazoxide (Proglycem, oral 
suspension, at a dose of 4-7 mg/kg, as explained below, using a syringe for precise measurement 
of dose) or matched placebo will be administered according to the random assignment. In the 
pilot phase of our study, participants will receive either diazoxide or placebo, but will not be 
randomized. In the main phase of the study, the participant will have an equal chance of being 
assigned to diazoxide or placebo first, and he/she will not be informed as to which medication 
he/she is receiving first. Since diazoxide can inhibit insulin secretion and potentially increase 
glucose concentration, hourly blood samples will be collected through the previously placed IV 
catheter for determinations of blood glucose, insulin, C-peptide, and glucagon. The expected total 
volume of blood drawn for these tests will not exceed approximately 50 cc. Additionally, as 
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IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
6
diazoxide has vasodilatory properties, vital signs (blood pressure and heart rate) will be measured 
at baseline and then hourly. Of note, in our previous studies we did not note any changes in heart 
rate, blood pressure or C-peptide levels with diazoxide administration, and therefore do not expect 
these to change in the current studies. Additionally, the 6 mg/kg dose of diazoxide was safe and 
well tolerated in our previous studies and we therefore anticipate using this dose in most of the 
subjects. There is also published data on using diazoxide to restore counterregulation to 
hypoglycemia that reported safe use of a dose of 7 mg/kg dose (13). We will plan to start with a 
lower dose and increase as needed to up to 7 mg/kg, if we don’t observe the expected response. 
We will consider using a lower dose (from 4 mg/kg) on a case by case basis, e.g. in subjects with 
low-normal baseline blood pressure. In the event of symptomatic or significant hypotension and/or 
tachycardia, the study will be stopped immediately and the subject will be asked to remain supine 
and will be given an IV saline infusion until his/her baseline blood pressure has been attained and 
he/she is asymptomatic.
Once the final session of fMRI has been completed, the subject will return to the Study Room, 
where he/she will receive a meal and final blood draw, if needed. Vital sign measurements and 
evaluation by research fellow will be done prior to being deemed safe to be discharged home. For 
participants consenting to take part in the pilot phase of this study, this will be the only visit. 
Study Visit 2
There will only be one study visit for participants in the pilot phase of this study. For participants 
in the main part of the study, study visit 2 will take place after the first study visit, at least 2 weeks 
apart. The study will be identical to Study visit 1, with the exception that the subject will receive 
the other study drug. 
Analytical Procedures:
Plasma hormone determinations: Measurements of plasma insulin, C-peptide, and glucagon 
will be performed by the ICTR Biomarker Analytic Research Core Lab (BARC) by human specific 
RIA and ELISA. Measurement of blood glucose during the study will be performed using an 
Analox glucose analyzer in the study room. Measurement of blood glucose during the overnight 
admission for insulin infusion in subject with T2D will be performed using a Precision Xceed Pro 
glucometer. 
fMRI Acquisition Method:
Pseudo-Continuous Arterial Spin Labeling (pCASL) provides high performance brain perfusion 
imaging at 3.0 Tesla without using contrast agents. Arterial Spin Labeling (ASL; a subtraction 
technique) is used to generate measures of CBF, an indicator of neuronal activity. In these studies 
we will employ optimal measurement conditions, including a 3 Tesla magnet and a 32 channel 
receive only coil, with improved acquisition methodologies that provide for improved measurement 
of CBF in regions of increased susceptibility, such as the hypothalamus (14).  
Arterial water is ‘labeled’ in the neck using radio frequency signals, after which the labeled water 
travels to the brain and exchanges with unlabeled water, producing an MRI signal change which 
can calculate perfusion using modified indicator dilution mathematics (15). During a baseline 
period, the MR system calibrations, adjustments, and anatomical MRI will be performed as per 
standard procedures. Optimized conditions will include a 32 channel receive only coil, with 
improved acquisition methodologies that incorporate multi-coil-sensitivity acceleration, a true 3-
dimensional (3D) acquisition method based on hybrid gradient and spin echo based method. This 
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Meredith A. Hawkins, MD, MS
7
reduces energy deposition while minimizing T2* based susceptibility artifacts.  Background (static) 
tissue suppression is used to reduce motion artifacts. Collectively, this permits the acquisition of 
higher signal-to-noise ratios in shorter time frames.  It further provides for improved measurement 
of CBF in regions of increased susceptibility, such as the hypothalamus. Blood flow will be 
calculated using the previously published formula (16).  All images and blood flow are processed 
using software written in MATLAB. Calculated CBF image maps are registered to anatomical 3D 
data and motion correction using FSL software.
STATISTICAL ANALYSES:  
Data collected from each subject will be edited, verified and entered into an Excel data sheet on 
a password protected computer in the study room.  Data quality checking will be performed by 
computer programs designed to detect errors using accepted ranges, logic checks, and missing 
values. Outliers will be checked against the original record and correct values will be entered into 
a final data file. Data from Excel files will be transferred into SPSS for statistical analysis. 
•
The parameter of interest will be CBF in hypothalamus (if visible) or thalamus
•
Non-paired t-test will be used to compare CBF between group without diabetes and group 
with T2D
•
Repeated measures ANOVA (if 3 scans performed) or Paired t-tests (if 2 scans) will be 
used to compare CBF in the same subjects under two different experimental conditions (diazoxide 
vs. placebo) in group without diabetes and group with T2D in Aims 1 and 2. 
POWER ANALYSIS:
This pilot study will generate preliminary data to perform a power calculation to define optimal 
group numbers. The power analysis will be based on an unpaired t-test (CBF response to 
diazoxide in non-diabetic vs. T2D subjects), using NCSS/Pass 2008 software (Number 
Cruncher Statistical Systems, Kaysville, Utah) with a two-tailed  of 0.05. In collaboration with 
our collaborating statistician, Dr. Kenny Ye, we will calculate the minimal sample size needed to 
achieve at least 80% power to detect a statistically significant difference in the effect of 
diazoxide on CBF. In the interest of feasibility, we plan to enroll 15 non-diabetic subjects and 15 
type 2 diabetic subjects. It is expected that we may have up to 33% attrition, and will only be 
able to analyze data from subjects who have completed both studies.
HUMAN SUBJECTS:
1) Subject Population:
All subjects will be screened in the Clinical Research Center (CRC) prior to enrollment in 
observance of the following inclusion and exclusion criteria:
Non-diabetic subjects (ND):
Inclusion Criteria:
•
Age: Between 21 and 70 y.o.
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 06/02/2021


Meredith A. Hawkins, MD, MS
8

BMI: <30

negative family history of diabetes among first-degree relatives

generally healthy (see below for exclusions)
Subjects with T2D: 
Inclusion Criteria:

Age: Between 21 and 70 y.o.

