Regulation of Endogenous Glucose Production by Central KATP Channels

• ClinicalTrials.gov Identifier: NCT03540758
• Recruitment Status: Suspended
• First Posted: May 30, 2018
• Last Update Posted: January 14, 2021
• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Meredith Hawkins, Albert Einstein College of Medicine

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 (Clinical Trial)
• Estimated Enrollment: 45 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.
• 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: August 1, 2018
• Estimated Primary Completion Date: April 2022
• Estimated Study Completion Date: April 2022

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 Name: 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.
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 Name: 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.
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 Name: 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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Endogenous glucose production (EGP) [ Time Frame: 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

• Ages Eligible for Study: 21 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, New York

Albert Einstein College of Medicine

Bronx, New York, United States, 10461

Sponsors and Collaborators

Albert Einstein College of Medicine

National Institutes of Health (NIH)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Meredith Hawkins, M.D., M.S.; Albert Einstein College of Medicine

More Information

• Responsible Party: Meredith Hawkins, Principal Investigator, Albert Einstein College of Medicine
• ClinicalTrials.gov Identifier: NCT03540758
• Other Study ID Numbers: 2018-9039; R01DK069861 ( U.S. NIH Grant/Contract )
• First Posted: May 30, 2018
• Last Update Posted: January 14, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Meredith Hawkins, Albert Einstein College of Medicine:

type 2 diabetes; diabetes; insulin resistance; diazoxide

Additional relevant MeSH terms:

Diabetes Mellitus, Type 2; Metabolic Diseases; Glucose Metabolism Disorders; Hyperglycemia; Diabetes Mellitus; Endocrine System Diseases; Niacin; Nicotinic Acids; Niacinamide; Diazoxide; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Vasodilator Agents; Vitamin B Complex; Vitamins; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Antihypertensive Agents