The Effects of Glucagon on Hepatic Metabolism

Phase 1

Recruiting

• Conditions: Type2diabetes; Obesity; NAFLD
• Interventions: Drug: Glucagon response study

• Registration Number: NCT05500586
• Lead Sponsor: Adrian Vella

Brief Summary

Whether impaired postprandial glucagon suppression in prediabetes and T2DM is an attempt to overcome resistance to glucagon's actions on hepatic AA catabolism, a defect in α-cell function, or a combination of both are important, unanswered questions. NAFLD is associated with T2DM risk and impaired insulin action. Unfortunately, it is unclear if glucagon resistance is caused by obesity, hepatic steatosis or both. The experiments outlined will determine if glucagon's actions on hepatic amino acid catabolism and EGP interact with hepatic lipid metabolism in lean and obese subjects with and without T2DM (and with varying degrees of hepatic steatosis).

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 intact. 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?

Study Timeline

• Study First Submitted: 2022-08-10
• Study First Submitted QC: 2022-08-11
• Study First Posted: 2022-08-15
• Study Start: 2022-10-20
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-28
• Last Update Posted: 2024-05-29
• Primary Completion: 2025-09-30
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Willing to participate
• Able to give consent

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: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adults with Type 2 Diabetes	Glucagon response study	We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.
Obese Adults	Glucagon response study	We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.
Healthy Adults	Glucagon response study	We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Primary Outcome Measures

Name	Time	Method
Rate of Amino acid catabolism in the presence / absence of glucagon	240 minutes of study	Tracer-dependent measurement of amino-acid clearance

Secondary Outcome Measures

Name	Time	Method
Effect of Diabetes on amino-acid catabolism	240 minutes of study	Tracer-dependent measurement of amino-acid clearance

Trial Locations

Locations (1)

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