BMI: <35

A1c 8.0-12.0%

generally healthy (see below for exclusions)

Not suffering from proliferative retinopathy, significant diabetic renal disease 
(urinarymicroalbumin <100 μg/dl) or severe neuropathy (including cardiovascular and 
gastrointestinal autonomic neuropathy per history.
Patients will be excluded if they have one or more of the following characteristics:

Age: Under 21 or over 70 y.o.

BMI: >35 for T2D and >30 for ND 

If BP > 150/90 or <90/60 on more than one occasion

Severe polydipsia and polyuria (in subjects with T2D) Since polydipsia and polyuria are 
common symptoms of T2D, the distinction “severe” denotes that the subject indicates a worsening 
in the symptoms and/or an experience of discomfort related to the symptoms

Urine microalbumin: >300 mg/g of creatinine (in subjects with T2D)

Uncontrolled hyperlipidemia defined as TG > 400 mg/dl and/or Total Cholesterol >300 
mg/dl

Clinically significant liver dysfunction: to include including thrombocytopenia (platelets 
<100,000), anemia (as below), hypoalbuminemia (<3.5), coagulopathy (INR > 1.5), and/or liver 
enzymes more than 3 times the upper limit of normal 

Clinically significant kidney dysfunction, GFR: <60 mg/dL 

Anemia: HgB <12.5 for men and <11.0 for women 

Clinically significant leukocytosis or leukopenia 

Clinically significant thrombocytopenia or thrombocytosis 

Coagulopathy 

Urine drug screen positive for any of the following: amphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, oxycodone, PCP. Amphetamines, oxycodone, 
opiates, methadone, and benzodiazepines have been shown to affect glucose metabolism 
(increased glycemia, increased resting insulin levels, delayed insulin response to food ingestion, 
insulin deficiency) (17, 18, 19). As the drug test available in the CRC is a 7-drug panel, we cannot 
specifically choose which drugs are screened for. Additionally, in the interest of selecting patients 
on the basis of their reliability and dependability, we would like to exclude participants using illicit 
drugs. Occasional use of cannabis (once or twice per week) is not an exclusion.

Urinalysis: Clinically significant abnormalities

Clinically significant electrolyte abnormalities 

Smoking >10 cig/day

Alcohol: Men >14 drinks/wk or > 4drinks/day, Women > 7 drinks/wk or > 3 drinks/day 
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
History of chronic liver disease, active hepatitis infection, HIV/AIDS, chronic kidney 
disease (stage 3 or greater), active cancer, cardiovascular disease or other heart disease, 
systemic rheumatologic conditions, seizures, bleeding disorders, muscle disease 

 Surgeries that involve removal of endocrine glands except for thyroidectomy (if 
euthyroid on thyroid hormone replacement – if such history fT4 and TSH will be checked)

Pregnant women

Subject enrolled in another study less than one month prior to their anticipated start date 
in this study besides those done in our group  

Family history: family history of premature cardiac death

Allergies to medication administered during study

Uncontrolled psychiatric disorders

Any contraindications for MRI: presence of any non-MRI compatible implants including 
pacemaker, aneurysm clip, cochlear implant, neurostimulator; history of eye injury with metal; 
history of ever being a metal worker; history of gunshot wounds or any other imbedded metal 
objects; history of claustrophobia or prior episodes of significant anxiety or discomfort while 
obtaining an MRI. In addition to our screening, additional comprehensive screening will be 
performed by MRRC personnel on the day of the study.

Perimenopausal women who are experiencing/have experienced hot flashes, given the 
potential that this would affect brain blood flow 

