NCT03540758

Regulation of Endogenous Glucose Production by Central KATP Channels

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 100 (estimated)
• Sponsor: Meredith Hawkins · Academic / Other
• Sex: All
• Age: 21 Years – 70 Years
• Healthy volunteers: Accepted

Summary

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.

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 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: participants with type 2 diabetes will be studied after receiving diazoxide or placebo in a randomized, single-blinded fashion to establish whether central regulation of glucose production is impaired in patients with T2D For Aim 2, the study population will consist of 15 subjects with moderate-to-poorly controlled Type 2 Diabetes Mellitus (HbA1c 8-12%). In these studies, the effects of diazoxide on EGP under the following 2 experimental conditions will be examined, on separate occasions at least 3 weeks apart, in random order and in double blinded fashion: 3. normoglycemic 'pancreatic clamp' studies with administration of placebo 4. normoglycemic 'pancreatic clamp' studies with administration of diazoxide 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 (FFA) levels to determine whether central regulation of glucose fluxes can be restored upon lowering FFA levels in T2D. Chronic, moderate increases in FFA levels characteristic of T2D can increase EGP through multiple effects on hepatic glucose fluxes, which may overwhelm the effects of activating central KATP channels. 15 nondiabetic and 15 T2D subjects will be studied under baseline conditions and following nicotinic acid administration, under the following experimental conditions. EGP will be assessed in each subject on separate occasions, at least 3 weeks apart. Placebo and diazoxide will be administered in random order and in double blinded fashion. Heart rate variability may be assessed as a measure of vagal nerve activation: 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

Conditions

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

Interventions

Type	Name	Description
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.
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.
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.

Timeline

• Start date: 2018-08-01
• Primary completion: 2027-04-01
• Completion: 2027-04-01
• First posted: 2018-05-30
• Last updated: 2025-04-01

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study