The Effects of Glucagon on Hepatic Metabolism in People With Type 2 Diabetes After Caloric Restriction

The Effects of Glucagon on Hepatic Metabolism in People With Type 2 Diabetes After Caloric Restriction

The Effects of Glucagon on Hepatic Metabolism in People With Type 2 Diabetes After Caloric Restriction

Caloric restriction (and RYGB) improves insulin action and lowers fasting glucose, glucagon and EGP, without changes in postprandial EGP and glucagon concentrations. Caloric restriction also improves hepatic steatosis and lowers fasting AA. These changes may represent restoration of glucagon's hepatic actions. This experiment will determine whether caloric restriction improves glucagon's actions on hepatic amino acid, carbohydrate and lipid metabolism in T2DM in comparison to a baseline experiment performed separately in people with T2DM.

T2DM and prediabetes are characterized by abnormal post-prandial suppression of glucagon, which contributes to postprandial hyperglycemia by increasing EGP. Although these effects are magnified by decreased and delayed insulin secretion, they are also apparent when insulin secretion is intact5. In rodents, altered glucagon signaling changes α-cell function and mass - an effect mediated by changes in circulating AA concentrations. Are the elevated concentrations of branched-chain AA and other AA metabolites in T2DM a cause or an effect of global α-cell dysfunction? Could altered glucagon signaling precipitate a vicious cycle resulting in T2DM? This study will determine how caloric restriction alters hepatic glucagon action. Elevated fasting AA concentrations are associated with T2DM risk. In addition, hepatic steatosis has been associated with an impaired ability of glucagon to stimulate hepatic clearance of AAs. Prior studies have shown that caloric restriction lowers fasting glucose, EGP and glucagon. However, the effects on these parameters in the postprandial period are unclear. This experiment will examine to what degree the improvements produced by caloric restriction can be explained by improved hepatic glucagon action. Because caloric restriction decreases hepatic fat content the experiment will also determine if a reduction in hepatic fat content is associated with changes in glucagon's effects on hepatic AA, glucose, and lipid metabolism.

20 subjects will be studied on one occasion, following 6 weeks of caloric restriction. They will be instructed to consume a diet of 900 kcal daily using meals derived from "Nutritional Guidelines after Bariatric Surgery". Compliance will be monitored by weekly meetings with the dietician using an electronic record of food intake. After this subjects will undergo a hyperglycemic clamp with 2 doses of glucagon infused.

Subjects will be instructed to consume a diet of 900 kcal daily using meals derived from "Nutritional Guidelines after Bariatric Surgery". Compliance will be monitored by weekly meetings with the dietician using an electronic record of food intake

Inclusion Criteria: We will recruit up to 20 weight-stable, subjects with type 2 diabetes BMI ≥ 28 Kg/M2 Diabetes is managed by diet alone or a combination of oral agents Exclusion Criteria: History of prior upper abdominal surgery e.g. gastric banding, pyloroplasty, vagotomy. Active systemic illness or malignancy. Symptomatic macrovascular or microvascular disease. Contraindications to MRI (e.g. metal implants, claustrophobia). Hematocrit < 35% TSH < 0.4 or > 5.5. Consumption of > 2 alcohol drinks per day or > 14 per week or a positive AUDIT questionnaire.