Any condition which in the opinion of the PI makes the subject ill-suited for participation in 
the study
2) Sources of Material/Use of Data:
All data and records obtained in this study will be used for research purposes only. The 
protocol will be submitted for review and approval by the Einstein Institutional Review Board 
(Einstein IRB). The Einstein IRB is responsible to ensure human subject protections in compliance 
with institutional policies and federal regulations including the HIPAA privacy law.
3) Recruitment/Consent Procedures: 
We will recruit up to 10 participants (both diabetic and non-diabetic) to participate in the pilot 
phase of this study. We will recruit a total of 15 healthy and 15 volunteers with T2D for the main 
study. Participants will be recruited using local and online advertising as well as from the clinical 
research center (CRC) database. We will also be identifying potential subjects for this study by 
accessing clinical/medical records from local clinics (eg, Montefiore endocrinology clinic, 
Montefiore Wellness Center). If potentially-eligible subjects are identified, we will contact their 
physician to ask the patient if they would be interested, and if we may contact them. If they agree, 
a member of our study team will contact them about the study. These subjects may include 
subjects who previously participated in our studies. 
Consent will be initially obtained during telephone screening performed by the PI, study 
coordinator or research nurse. Formal consent procedures which adhere to the Clinical 
Investigations Committee of the Albert Einstein College of Medicine will be followed by the PI, 
study coordinator or nurse. Specifically, each subject will be verbally informed in layman's 
language of the purpose, benefits and possible risks of the studies.  They will then read the written 
consent form in the presence of a member of the research team and a physician who will answer 
any further questions. The subject and the study team member shall be asked to sign the consent 
IRB NUMBER: 2018-9040
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Meredith A. Hawkins, MD, MS
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form, one copy of which will be kept in the patient’s chart and the other copy will be given to the 
subject. Each subject's potential participation in related experiments (for example, when each 
subject is asked to perform repeat studies) will be explicitly stated.
4) Risks and Benefits:
Safety and subject comfort
fMRI is a safe, well validated and generally well tolerated procedure. We will exclude any subjects 
with any contraindications to MRI, as listed in the “Exclusion criteria” (14). Since subjects can 
occasionally experience dizziness, they will be accompanied in and out of the MRI by a study 
team member and advised to rise slowly. To offset the noise of the MRI machine, they will be 
given earplugs. Between the fMRI sessions, they will be resting in the Study Room. After giving 
study medication, we will follow every subjects’ blood pressure, heart rate and blood glucose 
levels in hourly intervals. As noted above, in the event of symptomatic or significant hypotension 
and/or tachycardia, study will be stopped and the subject will be given IV saline infusion.
Potential Risks: 
Potential risks to the subjects include the following:
1. Blood withdrawal: The total amount of blood sampled will not exceed approximately 50 cc per 
study for healthy subjects and approximately 60 cc per study for subjects with T2D.
2. Intravenous Catheter - The intravenous catheter is associated with a small risk of local bruising.
3. Diazoxide (Proglycem, received from Weiler Pharmacy) – The risk associated with higher 
doses of diazoxide therapy is hypotension. Symptoms of low blood pressure are dizziness and 
light-headedness. During the study, there will be frequent monitoring of blood pressure. Please 
note that the amount of diazoxide given in this study will be much lower than the doses which 
cause lowering of blood pressure. Of note, the oral doses the subjects will receive have been 
used safely in human subjects in the preliminary studies without lowering blood pressure or any 
other side effects. Diazoxide is approved by the FDA.  
4. Insulin (Novolin R, received from Weiler Pharmacy)– Intravenous low-dose insulin infusion in 
T2D subjects performed with simultaneous hourly blood glucose checks should not cause any 
harm or discomfort to the subject. Transient hypoglycemia may occur during the overnight insulin 
infusion and will be dealt with as detailed in the overnight nursing protocol. Insulin is approved by 
the FDA.
5. Potassium chloride oral powder (Klor-Con 20mEq)– The most common adverse reactions with 
oral potassium chloride salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and 
diarrhea  Potassium chloride is approved for use by the FDA.
6. fMRI – fMRI studies may cause some mild discomfort associated with being in a confined space 
and/or a noisy environment. 
7. Withholding of diabetes medication: While unlikely, short-term discontinuation of usual 
diabetes medications may cause short-term hyperglycemia. Specifically, the “wash-out periods” 
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for each medication reflect the amount of time required for drug effects to abate (so that their 
presence will not affect study results), while avoiding an undue increase in glucose due to a 
prolonged period off medication. Therefore, this is not considered to put subjects at risk for 
hyperglycemia significantly above a subject’s usual blood glucose range.
5) Protection of Subjects: 
As noted above, recruitment involves meticulous exclusion of subjects with any embedded metal 
objects or medical devices, as well as history of claustrophobia. This is performed at initial 
screening of subjects as well as a subsequent in-depth questionnaire by MRRC study staff at the 
time of the fMRI study.
Procedures employed to protect subjects from undue risks include the following: 
1.
Blood withdrawal: Blood withdrawal during any single study will be limited to less than 
approximately 50 cc per study for healthy subjects and approximately 60 cc per study for subjects 
with T2D. Subsequent studies will be separated by at least a two-week interval.  
2.
Intravenous catheter - The infusion and withdrawal catheters may produce infection or 
local hematoma, but strict aseptic technique will be observed by the experienced physician or 
registered nurse performing the procedure.
3.
Diazoxide – As noted above, vital signs will be carefully monitored throughout the studies. 
An intravenous line will be established prior to the administration of diazoxide or placebo. In the 
very unlikely event that the blood pressure drops below 90/60, the patient will be maintained in a 
supine position and intravenous saline will be administered at a rate sufficient to correct any 
significant decrease in blood pressure. As noted above, it is highly unlikely that there will be any 
reduction in blood pressure.
4.
Insulin – as noted above, blood glucose will be carefully monitored every hour and insulin 
infusion rates will be adjusted accordingly. The floor nurse will be given both oral and written 
instructions regarding the overnight admission procedures. Fellow will be available to the floor 
nurse by cell phone or pager at all times. The P.I.’s contact information will be available to the 
floor nurse as well; in the case the floor nurse is unable to reach the fellow for any reason. Careful 
instructions are provided as to how to manage any episodes of hypoglycemia. 
5.
Potassium Chloride –  Potassium chloride will be given to prevent any significant drop in 
potassium with insulin infusion. An oral dose of 40 mEq of potassium chloride (oral powder 
dissolved in water) is in concordance with FDA-recommended dosing for oral powder. The total 
dose of up to 80 mEq that subjects receive is within the limit approved by the FDA (up to 100 
mEq/day). The powder will be given while the subject is sitting up and with a plenty of water. This 
is to prevent any gastrointestinal distress. Potassium chloride will be given to prevent any 
significant drop in potassium with insulin infusion.
6.
fMRI – in order to minimize discomfort for the subject the duration of the fMRI sessions 
will be limited to the minimal time sufficient to obtain necessary measures, which should be around 
30 min per session. Earplugs will be provided for noise reduction. Between the sessions the 
