use of functional mri to assess functional hypothalamic activation in response to diazoxide

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

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.

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.

Eligibility criteria:
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

Keywords: diabetes type 2 diabetes insulin resistance diazoxide mri