Regulation of Endogenous Glucose Production by Central KATP Channels

Type 2 diabetes (T2D) 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.

Study Overview

• Status: Recruiting
• Conditions: Glucose Metabolism Disorders; Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Diazoxide; Drug: Nicotinic acid

Detailed Description

In this study, the investigators will study healthy participants 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 body's ability to regulate glucose levels.

Aim 1: non-diabetic participants will be studied after receiving diazoxide or placebo in a randomized, single-blinded fashion to determine whether extra-pancreatic KATP channels regulate hepatic glucose fluxes in non-diabetic humans.

For Aim 1, 15 healthy, non-diabetic individuals will be studied under the following experimental conditions, in random order and in double blinded fashion:

1. normoglycemic 'pancreatic clamp' studies with administration of placebo
2. normoglycemic 'pancreatic clamp' studies with administration of diazoxide

Aim 2: these non-diabetic participants will also be studied after receiving diazoxide or placebo in a randomized, single-blinded fashion after lowering their free fatty acid (FFA) levels to determine whether central regulation of glucose fluxes can be restored upon lowering FFA levels.

1. normoglycemic (90 mg/dl) pancreatic clamp studies will be performed following nicotinic acid administration, and placebo
2. normoglycemic (90 mg/dl) pancreatic clamp studies will be performed following nicotinic acid administration, and diazoxide

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Meredith Hawkins, M.D., M.S.; Phone Number: 718-430-2903; Email: meredith.hawkins@einsteinmed.edu

Study Locations

• United States
  • New York
    • The Bronx, New York, United States, 10461
      • Recruiting
      • Albert Einstein College of Medicine
      • Principal Investigator: Meredith Hawkins, M.D., M.S.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

For healthy (non-diabetic) participants:

• Age: 21-70 years old
• Body Mass Index (BMI) under 40 kg/m^2
• Negative drug screen (see below)
• Normal Hemoglobin A1c (HbA1c) and fasting glucose
• In general good health (see below for exclusions)
• Not participating in any other research study besides those done by the study team

For T2D participants:

• Age: 21-70 years old
• BMI under 40 kg/m^2
• Stable and moderate-to-poor glycemic control (HbA1c: 8.0-12.0%)
• Negative drug screen (see below)
• Not suffering from a previously diagnosed proliferative retinopathy, significant diabetic renal disease (urinary microalbumin <100 μg/dl) or severe peripheral neuropathy (including cardiovascular and gastrointestinal autonomic neuropathy) per medical history
• Diabetic subjects will be otherwise in good health (see below for exclusions), taking no medications that might affect study eligibility based on review by study doctor, and not participating in any other research study besides those done by the study team

Exclusion Criteria:

• Age: Under 21 or over 70 years old
• BMI: >40 kg/m^2 for Type 2 Diabetes (T2D) and Non-Diabetic (ND) subjects
• Blood pressure >150/90 or <90/60 on more than one occasion
• Severe polydipsia and polyuria (in subjects with T2D). Since polydipsia and polyuria are common symptoms of T2D, the distinction "severe" denotes that the subject indicates a worsening in the symptoms and/or an experience of discomfort related to the symptoms at the time of screening and/or at the time of withdrawal from the medications
• Urine microalbumin: >300 mg/g of creatinine (in subjects with T2D)
• Uncontrolled hyperlipidemia defined as Triglycerides (TG) > 400 mg/dL and/or Total Cholesterol >300 mg/dL
• Clinically significant liver dysfunction including thrombocytopenia (platelets <100,000/uL), anemia (as below), hypoalbuminemia (<3.5 g/dL), coagulopathy (INR > 1.5), and/or liver enzymes more than 3 times the upper limit of normal
• Clinically significant kidney dysfunction, Glomerular Filtration Rate (GFR): <60 mg/dL
• Clinically significant anemia. Prospective subjects with hemoglobin below the lower limit of 12 g/dl for for men and 11 g/dL for women will be assessed with history and physical exam to rule out clinically significant anemia, defined as an individual with symptoms (e.g., fatigue, weakness, shortness of breath, palpitations), signs (pallor, brittle nails etc.), or currently under treatment for anemia. In the absence of a documented hemoglobin decrease or iron deficiency, subjects will not be excluded
• Clinically significant leukocytosis or leukopenia
• Clinically significant thrombocytopenia or thrombocytosis
• Coagulopathy
• Urine drug screen positive for any of the following: amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, oxycodone, phencyclidine (PCP). Amphetamines, oxycodone, opiates, methadone, and benzodiazepines have been shown to affect glucose metabolism (increased glycemia, increased fasting insulin levels, delayed insulin response to food ingestion, insulin deficiency). As the drug test available in the Clinical Research Center (CRC) is a 7-drug panel, the investigator team cannot specifically choose which drugs are screened for. Additionally, in the interest of selecting patients on the basis of their reliability and dependability, the investigator team would like to exclude participants using illicit drugs. Occasional use of cannabis (once or twice per week) is not an exclusion factor. If the test is read as "indeterminate" it will be repeated at the bedside and an additional sample will be sent to the lab. Decision to enroll subject that day prior to results from lab being available will be decided on a case-by-case basis, i.e., when all previous drug testing had been negative and clinical suspicion is very low
• Urinalysis: Clinically significant abnormalities
• Clinically significant electrolyte abnormalities
• Smoking >10 cigarettes/day
• Alcohol: Men >14 drinks/week or >4 drinks/day, Women >7 drinks/week 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 (if euthyroid on thyroid hormone replacement - if such history free thyroxine (fT4) and Thyroid Stimulating Hormone (TSH) will be checked)
• 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 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / 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) during 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: Non-diabetic (Diazoxide + Nicotinic Acid); Pancreatic clamp study will be done after giving Diazoxide (Proglycem) oral suspension to non-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) during the pancreatic clamp study.; Other Names: Proglycem; Drug: Nicotinic acid; Non-diabetic participants will receive nicotinic acid infusion based on weight (0.01 mg/kg/min) during the pancreatic clamp study.; Other Names: Niacin
Experimental: Non-diabetic (Nicotinic Acid + placebo for diazoxide); Pancreatic clamp study will be done after lowering free fatty acids with a nicotinic acid (Niacin) infusion in non-diabetic participants, and after giving a taste-matched placebo for Diazoxide (Proglycem) toon-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; Drug: Nicotinic acid; Non-diabetic participants will receive nicotinic acid infusion based on weight (0.01 mg/kg/min) during the pancreatic clamp study.; Other Names: Niacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Endogenous glucose production (EGP) rate	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 (e.g., placebo, diazoxide, nicotinic acid, nicotinic acid/diazoxide), by monitoring changes in the level of a non-radioactive, naturally occurring form of glucose (sugar). Measurement of blood glucose concentrations will either be performed with a Precision Xceed Pro glucometer or an Analox glucose analyzer in the study room. Increased EGP is the major cause of fasting hyperglycemia. EGP will be determined by subtracting the rates of glucose infusion from the tracer-derived Rates of glucose appearance (Ra). Rates of change in EGP will be reported in concentration/time and summarized by study arm using basic descriptive statistics.	7 hour infusions, 4 days in total, separated at least 1 month apart, up to 1 year duration