subjects will be resting in the Study Room. 
7.
Withholding diabetes medication - The subjects will be instructed to monitor their 
blood glucose four times daily in this period and to inform the study doctor of any 
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significant episodes of hyperglycemia (blood glucose > 300 mg/dl). Any incidents of 
hyperglycemia (>300 mg/dL) will be evaluated on a case-by-case basis by the P.I., who 
is an Endocrinologist. The assessment will therefore include a careful history of food 
intake and activity, timing of blood glucose readings, and symptoms of hyperglycemia. 
Please note that most patients will be on metformin and/or insulin and hence the entire 
period of washout will be no more than 2 days, and therefore marked elevations in blood 
glucose are unlikely to occur. In the unusual case of severe hyperglycemia, the subject 
will be advised to immediately resume their usual medications and the study will be 
rescheduled accordingly. 
Potential benefits:
The study will be of no direct benefit to the subject, although subjects may gain a better 
understanding of their own metabolic processes and contribute to generalizable knowledge by 
their participation.
Importance of the knowledge to be gained:
The risks involved are minimal as all procedures are well established. The study may result in a 
better understanding of the role of the central regulation of glucose production in humans. As 
described above, a number of mechanisms exist to ensure safety of subjects. All studies will be 
performed by a physician and nurse in attendance in the GCRC procedure unit with emergency 
equipment readily accessible. The PI, Co-investigator, and research team have a combined 
experience of over 20 years in human investigation, and sufficient care in choice of subjects 
should minimize the risks. The scientific value of these studies is to develop an understanding of 
the mechanism of an important and potentially-exciting novel therapeutic target for the treatment 
of diabetes.
RESEARCH INVOLVING CLINICAL TRIALS:
The study does not constitute a phase III clinical trial as defined by the NIH.
DATA SAFETY AND MONITORING PLAN (DSMP):
Though the studies outlined in this application do not constitute a clinical trial, as per the NCRR 
guidelines for CRC’s, all human subject research being conducted at the Einstein CRC must have 
a DSMP. The guidelines for Data and Safety Monitoring have been established by the CRC 
Research Subject Advocate (RSA), and approved by the Assistant Dean for Compliance who 
oversees human research subject safety at the Albert Einstein College of Medicine. 
http://gcrcweb.aecom.yu.edu/gcrc/dsm.htm
The PI and Co-Investigator will regularly review study progress and any adverse events (see 
Monitoring Plan below).  Reports of any adverse events will be transmitted to the Einstein IRB.
Monitoring Plan:  Study progress, including all adverse events, will be reviewed at bi-monthly 
research group meetings.  All abnormal findings from history and physical examination will be 
documented in the research chart and reviewed by the PI or Co-Investigator. Clinical and 
laboratory data will be reviewed within 24 hours of receipt and any adverse events will be reported 
according to Einstein IRB policy.  The investigators will periodically assess and review data 
collection and storage procedures to maintain confidentiality. In addition, annual reports 
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summarizing study progress (including recruitment progress, interim data analysis and data 
quality, adverse events and protocol changes) will be prepared and submitted to the Einstein IRB.  
Data Safety and Monitoring Board (DSMB): DSMB members will include Dr. Michal L. 
Melamed, Associate Professor of Medicine and Epidemiology & Population Health and Program 
Director of the Nephrology Fellowship, a highly experienced patient-oriented investigator who is 
not involved in this research protocol, but is very familiar with all of the proposed methodologies 
and the potential risks to human subjects, and Elina Jerschow, who is an experienced diabetes 
investigator. The DSMB will be chaired by Dr. Nir Barzilai, who has much experience with 
metabolic research as well as with serving on and chairing DSMBs. The DSMB members will 
routinely review the safety information related to this project at yearly intervals, and will be 
contacted immediately should a serious adverse event occur. 
Adverse Event Monitoring:
Process: Data and safety monitoring for this study will be performed by the principal investigator 
on an ongoing basis.  All volunteers will be seen by the P.I., Co-Investigator or research staff. 
Laboratory data will be reviewed by the P.I. within 24 hours of receipt.
Reporting: All adverse events will be compiled, and reported in summary form, on an annual basis 
to the IRB, and at the conclusion of the study.  Unanticipated (non-serious) adverse events will 
be reported to the IRB within 30 days and serious adverse events will be reported to the IRB 
within 48 hours by phone, email or fax.
Recruitment Monitoring:
Process: The PI and Co-Investigator will assess the recruitment and retention of study subjects 
on an ongoing basis.  The recruitment goal for this protocol is for 30 subjects to complete ALL of 
the proposed studies, with a planned enrollment of >45 subjects. We may enroll up to 10 
participants for the pilot phase of this study to allow us to optimize the MRI software.
Reporting: Summary statistics regarding recruitment and retention of study subjects will be 
reported to the IRB on an annual basis, and at the conclusion of the study.
Early Study Termination:
Process: The PI and Co-Investigator will determine if the study is to be terminated prior the 
scheduled study conclusion.  Early study termination will be considered in the event of an 
unanticipated serious adverse event determined to be possibly, probably or definitely related to 
the study.
Reporting: The P.I. will report the decision to terminate the study to the IRB within 48 hours of this 
determination.  The P.I. will submit a narrative description of the reasons for early termination of 
the study within 10 days.
DATA SHARING:
We respect that the rights and privacy of people who participate in NIH-sponsored research must 
be protected at all times.  Thus, data intended for broader use will be free of identifiers that would 
permit linkages to individual research participants. We and our collaborators will make the data 
and associated documentation available to users only if they provide: (1) a commitment to using 
the data only for research purposes and not to identify any individual participant; (2) a commitment 
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to securing the data using appropriate computer technology; and (3) a commitment to destroying 
or returning the data after analyses are completed. We expect that the results of this study will be 
presented at national scientific meetings and published in peer reviewed journals. 
COST AND COMPENSATION TO SUBJECTS: 
There will be no costs to the participants in the study. Subjects will receive payment by Clincard 
Greenphire Payment for time and inconvenience associated with the study. Subjects will be asked 
to provide their social security numbers to receive monetary compensation, which will be loaded 
within 24-48 business hours from the day of their study. It will be kept confidential. For completion 
of the pilot phase of this study, subjects will receive $50 per fMRI session study visit for a total of 
up to $150. Pilot phase subjects with T2D will receive an additional $100 for the overnight 
admission. For completion of the main study, subjects will receive $50 per fMRI session study 
visit for a total of up to $150. Subjects with T2D will receive an additional $100 for the overnight 
admission. If subjects choose to withdraw or cannot complete the study, the compensation will be 
prorated based on the time spent. All subjects will be drug-tested on arrival to the CRC utilizing 
an instant result drug panel (Alere iCup Dx14). If the test is positive, the subject will be withdrawn 
from the study based on our exclusion criteria.
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REFERENCES: 
1.
Pocai A et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 
2005;434(7036): 1026-1031.
2.
Aguilar-Bryan L, Bryan J. Molecular biology of adenosine triphosphate-sensitive 
