NCT04347252

Glucagon Regulation of Glucose Metabolism

Completed Phase 1 Last updated 14 May 2021

What this trial tests

Phase 1 trial testing Glucagon in Insulin Secretion in 19 participants. Completed in 16 April 2021.

Timeline

24 September 2019

Primary endpoint
16 April 2021

16 April 2021

Quick facts

Lead sponsor	David D'Alessio, M.D.
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	none
Primary purpose	basic science
Enrollment	19
Start date	24 September 2019
Primary completion	16 April 2021
Estimated completion	16 April 2021
Sites	1 location across United States

Drugs / interventions tested

• Glucagon (GLUCAGON) — full drug profile →

Conditions studied

• Insulin Secretion — all drugs for Insulin Secretion →

Sponsor

David D'Alessio, M.D. — full company profile →

Who can join

Adults 18 to 65, any sex, with Insulin Secretion. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans.
   Gray SM, Goonatilleke E, Emrick MA, Becker JO, et al · · 2024 · cited 14× · PMID 38015721 · DOI 10.2337/db23-0201