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

Phase 2

Terminated

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

Interventions: Drug: Diazoxide
Drug: Placebo

Registration Number: NCT03566511

Lead Sponsor: Meredith Hawkins

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 37

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Healthy (Diazoxide)	Diazoxide	Proglycem, oral suspension (4-7 mg/kg). Healthy participants will receive diazoxide between MRI scans.
Healthy (Placebo)	Placebo	Taste-matched placebo. Healthy participants will receive placebo between MRI scans.
T2D (Diazoxide)	Diazoxide	Proglycem, oral suspension (4-7 mg/kg). Type 2 diabetic (T2D) participants will receive diazoxide between MRI scans.
T2D (Placebo)	Placebo	Taste-matched placebo. T2D participants will receive placebo between MRI scans.

Primary Outcome Measures

Name	Time	Method
Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing	2 hours and 5 hours post dosing	Arterial Spin Labeling data was acquired and converted by the Gruss Magnetic Resonance Research Center (MRRC) and reported as Hypothalamic Cerebral Blood Flow (CBF) which is a more meaningful clinical endpoint measurement. Data was collected at three time points during each of the two study visits (pre dosing, 2 hours post dosing, and 5 hours post dosing). CBF values at the respective timepoints are summarized in mL/100g/min units and reported by study arm. An increase in CBF is correlated with an increase in brain activity.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (1): Albert Einstein College of Medicine
🇺🇸
Bronx, New York, United States
Albert Einstein College of Medicine
🇺🇸Bronx, New York, United States