potassium channels. Endocr Rev 1999;20(2): 101-135.
3.
Kishore P et al. Activation of K(ATP) channels suppresses glucose production in 
humans. J Clin Invest 2011;121(12): 4916-4920.
4.
Rossetti L et al. Hypothalamic KATP channels control hepatic glucose production. Nature. 
2005: 1026-1031.
5.
Esterson YB et al. Central Regulation of Glucose Production May Be Impaired in Type 2 
Diabetes. Diabetes 2016;65(9): 2569-2579.
6.
Busija DW et al. Impaired mitochondria-dependent vasodilation in cerebral arteries of 
Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol. 2009; 
296:R289-298.
7.
Spanswick D et al. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons 
of lean, but not obese rats. Nat Neurosci. 2000;3(8):757-758.
8.
DeFronzo R.: The triumvirate: beta cell, muscle and liver; a collusion responsible for 
T2DM. Diabetes 37: 667-87, 1988. 
9.
Campbell P., Mandarino L., Gerich J.: Quantification of the relative impairment in action 
of insulin on HGP & peripheral glucose uptake in T2DM: Metabolism 37: 15-22, 1988. 
10.
Hawkins et al. Glycemic Control Determines Hepatic and Peripheral Glucose 
Effectiveness in Type 2 Diabetic Subjects. Diabetes 2002 Jul; 51(7): 2179-2189
11.
Heni M et al. Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose 
Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in 
12.
Oz G et al. Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia 
by MRI at 3T. J Magn Resozn Imaging. 2017;45:681-691.
13.
Priya S. George, Roger Tavendale, Colin N.A. Palmer, and Rory J. McCrimmon. 
Diazoxide Improves Hormonal Counterregulatory Responses to Acute Hypoglycemia in Long-
standing Type 1 Diabetes. Diabetes 2015;64:2234–2241.
14.
Alsop DC, Detre JA, Golay X, Gunther M, Hendrikse J, Hernandez-Garcia L, Lu H, 
Macintosh BJ, Parkes LM, Smits M, van Osch MJ, Wang DJ, Wong EC, Zaharchuk G. 
Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A 
consensus of the ISMRM perfusion study group and the European consortium for ASL in 
dementia. Magn Reson Med. 2014. doi: 10.1002/mrm.25197.
15.
K.L. Z. theoretical basis of indicator dilution methods for measuring flow and volume. Circ 
Res. 1962;x:393-407.
16.
Buxton RB, Frank LR, Wong EC, Siewert B, Warach S, Edelman RR. A general kinetic 
model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med. 
1998;40(3):383-96.
17.
Chevassus H, Mourand I, Molinier N, Lacarelle B, Brun J-F, Petit P: Assessment of single-
dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy 
volunteers: a double-blind, placebo-controlled, randomized cross-over trial. BMC Clinical 
Pharmacology. 2004;4:3. 
18.
Branis N, Wittlin S: Amphetamine-like analogues in diabetes: Speeding towards 
ketogenesis. Case Reports in Endocrinology. 2015; 2015. 
19.
Mysels DJ, Sullivan MA. The relationship between opioid and sugar intake: Review of 
evidence and clinical applications. Journal of Opioid Management. 2010;6(6):445-452.
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Appendix 1: DZX Nursing Protocol
DR. HAWKINS NURSING PROTOCOL
TYPE 2 DIABETES INPATIENTS
STUDY (Diazoxide) 
Overnight Admission 
Purpose:
These subjects (with Type 2 diabetes) will be participating in experimental studies to assess glucose 
metabolism. The Prinicipal Investigator is Dr. Meredith Hawkins.
Admission Day 1:
Subjects will arrive in Room 2S-42 (GCRC Study suite) on the evening of admission to Weiler Hospital. They 
will arrive on 11 South before dinner. Routine admission procedure will be followed including vital signs 
and nursing assessments. Orders will be placed by the research team.
1. Diet and Activity:
The orders will be written by the research fellow. The diet is diabetic consistent carb test diet. The patient 
should be ambulatory. Vitals signs per shift. Dinner should be provided at approx. 6:00 pm. Pre-bedtime 
snack will be given at approx. 9:30 pm. The patient should have nothing to eat after 10:00 P.M except 
drinking free water is allowed ad lib and encouraged. Please record the time snack and dinner are 
consumed on the blood glucose monitoring sheet in the space provided.
2. Medications:
The subjects will have washed out from their usual diabetes medication, medications for other indications 
such as hypertension will be taken as usual.
3. I.V Access: 
An 18 to 20 gauge catheter must be inserted in one arm for insulin infusion. Should there be any difficulty 
in placing line (i.e. more than 2 attempts on one side) please call the research fellow on call. Another 18-
20 gauge IV catheter may be placed in the other arm for blood sampling.
4. Insulin:
Insulin infusion: will be started at approximately 01 am and continued through the morning of Day 2 until 
the patient is ready to be transferred to the Room 2S-42 (GCRC Study suite) for the study around 7.45 am 
on Day 2. Please do not stop the insulin pump until the patient is ready to be transferred immediately 
to the GCRC Study suite as holding insulin will result in hyperglycemia. 
The insulin infusion will be prepared per the standard hospital pharmacy protocol for Insulin regular (e.g. 
Humulin R) 100 units in 100cc of 0.9% NaCl (1unit/cc). Connect the bag to the IV tubing, flush and discard 
approx. 20ml to avoid changes in insulin concentration due to adherence to the tubing. The insulin 
infusion should be administered using a usual insulin pump on the floor. 
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On admission and then hourly at the beginning and during the insulin infusion, blood glucose should be 
checked on a glucose meter using a drop of blood from the fingerstick. The results of blood glucose should 
be logged in the EPIC and the provided blood glucose flowsheet. The following formula should be used to 
adjust the insulin infusion rate. 
INSULIN INFUSION PROTOCOL
Blood Glucose
Intravenous Infusion Rate
Insulin Infusion Rate
mg/dL
(mL/hr)
(U/hr)
>250
6
6
201-250
5
5
171-200
4
4
141-170
3
3
121-140
2
2
101-120
1
1
80-100
0.5
0.5
<80
only normal saline
only normal saline
Check glucose levels every 30 minutes if the previous value was <80 and insulin infusion was stopped. If 
you don’t run any insulin infusion, please change that line to saline to keep vein open. 
5. Treating hypoglycemia: 
If at any time the blood glucose is less than 70mg/dl or patient experiences signs/symptoms of 
hypoglycemia the patient should be given D10% glucose at the rate of 100cc/hr and recheck the blood 
glucose within 30 minutes as described above. If there are any problems with persistent hypo or 
hyperglycemia, or if intravenous catheter fails to work properly, please call Research Fellow (the name 
and number provided on the form). Please do not omit hourly blood sugar determinations at any point 
because blood glucose may fall quickly. 
6. Potassium supplementation: 
Patient should receive 40 mEq of KCl PO once at approximately 01 am prior to starting insulin infusion to 
prevent hypokalemia. 
Admission Day 2.
Last glucose value will be checked at approximately 7:30 am and insulin continued based on the algorithm 
unless below 80 mg/dl. 
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At around 7:45 am, the subject should void and then be transferred to the bed in room 2S-42 (ext. 
2190). Please continue insulin infusion when the subject is brought to 2S-42. IT IS VITALLY IMPORTANT 
THAT THE INSULIN NOT BE STOPPED!!!
The subject will then undergo the research procedure. The experimental protocol will end between 4 
and 5 pm. The subject will be discharged after a period of observation at approximately 6pm. For any 
questions, call Dr. Sandra Aleksic 718-664-3408, pager 917-956-6638 or Dr. Meredith Hawkins 646-708-
2721                                               THANK YOU!
Overnight Insulin Record
Protocol (Diazoxide)
Patient MR#_______________
GCRC#________________
Date_____________________
Research fellow name & number: _____________________________
Time
Blood 
Glucose 
(mg/dL)
Insulin Infusion 
Rate (units/hour)
Saline Infusion 
Rate/Comments
1.00 am
2.00 am
3.00am
4.00am
5.00am
6.00am
7.00am
7.30am
Time dinner consumed (use 24 hour clock): _______________
Time snack consumed (use 24 hour clock): ________________
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______________________
________________________
___________
Print name and title                              Signature                                            Date
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DR. HAWKINS STUDY ROOM PROTOCOL
TYPE 2 DIABETES PARTICIPANTS 9040-2018 MRI STUDY 
DAY(Diazoxide) 
 
