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Regulation of Endogenous Glucose Production by Central KATP Channels

Primary Purpose

Type 2 Diabetes Mellitus, Glucose Metabolism Disorders, Glucose, High Blood

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Diazoxide

Nicotinic acid

Placebo

About this trial

This is an interventional basic science trial for Type 2 Diabetes Mellitus focused on measuring type 2 diabetes, diabetes, insulin resistance, diazoxide

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Albert Einstein College of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Arm Label

Non-diabetic (Diazoxide)

Non-diabetic (Placebo)

T2D (Diazoxide)

T2D (Placebo)

T2D (Diazoxide + Nicotinic Acid)

T2D (Nicotinic Acid + placebo for diazoxide)

Arm Description

Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to non-diabetic participants.

Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to non-diabetic participants.

Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to type 2 diabetic participants.

Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to type 2 diabetic participants.

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.

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.

Outcomes

Primary Outcome Measures

Endogenous glucose production (EGP)

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).

Secondary Outcome Measures

Full Information

NCT ID

NCT03540758

First Posted

May 17, 2018

Last Updated

September 8, 2023

Sponsor

Albert Einstein College of Medicine

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT03540758

Brief Title

Regulation of Endogenous Glucose Production by Central KATP Channels

Official Title

Regulation of Endogenous Glucose Production by Central KATP Channels

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 1, 2018 (Actual)

Primary Completion Date

April 2027 (Anticipated)

Study Completion Date

April 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Albert Einstein College of Medicine

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus, Glucose Metabolism Disorders, Glucose, High Blood

Keywords

type 2 diabetes, diabetes, insulin resistance, diazoxide

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

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

Participant

Masking Description

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

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Non-diabetic (Diazoxide)

Arm Type

Experimental

Arm Description

Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to non-diabetic participants.

Arm Title

Non-diabetic (Placebo)

Arm Type

Placebo Comparator

Arm Description

Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to non-diabetic participants.

Arm Title

T2D (Diazoxide)

Arm Type

Experimental

Arm Description

Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to type 2 diabetic participants.

Arm Title

T2D (Placebo)

Arm Type

Placebo Comparator

Arm Description

Pancreatic clamp study will be done after giving a taste-matched placebo for Diazoxide (Proglycem) to type 2 diabetic participants.

Arm Title

T2D (Diazoxide + Nicotinic Acid)

Arm Type

Experimental

Arm Description

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.

Arm Title

T2D (Nicotinic Acid + placebo for diazoxide)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Diazoxide

Other Intervention Name(s)

Proglycem

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Nicotinic acid

Other Intervention Name(s)

Niacin

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Control

Intervention Description

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.

Primary Outcome Measure Information:

Title

Endogenous glucose production (EGP)

Description

Time Frame

7-7.5 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Meredith Hawkins, M.D., M.S.

Phone

718-430-2903

meredith.hawkins@einsteinmed.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Meredith Hawkins, M.D., M.S.

Organizational Affiliation

Albert Einstein College of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Albert Einstein College of Medicine

City

Bronx

State/Province

New York

ZIP/Postal Code

10461

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Meredith Hawkins, M.D., M.S.

12. IPD Sharing Statement

Plan to Share IPD

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Regulation of Endogenous Glucose Production by Central KATP Channels

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