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

Sponsor

Albert Einstein College of Medicine (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03566511

Collaborator

National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

Arms

51.6

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2 Glucose, High Blood Glucose Metabolism Disorders (Including Diabetes Mellitus)	Drug: Diazoxide Drug: Placebo	Phase 2

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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Single (Participant)

Masking Description:

The subject will be blinded to which study drug is received first (Drug or Placebo).This protocol follows a double blinded, randomized, crossover design.

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jun 12, 2018

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Change in Arterial Spin Labeling (ASL) signal measured using 3T MRI from Baseline to 2 hours post dosing [Baseline, 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.
Change in Arterial Spin Labeling (ASL) signal measured using 3T MRI from 2 hours post dosing to 4 hours post dosing [2 hours post dosing, 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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