Purpose:
These subjects (with Type 2 diabetes) will be participating in experimental studies to assess glucose 
metabolism. The Prinicipal Investigator is Dr. Meredith Hawkins.
MRI Study Day/Study Medication:
Subjects will be discharged from the inpatient floor and checked in to the GCRC Study Room at 
approximately 8:00 AM. Weight, vital signs, and IV placement (as needed) will be done at this time. 
Participant blood glucose will be monitored according to flowsheet below. Participant will be escorted to 
the Gruss Magnetic Resonance Research Center of the Albert Einstein College of Medicine for their first 
MRI scan at approximately 9 AM. The first MRI scan will last approximately 30 minutes. After the scan, 
the participant is escorted back to the GCRC Study Room by the study coordinator. They are given study 
medication (diazoxide or placebo according to randomization) at the beginning of their 2 hour rest period 
before their second scan. Participants blood glucose and vital signs are monitored during this rest period 
as described below. The second MRI scan is at approximately 12 noon, and the third MRI scan (if done) is 
at approximately 3 PM with a 2-hour rest period between scans as described above. 
1. Diet and Activity:
Participant is fasting for entire period of study except for water and diet soda. Participant is encouraged 
to remain resting during the break periods between scans. They are given a meal upon the completion of 
the last MRI scan.
2. Medications:
Participants will have washed out from their usual diabetes medication, medications for other indications 
such as hypertension will be taken as usual.
3. I.V Access: 
Participant will have an 18 to 20 gauge catheter placed in the arm during overnight admission. This 
catheter should be used for blood draws between the MRI scans, if functional, and if not needed for 
ongoing insulin infusion (as below). In the case that insulin infusion is needed or if the catheter is not 
functioning, another 18-20 gauge IV catheter will be placed in the other arm for blood sampling.
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4. Insulin:
Insulin infusion: If blood glucose exceeds 200 mg/dL, we will begin intravenous insulin infusion using the 
insulin infusion protocol below during the 2-hr breaks between scans. In the event that the subject’s blood 
glucose level exceeds 300 mg/dL, we will resume insulin infusion and stop the study. At the end of the 
MRI scans, the subject will subsequently be monitored until blood glucose is below 200 mg/dL and 
discharged with the advice to resume home diabetes medication(s).
The insulin infusion will be prepared per the standard hospital pharmacy protocol for Insulin regular 
(Humulin R) 100 units in 100cc (or 50 units in 50 cc, depending on availability) of 0.9% NaCl (1unit/cc). 
Connect the bag to the IV tubing, flush and discard approx. 20ml to avoid changes in insulin concentration 
due to adherence to the tubing. The insulin infusion should be administered using a hospital pump, if still 
available from overninght admission, or a usual insulin pump in the GCRC. 
Glucose: On arrival to GCRC Study Room, and then hourly at the beginning and during the insulin infusion, 
blood glucose should be checked on a glucose meter using a drop of blood from a fingerstick or from IV 
draw using Analox machine. The results of blood glucose should be logged in the provided blood glucose 
flowsheet. The following protocol should be used to adjust the insulin infusion rate:
INSULIN INFUSION PROTOCOL
Blood Glucose
Intravenous Infusion Rate
Insulin Infusion Rate
mg/dL
(mL/hr)
(U/hr)
>250
6
6
201-250
5
5
171-200
4
4
141-170
3
3
121-140
2
2
101-120
1
1
80-100
0.5
0.5
<80
only normal saline
only normal saline
Check glucose levels every 30 minutes if the previous value was <80 and insulin infusion was stopped. If 
you don’t run any insulin infusion, please change that line to saline to keep vein open. 
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5. Treating hypoglycemia: 
If at any time the blood glucose is less than 70mg/dl or patient experiences signs/symptoms of 
hypoglycemia the patient should be given D20% glucose at the rate of 100cc/hr and blood glucose should 
be rechecked within 30 minutes as described above. 
Discharge:
After finishing the last MRI scan, participants will be given a meal and will have their blood glucose 
monitored. Once blood glucose levels are <200 mg/dl, participants will have vital signs and a final blood 
glucose check done. Participant is monitored for general comfort during this time. The participant will 
be discharged after a period of observation after research fellow clears participant to go home. At the 
end of the study visit, participant will be escorted to transportation by the research coordinator.
For any questions, call Dr. Shiksha Sharma 201-683-1500, Dr. Sandra Aleksic 718-664-3408 or Dr. 
Meredith Hawkins 646-708-2721                                               
THANK YOU!!
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Study Day Insulin Record (if given)
Protocol (9040-2018 MRI STUDY Diazoxide)
Patient MR#_____________   GCRC#______________    Date___________________
Research fellow name: _____________________________
______________________
________________________
___________
Print name and title                              Signature                                            Date
Time
Blood 
Glucose 
(mg/dL)
Insulin Infusion 
Rate 
(units/hour)
Saline 
Infusion 
Rate
Additional 
Comments and 
Measurements
8:00 AM
9:00 AM
10:00 AM
(If done, participant 
may be in MRI scan)
11:00 AM
12:00 PM
(If done, participant 
may be in MRI scan)
1:00 PM
2:00 PM
3:00 PM
(If done, participant 
may be in MRI scan)
4:00 PM
5:00 PM
6:00 PM
(if needed)
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ICF_001.pdf: 
Diazoxide/fMRI/ND
Page 1 of 7
ALBERT EINSTEIN COLLEGE OF MEDICINE 
MONTEFIORE MEDICAL CENTER
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION
Introduction
You are being asked to participate in a research study Use of Functional MRI to Assess 
Functional Hypothalamic Activation in Response to Diazoxide. Your participation is voluntary 
-- it is up to you whether you would like to participate. It is fine to say “no” now or at any time after 
you have started the study. If you say “no,” your decision will not affect any of your rights or 
benefits or your access to care.
The researcher in charge of this project is called 
the “Principal Investigator.” Her name is Dr. 
Meredith Hawkins. You can reach Dr. Hawkins 
at: 
Office Address: 1300 Morris Park Avenue
Bronx, NY 10461
Telephone #: 718-430-3186
For questions about the research study, or if you 
believe you have an injury, contact the Principal 
Investigator or the IRB.
Support for this research study is provided by 
the National Institute of Health (NIH).
The Institutional Review Board (IRB) of 
the Albert Einstein College of Medicine 
and Montefiore Medical Center has 
approved this research study. The IRB # is 
in the stamp in the upper right hand 
corner. If you have questions regarding 
your rights as a research subject you may 
contact the IRB office at 718-430-2253, by 
e-mail at irb@einstein.yu.edu, or by mail:
Einstein IRB 
Albert Einstein College of Medicine
1300 Morris Park Ave., Belfer Bldg #1002
Bronx, New York 10461
Why is this study being done? 
The goal of this study is to understand how activating control centers of the brain can affect how 
much glucose (sugar) is produced by the liver. This is particularly important for people with 
diabetes who have very high production of glucose, since this could be at least in part due to 
impaired regulation of the liver by the brain. 
This study will use functional MRI, a way of imaging the blood flow to parts of the brain, to observe 
how activating areas of the brain is linked to regulation of blood sugar.
Why am I being asked to participate? 
You are being asked to participate in this study because you are a healthy volunteer. 
How many people will take part in the research study?
You will be one of about 15 people who will be participating in this study.
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


