Glucagon Regulation of Glucose Metabolism

Summary

Glucagon is a 30 amino acid peptide hormone that is produced exclusively in alpha-cells of the pancreatic islets. Glucagon binds to a G-protein coupled receptor and activates intracellular signaling by increasing the synthesis of cyclic AMP by adenylate cyclase. The glucagon receptor is most prominently expressed by hepatocytes and the cardinal action of glucagon is to stimulate hepatic glucose output by increasing glycogenolysis and gluconeogenesis. A deep body of literature supports physiologic actions of glucagon to maintain fasting blood glucose and counter-regulate hypoglycemia, and the current view of glucose metabolism is that insulin and glucagon have opposing and mutually balancing effects on glycemia. However, it has long been appreciated that glucagon actually stimulates insulin secretion and islet β-cells express the glucagon receptor and respond to its activation by increasing cAMP.

The most potent stimulus for glucagon release is hypoglycemia and both low glucose per sé, as well as sympathetic nervous system activity are potent activators of the alpha-cell. However, glucagon is also stimulated by elevations of circulating amino acids, including after protein containing meals; this setting is one in which the release of glucagon during a period of elevated glycemia could contribute to postprandial insulin secretion. In fact, we have demonstrated that normal mice injected with glucagon while fasting (BG 75 mg/dl) have a prompt rise in blood glucose, whereas mice given glucagon while feeding (BG 150 mg/dl) increase insulin output 3 fold and have a decrease in glycemia. Moreover, in studies with isolated mouse and human islets we have demonstrated that glucagon stimulates insulin release by activating both the glucagon and GLP-1 receptors. This counter-intuitive observation has been reported by several other groups as well as ours.

In the studies proposed herein we wish to extend our novel observations to humans. The possibility that glucagon acts in the fed state to promote insulin secretion and glucose disposal would change current views of physiology in both healthy and diabetic persons. Moreover, since one of the more promising area of drug development is the creation of peptides that activate multiple receptors (GLP-1 + glucagon, GLP-1 + GIP + glucagon) the results of our studies have potential implications for therapeutics as well.

Conditions

• Insulin Secretion

Interventions

DRUG

Glucagon

Intravenous infusion of glucagon at fasting or elevated glycemia. Blockade of the GLP-1 receptor during hyperglycemia with and without glucagon.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  collaborator NIH

• David D'Alessio, M.D.

  lead OTHER

Principal Investigators

• David D'Alessio, MD · Duke University

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-09-24

Primary Completion

2021-04-16

Completion

2021-04-16

FDA Drug

Yes

Countries

• United States

Study Locations