Regulation of Endogenous Glucose Production by Central KATP Channels
Purpose
Type 2 diabetes affects the ability of the body to process glucose (sugar). Under fasting conditions, the liver is able to make sugar to maintain glucose levels in an important process called endogenous glucose production (EGP). Previous studies suggest that the central nervous system (CNS), including the brain, helps to regulate levels of glucose in the body by communicating with the liver. This process can be impaired in people with type 2 diabetes, and can contribute to the high level of glucose seen in these individuals. The purpose of this study is to understand how activating control centers of the brain with a medication called diazoxide can affect how much glucose (sugar) is made by the liver. This is particularly important for people with diabetes who have very high production of glucose, which in turn can lead to diabetes complications.
Conditions
- Type 2 Diabetes Mellitus
- Glucose Metabolism Disorders
- Glucose, High Blood
Eligibility
- Eligible Ages
- Between 21 Years and 70 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
For healthy participants:
- Age: 21-70 y.o.
- BMI under 30
- Negative drug screen
- Normal A1C and fasting glucose
- No family history of diabetes among first degree relatives (eg. mother, father)
For T2D participants:
- Age: 21-70 y.o.
- BMI under 35
- A1c 8.0-12.0%
- Negative drug screen
- Not suffering from a previously diagnosed proliferative retinopathy, significant diabetic renal disease or severe neuropathy (including cardiovascular and gastrointestinal autonomic dysfunction).
Exclusion Criteria
- Age: Under 21 or over 70 y.o.
- BMI: >35 for T2D and >30 for non-diabetic (ND)
- Blood pressure >150/90 or <90/60 on more than one occasion
- Severe polydipsia and polyuria
- Urine microalbumin: >300 mg/g of creatinine (in subjects with T2D)
- Uncontrolled hyperlipidemia
- Clinically significant liver dysfunction
- Clinically significant kidney dysfunction
- Clinically significant 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, besides those done by our group
- Family history: family history of premature cardiac death
- Allergies to medication administered during study
- Uncontrolled psychiatric disorders
- Any condition which in the opinion of the PI makes the subject ill suited for participation in the study
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover Assignment
- Intervention Model Description
- In Aim 1, non-diabetic participants will be studied after receiving diazoxide or placebo in a randomized, single-blinded fashion. In Aim 2, participants with type 2 diabetes will be studies after receiving diazoxide or placebo in a randomized, single-blinded fashion. In Aim 3, participants with type 2 diabetes will be studied after receiving diazoxide or placebo in a randomized, single-blinded fashion after lowering their free fatty acid levels.
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
- Masking Description
- The subject will be blinded as to which study drug he/she is receiving first (Drug or Placebo).
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Non-diabetic (Diazoxide) |
Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to non-diabetic participants. |
|
|
Placebo Comparator Non-diabetic (Placebo) |
Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to non-diabetic participants. |
|
|
Experimental T2D (Diazoxide) |
Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to type 2 diabetic participants. |
|
|
Placebo Comparator T2D (Placebo) |
Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to type 2 diabetic participants. |
|
|
Experimental T2D (Diazoxide + Nicotinic Acid) |
Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to type 2 diabetic participants after lowering free fatty acids with a nicotinic acid (Niacin) infusion. |
|
|
Experimental T2D (Nicotinic Acid Only) |
Pancreatic clamp study will be done after lowering free fatty acids with a nicotinic acid (Niacin) infusion in type 2 diabetic participants. |
|
Recruiting Locations
Bronx, New York 10461
More Details
- Status
- Recruiting
- Sponsor
- Albert Einstein College of Medicine
Detailed Description
In this study, the investigators will study healthy participants and participants with type 2 diabetes through a procedure called a "pancreatic clamp" study. During the clamp procedure, glucose (a sugar) and insulin (a hormone produced in the pancreas that regulates the amount of glucose in the blood) are infused with an intravenous catheter, and blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism. Endogenous glucose production (a measure of the body's production of sugar) will be measured in patients given diazoxide (a medication that activates potassium channels in the brain that may affect glucose production in the liver through brain-liver signaling), compared with when a placebo is given. This study will also investigate whether lowering free fatty acid levels which may help improve the the body's ability to regulate glucose levels.