Diazoxide/fMRI/ND
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How long will I take part in this research?
It will take you between 2 weeks and 2 months to complete this research study.  During this time, 
we will ask you to make 2 study visits to Albert Einstein College of Medicine.
What will happen if I participate in the study? 
The Screening Visit will take about 1.5 hours.  During this visit, we will do some tests and 
procedures to see if you eligible to take part in this research study.  The study doctor will review 
the results of these tests and procedures.  If you aren’t eligible, the study doctor will tell you why.  
At this visit we will:

Ask you about your medical history

Give you a physical exam, including height, weight, and “vital signs” (blood pressure,
temperature, heart and breathing rates)

Draw a blood sample

Take an EKG

Ask you for a urine sample

Test your urine for certain drugs

Test your urine for pregnancy, if you are a female able to become pregnant.  Pregnant
women cannot take part in this research study.
To obtain the blood sample, we will wipe the skin on your arm with alcohol to clean it. Then, we 
will insert a small needle into a vein. 4-5 tubes of blood will be drawn, which is about 7 teaspoons. 
If you are eligible for the study, you will be asked to maintain a consistent diet for 3 days prior to 
the study.
If you are not eligible, you will be informed by phone or in writing and records of the evaluation 
will be forwarded to you, if you’d like them. 
If you are eligible for the study, we will assign you by chance (like a coin toss) to first receive 
either diazoxide or placebo.  You and the study doctor cannot choose your study order.  You will 
have an equal chance of being assigned to diazoxide or placebo on your first study visit.
Diazoxide is an FDA approved medication used to treat hyperinsulinism (a condition where your 
pancreas secretes too much insulin, causing low blood sugar). Please note that the amount of 
diazoxide given in this study will be lower than the daily doses typically used in a clinical setting. 
This research study will compare diazoxide to placebo. The placebo looks exactly like diazoxide, 
but contains no drugs.  During this study you may get a placebo instead of diazoxide. Placebos 
are used in research studies to see if the results are due to the study drug or due to other reasons.
Study Visit 1:

You will come to the GCRC Study Room at Jack D. Weiler hospital on the morning of the
study at around 8:00AM. You will be asked to not exercise the day before the study or eat 
after 10 PM the night before the study (but you can drink water). An MRI safe intravenous 
catheter will be inserted into your arm. Blood samples will be collected every hour for up 
to 8 hours for measurements of your blood sugar and other hormones.
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


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
You will then be escorted to the Gruss Magnetic Resonance Research Center of the
Albert Einstein College of Medicine.

At approximately 9AM on the morning of the study, you will be asked to lie in the MRI
scanner for approximately 30 minutes. During this time, the MRI pictures will be taken.

You will then be given diazoxide orally at a dose of 4mg/kg-7mg/kg once or placebo.

You will then return to the MRI scanner at approximately 2 hour intervals for approximately
30 minutes each interval. You will rest in a separate room in between MRI measurements. 
There will be up to 3 MRI measurements during one day. The number of scans you will 
receive will depend on the results of the data analysis collected from previous studies. 
You will be told how many scans you will receive when you are scheduled for the study. 

Your vital signs (blood pressure and heart rate) will be monitored before and after each
MRI scan.

Following the final scan, you will be given a meal, and discharged home.

The anticipated length of the study is about seven hours including preparation, study,
and post study observation. 
Study Visit 2: Study Visit 2 will take place after the previous study. It will be identical to the first 
study, with the exception that you will receive the study drug you did not receive on the first 
study visit (e.g. if you received diazoxide on the first study visit, you will receive placebo on this 
visit). 
Magnetic Resonance Imaging (MRI) is a test that uses magnets and radio waves to make 
pictures of organs and structures inside the body. For an MRI test, the area of the body being 
studied is placed inside a machine that contains a strong magnet. Pictures from an MRI scan 
are saved and stored on a computer for more study. Although the MRI you will have in this 
study is being done for research purposes only, it is possible that doctors may notice something 
that could be important to your health. If so, we will contact you to explain what was seen and 
tell you whether you should consult your doctor. We will make the MRI report available to your 
doctor, and if you want, we will talk with your private physician or refer you to someone for 
follow-up. 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
Genetic Testing 
This study will not involve genetic research or genetic testing. 
Specimen Banking (Future Use and Storage)
We will store your specimens and information about you in a “biobank”, which is a library of 
information and specimens (tissue and blood) from many studies. These specimens and 
information cannot be linked to you. In the future, researchers can apply for permission to use the 
specimens and information for new studies to prevent, diagnose, or treat disease, including 
genetic research. Your specimens and information may be kept for a long time, perhaps longer 
than 50 years. If you agree to the future use, some of your de-identified genetic and health 
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


Diazoxide/fMRI/ND
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information (not linked to you) may be placed into one or more scientific databases. These may 
include databases maintained by the federal government.
You can choose not to participate in the biobank and still be part of the main study and this will 
not affect your treatment at this facility.
INITIAL ONE (1) OF THE FOLLOWING OPTIONS
_______ I consent to have my specimens and information about me used for future research 
studies.
_______ I do NOT consent to have my specimens and information about me used for future 
research studies. Information about me will be kept as long as required by regulations and 
institutional policy, but will not be used for future studies.
Will I be paid for being in this research study? 
You will receive payment by Clincard Greenphire. A social security number is required. It will be 
kept confidential. Clincards are typically loaded with compensation within 24-48 business hours 
from the day of your study. You will not be reimbursed for child care expenses but only for travel 
expenses. You will receive $50 per MRI scan (up to 3 scans per study visit). If you choose to 
withdraw or cannot complete the study because you feel unwell during the study, or the study 
needs to be stopped due to a logistical or technical issue, the compensation will be pro-rated 
based on the time spent. You will be drug-tested the morning of the study before we begin any 
study procedures. If the drug test is positive, you will be withdrawn from the study. 
Some researchers may develop tests, treatments or products that are worth money. You will not 
receive payment of any kind for your specimens and information or for any tests, treatments, 
products or other things of value that may result from the research.
Will it cost me anything to participate in this study? 
There will be no cost to you to participate in the study.
What will happen if I am injured because I took part in this study?
If you are injured as a result of this research, only immediate, essential, short-term medical 
treatment as determined by the participating hospital, will be available for the injury without charge 
to you personally. 

