Central Mechanisms That Regulate Glucose Metabolism in Humans

Central Mechanisms That Regulate Glucose Metabolism in Humans

Type 2 diabetes is a chronic condition that affects the ability of the body to regulate glucose (sugar). When glucose levels are low, the liver can make glucose to increase levels in the body. This important process is called endogenous glucose production (EGP). Previous studies suggest that the central nervous system (CNS), including the brain, helps to coordinate this process by communicating with the liver through potassium channels. Control of EGP can be impaired in people with type 2 diabetes, which may contribute to the high levels of glucose seen in these individuals.

The purpose of this study is to understand how activating these potassium channels in the control centers of the brain with a medication called diazoxide might inhibit the amount of glucose made by the liver. This is particularly important for people with diabetes who have very high production of glucose, which in turn causes hyperglycemia (high levels of sugar in the blood) that leads to diabetes complications.

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 (the production of sugar by the liver) 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.

All experiments will consist of 240 min insulin/somatostatin (250 μg/hr) infusions with replacement of glucoregulatory hormones (glucagon 1 ng/kg·min; growth hormone 3 ng/kg·min). Throughout the study, the plasma glucose concentration will be maintained at basal levels ( ~90 mg/dl). This will be attained by infusion of insulin at adequate rates to maintain normoglycemia without requiring glucose infusion. Primed continuous infusions of High-performance liquid chromatography-purified [3-3H]-glucose will be initiated at t=0 (21.6 μCi bolus, then 0.15 μCi/min), to measure glucose fluxes. All infusions will be stopped at t=240 min. From t=0 to t=240 min, blood samples will be obtained for determinations of plasma glucose, insulin, glucagon, C-peptide, cortisol, growth hormone, free fatty acids (FFA), glycerol, and lactate, and for 3-3H-glucose determinations.

This registration is exclusive to Aim 1 of the study protocol, which determined the effect of diazoxide on hepatic glucose production in nondiabetic, healthy, young individuals under fixed hormonal conditions. Euglycemic (90 mg/dl x 4 hours) pancreatic clamp studies (n= 10), with either saline or diazoxide infusion.

Inclusion Criteria:

• Healthy volunteers
• Be no more than 140% of body weight
• No concurrent illnesses

Exclusion Criteria:

• No clinical history or laboratory evidence of hyperlipidemia (LDL cholesterol < 160 mg/dL)
• Clinical history of Hypertension
• Clinical history of Heart disease
• Clinical history of Cerebrovascular disease
• Clinical history of Seizures
• Clinical history of Bleeding disorders
• Clinical history of Muscle disease
• Smokers
• Mentally disabled persons
• Prisoners
• Pregnancy
• Clinical history of ethanol or drug or toxin exposure which could be associated with neuropathy
• Subjects incapable of giving voluntary informed consent
• History of bleeding disorder
• Clinical history of prolonged Prothrombin Time (PT) or Partial Thromboplastin Time