Regulation of Endogenous Glucose Production by Central KATP Channels

Sponsor

Albert Einstein College of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT03540758

Collaborator

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

Enrollment

Location

Arms

104.9

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

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.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.

Masking:

Single (Participant)

Masking Description:

The subject will be blinded as to which study drug he/she is receiving first (Drug or Placebo).

Primary Purpose:

Basic Science

Official Title:

Regulation of Endogenous Glucose Production by Central KATP Channels

Actual Study Start Date :

Aug 1, 2018

Anticipated Primary Completion Date :

Apr 30, 2027

Anticipated Study Completion Date :

Apr 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Non-diabetic (Diazoxide) Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to non-diabetic participants.	Drug: Diazoxide Non-diabetic participants will receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. Other Names: Proglycem
Placebo Comparator: Non-diabetic (Placebo) Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to non-diabetic participants.	Drug: Placebo Non-diabetic participants will receive placebo and undergo the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive a taste-matched placebo for diazoxide before undergoing the pancreatic clamp study. Other Names: Control
Experimental: T2D (Diazoxide) Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to type 2 diabetic participants.	Drug: Diazoxide Non-diabetic participants will receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. Other Names: Proglycem
Placebo Comparator: T2D (Placebo) Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to type 2 diabetic participants.	Drug: Placebo Non-diabetic participants will receive placebo and undergo the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive a taste-matched placebo for diazoxide before undergoing the pancreatic clamp study. Other Names: Control
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.	Drug: Diazoxide Non-diabetic participants will receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive diazoxide at a dose of 4-7 mg/kg (based upon weight) before undergoing the pancreatic clamp study. Other Names: Proglycem Drug: Nicotinic acid T2D participants will have their blood sugar levels normalized and will additionally receive nicotinic acid infusion based on weight (0.01 mg/kg/min) to lower free fatty acid levels before undergoing the pancreatic clamp study. Other Names: Niacin
Experimental: T2D (Nicotinic Acid + placebo for diazoxide) Pancreatic clamp study will be done after lowering free fatty acids with a nicotinic acid (Niacin) infusion in type 2 diabetic participants, and after giving a taste-matched placebo for Diazoxide (Proglycem) to type 2 diabetic participants.	Drug: Nicotinic acid T2D participants will have their blood sugar levels normalized and will additionally receive nicotinic acid infusion based on weight (0.01 mg/kg/min) to lower free fatty acid levels before undergoing the pancreatic clamp study. Other Names: Niacin Drug: Placebo Non-diabetic participants will receive placebo and undergo the pancreatic clamp study. T2D participants will have their blood sugar levels normalized, and will then receive a taste-matched placebo for diazoxide before undergoing the pancreatic clamp study. Other Names: Control

Outcome Measures

Primary Outcome Measures

Endogenous glucose production (EGP) [7-7.5 hours]
Rates of EGP (a measure of the body's production of sugar) will be measured using analysis of blood samples taken throughout the pancreatic clamp procedure under various treatment conditions (eg, placebo, diazoxide, nicotinic acid, nicotinic acid/diazoxide), by monitoring changes in the level of a non-radioactive, naturally occurring form of glucose (sugar).

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

For healthy participants:

Age: 21-70 y.o.
BMI under 35
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
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