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

Phase 2

Recruiting

• Conditions: Type2diabetes
• Interventions: Behavioral: Caloric Restriction; Drug: Hyperglycemic clamp

• Registration Number: NCT05499702
• Lead Sponsor: Adrian Vella

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2022-08-10
• Study First Submitted QC: 2022-08-11
• Study First Posted: 2022-08-12
• Study Start: 2022-12-15
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-28
• Last Update Posted: 2024-05-29
• Primary Completion: 2026-06-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Adults with type 2 diabetes	Hyperglycemic clamp	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.
Adults with type 2 diabetes	Caloric Restriction	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.

Primary Outcome Measures

Name	Time	Method
Rate of leucine oxidation in response to rising glucagon concentrations	240 minutes of study	tracer-determined amino acid catabolism

Trial Locations

Locations (1)

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States