Use of Functional MRI to Assess Functional Hypothalamic Activation in Response to Diazoxide

Study Overview
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Brief Summary
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The goal of this study is to determine whether metabolic control centers in the brain can be activated in patients with type 2 diabetes 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
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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 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.

Official Title
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Use of Functional MRI to Assess Functional Hypothalamic Activation in Response to Diazoxide

Conditions
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Diabetes Mellitus, Type 2, Glucose, High Blood, Glucose Metabolism Disorders (Including Diabetes Mellitus)

Intervention / Treatment
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* Drug: Diazoxide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes (T2D) Age: Between 21 and 70 y.o. BMI: <35 A1c 8.0-12.0% Negative drug screen Not suffering from proliferative retinopathy, significant diabetic renal disease or severe neuropathy (including cardiovascular and gastrointestinal autonomic dysfunction) Healthy (ND) Age: Between 21 and 70 y.o. BMI: <30 Negative drug screen No family history of diabetes among first-degree relatives (mother, father) Exclusion Criteria: Age: Under 21 or over 70 y.o. BMI: >35 for T2D and >30 for ND Hypertension Severe polydipsia and polyuria Uncontrolled hyperlipidemia Clinically significant liver dysfunction Clinically significant kidney dysfunction Anemia Clinically significant leukocytosis or leukopenia Clinically significant thrombocytopenia or thrombocytosis Coagulopathy Positive urine drug screen Urinalysis: Clinically significant abnormalities Clinically significant electrolyte abnormalities Smoking >10 cig/day Alcohol: Men >14 drinks/wk or > 4 drinks/day, Women >7 drinks/wk or >3 drinks/day 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 Pregnant women Subject enrolled in another study less than one month prior to the anticipated start date of the proposed study Family history: family history of premature cardiac death Allergies to medication administered during study Uncontrolled psychiatric disorders Perimenopausal women who are experiencing/have experienced hot flashes 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. Any condition which in the opinion of the PI makes the subject ill-suited for participation in the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy (Diazoxide)<br>Proglycem, oral suspension (4-7 mg/kg). Healthy participants will receive diazoxide between MRI scans. | Drug: Diazoxide<br>* 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.<br>* Other names: Proglycem;|
| Placebo Comparator: Healthy (Placebo)<br>Taste-matched placebo. Healthy participants will receive placebo between MRI scans. | Drug: Placebo<br>* Healthy and T2D participants will receive placebo between baseline MRI scan and second MRI scan.<br>|
| Experimental: T2D (Diazoxide)<br>Proglycem, oral suspension (4-7 mg/kg). Type 2 diabetic (T2D) participants will receive diazoxide between MRI scans. | Drug: Diazoxide<br>* 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.<br>* Other names: Proglycem;|
| Placebo Comparator: T2D (Placebo)<br>Taste-matched placebo. T2D participants will receive placebo between MRI scans. | Drug: Placebo<br>* Healthy and T2D participants will receive placebo between baseline MRI scan and second MRI scan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Arterial Spin Labeling (ASL) signal measured using 3T MRI from Baseline to 2 hours post dosing | ASL is a measure of brain blood flow, and an increase in ASL is interpreted as an increase in brain activity. Data is collected at three time points during each of the two visits (pre dosing, 2 hours post dosing, 4 hours post dosing). Data is compared between Non-Diabetic and Type 2 Diabetic Subjects. | Baseline, 2 hours post dosing | 
| Change in Arterial Spin Labeling (ASL) signal measured using 3T MRI from 2 hours post dosing to 4 hours post dosing | ASL is a measure of brain blood flow, and an increase in ASL is interpreted as an increase in brain activity. Data is collected at three time points during each of the two visits (pre dosing, 2 hours post dosing, 4 hours post dosing). Data is compared between Non-Diabetic and Type 2 Diabetic Subjects. | 2 hours post dosing, 4 hours post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, type 2 diabetes, insulin resistance, diazoxide, MRI