No monetary compensation will be offered.

You are not waiving any of your legal rights by signing this informed consent document.

If additional treatment is required as a result of a physical injury related to the research,
necessary medical treatment will be provided to you and billed to your insurance 
company or to you as part of your medical expenses. 
Immediately report any discomforts, problems or injuries you experience during the course of 
your participation in the study to Dr. Meredith Hawkins (718-430-3186).
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


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What else do I have to do?

You must tell the research study doctor about any past and present diseases or allergies
you are aware of and about all medications you are taking including “over-the-counter”
remedies and nutritional supplements or herbs.

If you do not feel well at any time, call your doctor or the research study doctor
immediately.

If you think you have become pregnant, contact your research study doctor immediately.

You may carry out all your normal daily activities.
Confidentiality
The researchers and study staff follow federal and state laws to protect your privacy. This part 
of the consent form tells you what information about you may be used and shared in the 
research described in this form. You do not have to sign this form but, if you do not, you may not 
participate in the research. 
The health information that we may use or disclose for the research described in this form 
includes information from your entire medical record, such as your name, phone number, email, 
medical diagnoses, dates, test results, social security number, medical record numbers, etc. 
Your information and research records will be kept confidential. Your study information will be 
kept as long as they are useful for the research described in this form.
The only people who can see your research records are:

the research team and staff who work with them

the organization that funded the research

groups that review research (the Einstein IRB, and the Office for Human Research
Protections, and the US Food and Drug Administration)
The purposes of these uses and disclosures are to (1) conduct the study and (2) make sure the 
study is being done correctly. The information covered under this form may no longer be 
protected by federal privacy laws (such as HIPAA) once disclosed, and those persons who 
receive your health information may share your information with others without your additional 
permission. All of these groups have been asked to keep your information confidential. 
Medical information collected during the research, such as test results, may be entered into your 
Montefiore electronic medical record and will be available to clinicians and other staff at 
Montefiore who provide care to you. 
To maintain the integrity of this research study, you generally will not have access to your 
research-related personal health information. If it is necessary for your care, your research-
related health information will be provided to you or your physician.
Certificate of Confidentiality
As a way to protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health, which is funding this study.  If information from this study was 
requested or subpoenaed by government agencies or the courts, we will use the Certificate to 
attempt to legally refuse to provide it.  This is rare – in only a few cases did researchers have to 
use the Certificate, and it was honored most of the time, but not every time. There are several 
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


Diazoxide/fMRI/ND
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kinds of situations that the Certificate does not apply. For example, we are still required to report 
child abuse and some diseases, and we must make data available to the government for a review 
or evaluation of our research. The Certificate does not prevent you or a member of your family 
from voluntarily sharing information. Similarly, if an insurer, employer, or other person obtains 
your written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.
Are there any risks to me? 
Blood Draw: Rarely, the vein where we inserted the needle will become sore or red. Sometimes, 
a temporary harmless “black and blue” may develop. Very rarely, fainting may occur. 
MRI: Some people are bothered by feelings of confinement (claustrophobia), and by the noise 
made by the machine during the test. You will be asked to wear earplugs and MRI compatible 
earphones while in the machine. You may not participate in this study if you have a pacemaker, 
an implanted defibrillator or certain other implanted electronic or metallic devices. It is important 
for you to tell the MRI staff if you have had brain surgery for a cerebral aneurysm, or if you have 
implanted medical or metallic devices, shrapnel or other metal, such as metal in your eye. 
Diazoxide: The risk associated with higher doses of diazoxide therapy is hypotension (low blood 
pressure). Symptoms of low blood pressure are dizziness and light-headedness. During the study, 
there will be frequent monitoring of blood pressure, and if your blood pressure drops, the study 
will be stopped and treatment (intravenous salt solution) will be given until blood pressure returns 
to normal. Please note that the amount of diazoxide given in this study will be much lower than 
the doses which cause lowering of blood pressure. Another side effect of higher dose, long-term 
oral diazoxide is fluid retention and swelling. 
Intravenous Catheter: The amount of blood drawn during the procedure (approximately 15 
teaspoons for each separate study) is considerably less than that donated at a blood bank and 
will be replaced with intravenous fluid. The intravenous catheter is associated with a small risk of 
local bruising and discomfort. 
Allergic Reaction to Study Drug
Any drug can cause an allergic reaction which could be mild or more serious and can even result 
in death.  Common symptoms of an allergic reaction are rash, itching, skin problems, swelling of 
the face and throat, or trouble breathing.  If you are having trouble breathing, call 911 immediately.
New Findings
If we learn any significant new findings during the study that might influence your decision to 
participate, we will contact you and explain them.
Unknown Risks
We have described all the risks we know. However, because this is research, there a possibility 
that you will have a reaction that we do not know about yet and is not expected. If we learn 
about other risks, we will let you know what they are so that you can decide whether or not you 
want to continue to be in the study.
Are there possible benefits to me? 
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021


Diazoxide/fMRI/ND
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You will not experience any direct benefit personally from participating in this study. We hope you 
will participate because this study may result in a better understanding of role of the brain in 
glucose production in people with diabetes.
Are there any consequences to me if I decide to stop participating in this study?
No. If you decide to take part, you are free to stop participating at any time without giving a reason. 
This will not affect your care and you will continue to be treated at this facility. However, some of 
the information may have already been entered into the study and that will not be removed. The 
researchers may continue to use and share the information they have already collected.
To revoke (take back) your consent and authorization, you must contact the Principal Investigator 
in writing at the address on page 1 of this form. However, you may first call or speak to the 
Principal Investigator and she will stop collecting new information about you.  If you take back 
your consent and authorization, you will not be allowed to continue to participate in this research 
study.
Can the study end my participation early?
We will not let you participate in the study any more if 1) you experience an adverse reaction 
to the study drug, 2) you test positive to a drug test during the screening or morning of 
the study. In addition, your participation will end if the investigator or study sponsor stops the 
study earlier than expected.
CONSENT TO PARTICIPATE
I have read the consent form and I understand that it is up to me whether or not I participate. I 
know enough about the purpose, methods, risks and benefits of the research study to decide 
that I want to take part in it. I understand that I am not waiving any of my legal rights by signing 
this informed consent document. I will be given a signed copy of this consent form.
Printed name of participant
Signature of participant
Date
Time
Printed name of the person 
conducting the consent 
process
Signature
Date
Time
IRB NUMBER: 2018-9040
IRB APPROVAL DATE: 04/22/2020
IRB EXPIRATION DATE: 04/21/2021