Glucagon Regulation of Glucose Metabolism

NCT04347252 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: Pro00065698_1R01DK101991
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

glucagon; GLP-1 receptor; insulin secretion; glucose tolerance

Outcome Measures

Primary Outcomes (2)

• Change in insulin secretion

  Derived from plasma insulin and C-peptide concentrations

  before and after glucagon administration, up to 1 hour

• hepatic glucose production

  Derived from isotope dilution based on deuterated glucose enrichment

  before and after glucagon administration, up to 1 hour

Secondary Outcomes (2)

• Change in Glucagon concentrations

  before and after glucagon administration, up to 1 hour

• Change in Beta-hydroxybutyrate concentrations

  before and after glucagon administration, up to 1 hour

Study Arms (3)

Glucagon at basal glycemia

EXPERIMENTAL

Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes.

Drug: Glucagon

Glucagon at hyperglycemia

EXPERIMENTAL

Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes.

Drug: Glucagon

Glucagon at hyperglycemia with GLP-1R blockade

EXPERIMENTAL

Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study; concurrently exendin-(9-39) will be infused at 750 pmol/kg/min, also for the remaining 180 minutes. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes.

Drug: Glucagon

Interventions

Glucagon DRUG

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

Also known as: exendin-(9-39); hyperglycemia

Glucagon at basal glycemia; Glucagon at hyperglycemia; Glucagon at hyperglycemia with GLP-1R blockade

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy, fasting glucose values ≤ 95 mg/dL or A1c ≤ 5.9%, and no first degree family members with T2DM.

You may not qualify if:

• Active infectious, malignant or inflammatory conditions; unstable angina or uncompensated heart failure; pulmonary disorders including COPD and asthma; malabsorptive GI disease; significant hepatic disease; renal insufficiency (eGFR \< 60 ml/kg/min); anemia (hematocrit \< 34%); pregnancy; and uncontrolled hypertension. Subjects will be excluded if they require daily medications that alter glucose metabolism or GI function (glucocorticoids, psychotropics, narcotics, metoclopramide).

Sponsors & Collaborators

• David D'Alessio, M.D.: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Duke Center for Living

Durham, North Carolina, 27705, United States

Location

MeSH Terms

Interventions

Glucagon; exendin (9-39)

Intervention Hierarchy (Ancestors)

Proglucagon; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• David D'Alessio, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Division Chief of Endocrinology

Model Details: Within-subject design with each subject receiving 3 separate single day interventions.

Study Record Dates

• First Submitted: March 31, 2020
• First Posted: April 15, 2020
• Study Start: September 24, 2019
• Primary Completion: April 16, 2021
• Study Completion: April 16, 2021
• Last Updated: May 14, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)