Diabetes Mellitus, Type 2, Glucose, High Blood, Glucose Metabolism Disorders (Including Diabetes Mellitus)
Conditions
Keywords
diabetes, type 2 diabetes, insulin resistance, diazoxide, MRI
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.
Interventions
DRUGDiazoxide
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.
DRUGPlacebo
Healthy and T2D participants will receive placebo between baseline MRI scan and second MRI scan.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
American Diabetes Association
Meredith Hawkins
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
The subject will be blinded to which study drug is received first (Drug or Placebo).
Intervention model description
Study was initially intended to be a double blinded, randomized, crossover design; however, it was terminated early due to issues with magnetic resonance (MR) system.
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
37 patients signed consent and were screened for eligibility. Following screening, 22 patients were deemed eligible. Of the 22, 11 did not enroll in the study after passing the screening for various reasons including being lost to follow-up or unable to commit. In summary, 11 patients were enrolled and randomized into the study; however, randomization order cannot be verified from documentation for 3 study patients. These 3 patients did not complete the overall study and were never unblinded.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Proglycem, oral suspension (4-7 mg/kg). Healthy participants will receive Diazoxide between MRI scans.
Diazoxide: Participants will receive Diazoxide at a dose of 4-7 mg/kg (based upon body weight) between baseline MRI scan and second MRI scan.
Participants will receive placebo between baseline MRI scan and second MRI scan. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1st Intervention (1 Day) | Study terminated and participant never received Diazoxide (DZX) | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 11 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 11 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 9 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 1 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 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.
Time frame: 2 hours and 5 hours post dosing
Population: 7 patients were able to complete both studies within the crossover design as described in the 'Participant Flow' module and have their data analyzed. An additional 4 patients (3 healthy, and 1 T2D) were not able to complete their measurements and, therefore, no data are available for these patients. Standard error (SE) data for the DZX studies were derived from visual estimates of the bar graphs. SE data for the Placebo studies were extrapolated from DZX studies.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diazoxide | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | Baseline | 29.78 mL/100g/min | Standard Error 1.3 |
| Diazoxide | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | 2 hours | 26.52 mL/100g/min | Standard Error 1.7 |
| Diazoxide | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | 5 hours | 28.88 mL/100g/min | Standard Error 1.4 |
| Matched Placebo | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | Baseline | 28.36 mL/100g/min | Standard Error 1.3 |
| Matched Placebo | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | 2 hours | 26.25 mL/100g/min | Standard Error 2 |
| Matched Placebo | Change in Arterial Spin Labeling (ASL) Signal Measured Using 3T MRI From Baseline to 5 Hours Post Dosing | 5 hours | 27.75 mL/100g/min | Standard Error 1.4 |