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH); Vanderbilt University Medical Center; American Diabetes Association; Rutgers University
• Investigators: Principal Investigator: Meredith Hawkins, M.D., M.S., Albert Einstein College of Medicine

Publications and helpful links

General Publications

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• Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes. 37(8):1020-4, 1988.
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• Massillon, D, Barzilai, N, Hawkins, M, Prus-Wertheimer, D, Rossetti, L. Induction of hepatic glucose-6- phosphatase gene expression by lipid infusion. Diabetes 46:153-7, 1997.
• van de Werve G, Lange A, Newgard C, Mechin MC, Li Y, Berteloot A. New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system. Eur J Biochem. 267(6): 1533-49, 2000.
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• Lam, TK, van de Werve, G, Giacca, A. Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab. 284:E281-90, 2003.
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• Hawkins M, Gabriely I, Wozniak R, Mevorach M, Rossetti L, Shamoon H. The Effect of Glycemic Control on Hepatic and Peripheral Glucose Effectiveness in Type 2 Diabetes Mellitus. Diabetes 2002; 51:2179 89.
• Hawkins M, Tonelli J, Kishore P, Stein D, Ragucci E, Gitig A, Reddy K. Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes. Diabetes 2003; 52(11):2748-58
• Cota D, Proulx K, Seeley RJ. The role of CNS fuel sensing in energy and glucose regulation. , Gastroenterology 2007; 132(6):2158-68
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• Lam TKT, Gutierrez-Juarez R, Pocai A, Rossetti L. Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism. Science. 2005;309(5736):943-7.
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• Lam TKT, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005;11(3):320-
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• Seino S, Iwanaga T, Nagashima K, Miki T. Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. Diabetes 49:311-318, 2000
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• Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats. McCrimmon RJ, Evans ML, Fan X, McNay EC, Chan O, Ding Y, Zhu W, Gram DX, Sherwin RS. Diabetes. 2005 Nov;54(11):3169 74.
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• Schiwek, A., Lee, D.E., Saper, M., Rossetti, L., Kishore, P., and Hawkins, M. Diazoxide suppresses endogenous glucose production in humans. Diabetes 56:A393, 2007
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Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: May 17, 2018
• First Submitted That Met QC Criteria: May 17, 2018
• First Posted (Actual): May 30, 2018

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; endogenous glucose production; diazoxide; Central KATP Channels
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sulfonamides; Sulfones; Acids, Heterocyclic; Nicotinic Acids; Benzothiadiazines; Thiazides; Niacin; Diazoxide
• Other Study ID Numbers: 2018-9039; R01DK069861 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data intended for broader use will be free of identifiers that would permit linkages to individual research participants. Data and associated documentation will be made available to users only if:

1. a commitment to using the data only for research purposes and not to identify any individual participant is provided;
2. a commitment to securing the data using appropriate computer technology; and
3. a commitment to destroying or returning the data after analyses are completed.

• IPD Sharing Time Frame: Following publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• 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