The Effects of Glucagon on Hepatic Metabolism

Adrian Vella

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Type2diabetes; Obesity; NAFLD

Treatments: Drug: Glucagon response study

Study type: Interventional

Funder types: Other

Identifiers

NCT05500586

22-000113

Details and patient eligibility

About

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).

Full 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?

Enrollment: 60 estimated patients

Sex: All

Ages: 25 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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60 participants in 3 patient groups

Healthy Adults

Experimental group

Description:

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Treatment:

Drug: Glucagon response study

Obese Adults

Experimental group

Description:

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Treatment:

Drug: Glucagon response study

Adults with Type 2 Diabetes

Experimental group

Description:

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Treatment:

Drug: Glucagon response study