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

NCT ID: NCT05499702

Last Updated: 2025-06-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-12-15
• Study Completion Date: 2026-12-31

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.

Conditions

Type2diabetes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Adults with type 2 diabetes

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.

Group Type: EXPERIMENTAL

Caloric Restriction

Intervention Type: BEHAVIORAL

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

Hyperglycemic clamp

Intervention Type: DRUG

Hyperglycemic clamp to measure the effect of glucagon on hepatic metabolism

Interventions

Caloric Restriction

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

Intervention Type: BEHAVIORAL

Hyperglycemic clamp

Hyperglycemic clamp to measure the effect of glucagon on hepatic metabolism

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Adrian Vella

OTHER

Sponsor Role: lead

Responsible Party

Adrian Vella

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Adrian Vella

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jeanette Laugen

Role: CONTACT

Laugen.Jeanette@mayo.edu

5072558110

Other Identifiers

22-000233

Identifier Type: -

Identifier Source: org_study_id