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Regulation of Endogenous Glucose Production by Central KATP Channels

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ClinicalTrials.gov Identifier: NCT03540758
Recruitment Status : Recruiting
First Posted : May 30, 2018
Last Update Posted : September 17, 2019
Sponsor:
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
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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
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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 : November 2020
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 be admitted the evening before the study day to normalize blood sugar levels to that of a healthy person. They will then receive placebo the next morning and undergo 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 be admitted the evening before the study day to normalize blood sugar levels to that of a healthy person. They will then receive placebo the next morning and undergo 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 Only)
Pancreatic clamp study will be done after lowering free fatty acids with a nicotinic acid (Niacin) infusion in 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


Outcome Measures
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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
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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 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
  • 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03540758


Contacts
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Contact: Joy Moy 718-430-2903 joy.moy@einstein.yu.edu

Locations
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United States, New York
Albert Einstein College of Medicine Recruiting
Bronx, New York, United States, 10461
Principal Investigator: Meredith Hawkins, M.D., M.S.         
Sponsors and Collaborators
Albert Einstein College of Medicine
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Meredith Hawkins, M.D., M.S. Albert Einstein College of Medicine
More Information
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Responsible Party: Meredith Hawkins, Principal Investigator, Albert Einstein College of Medicine
ClinicalTrials.gov Identifier: NCT03540758     History of Changes
Other Study ID Numbers: 2018-9039
R01DK069861 ( U.S. NIH Grant/Contract )
First Posted: May 30, 2018    Key Record Dates
Last Update Posted: September 17, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Diabetes Mellitus, Type 2
Metabolic Diseases
Glucose Metabolism Disorders
Hyperglycemia
Diabetes Mellitus
Endocrine System Diseases
Niacin
Niacinamide
Nicotinic Acids
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