The Effect of the Interaction of Glucagon and Insulin on Endogenous Glucose Production in Humans

Study A (Insulin 0.4mU/Kg/min): Subjects will be admitted to the CRTU at approximately 1700 on the day prior to study. They will then consume a standard 10kcal/kg meal (55% carbohydrate, 30% fat, 15% protein, caffeine free) and fast overnight. Blood will then be sampled for baseline enrichment and 2H20 (1.67g/kg of body water) will be given in 3 divided doses at 2200, 2400 and 0200. The following morning (approximately 0530), a forearm vein will be cannulated to allow infusions to be performed. In addition, a cannula will be inserted retrogradely into a vein of the contra-lateral dorsum of the hand. This will be placed in a heated Plexiglas box maintained at around 120oF to allow sampling of arterialized venous blood. At approximately 0600 (-180 min), a primed, (10microCi prime, 0.1microCi/min continuous) infusion containing trace amounts of glucose labeled with [3-3H] glucose will be started and continued till 0900 (0 min).

At 0900 (0 min), the infusion will be varied so as to mimic the anticipated pattern of fall of EGP. In addition, glucose also labeled with [3-3H] glucose will be infused so as to maintain glucose concentrations at ~ 95mg/dL. Peripheral venous glucose concentrations will be measured every 10 minutes to allow the infusion rate of glucose to be adjusted as necessary.

Simultaneously, an infusion of somatostatin (60ng/kg/min) will be started at time 0 to inhibit endogenous islet secretion and therefore ensure identical portal insulin concentrations on the two study days. Insulin will be infused at a constant rate known to produce ~ 50% suppression of EGP (0.4mU/Kg/min).

From 0900 (0 min) to 1030 (90 min) no glucagon will be infused. Subsequently, a glucagon infusion will commence (91 - 180 min) at 0.35 ng/Kg/min and then increase to 0.70 ng/Kg/min (181- 270 min), a rate which will be maintained till the end of the study (1330).

Study B (0.8mU/Kg/min): Approximately 1-2 weeks after the first study visit, subjects will be asked to return to the CRTU. This study visit will be similar to Study A. However, insulin will be infused at 0.8mU/Kg/min 0 to 270 minutes.

Inclusion criteria

• We will recruit 15 otherwise healthy subjects using intramural and local extramural advertising after approval from the Mayo Clinic Institutional Review Board. Individuals who express interest in participating will be invited for a screening visit. Individuals with a BMI < 19 or > 28 kg/m2 will be excluded from the study to avoid potential confounding effects that may result from extreme leanness or from obesity. Subjects will have no known systemic illness, taking any medication that could affect glucose metabolism and no history of upper gastrointestinal surgery.

Exclusion criteria

• Subjects < 18 years of age or > 40 years of age will not be studied to minimize the potential confounding effects of age on glucagon and insulin action. The subjects will not be taking medications that affect glucose metabolism (to be determined by PI) and have no history of chronic illness or upper gastrointestinal surgery. We are seeking to recruit subjects who do not have diabetes (fasting glucose <100mg/dL).