A Dose-response Study Examining the Contribution of GLP-1 Receptor Signaling to Glucagon-stimulated Insulin Secretion

Phase 3

Completed

Conditions: Healthy

Interventions: Biological: Exendin-9,39
Other: Saline

Registration Number: NCT04459338

Lead Sponsor: Adrian Vella

Brief Summary: The GLP-1 receptor (GLP1R) gene is found on the beta cells of the pancreas. Its role is in the control of blood sugar level by enhancing insulin secretion from the pancreas after eating a meal. The purpose of this research study is to evaluate the role of GLP1R in the response to elevated glucagon concentrations.

Detailed Description: Glucagon within the islet can signal the β-cell through GLP1R, and acts as an insulin secretagogue. This signaling is blocked by exendin-9,39. The relative importance of glucagon signaling through its cognate receptor or through GLP1R is unknown. Despite the lower affinity of GLP1R for glucagon, intra-islet concentrations of glucagon are sufficiently high to stimulate GLP1R. The other situation where this may occur is in response to pharmacologic doses of glucagon as used for β-cell function testing or raising peripheral glucagon concentrations above fasting values. The experiments proposed will characterize the role of GLP1R in glucagon's actions on the β-cell and the potential therapeutic role of dual (GLP-1R and glucagon receptor) agonists for the treatment of T2DM and obesity.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

Inclusion Criteria

20 weight-stable, non-diabetic subjects

Exclusion Criteria

Age < 25 or > 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose).
HbA1c ≥5.9%
Use of glucose-lowering agents.
For female subjects: positive pregnancy test at the time of enrollment or study
History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
Active systemic illness or malignancy.
Symptomatic macrovascular or microvascular disease.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Saline, Then Exendin-9,39	Saline	A week or two after screening, participants were admitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.
Exendin-9,39, Then Saline	Saline	A week or two after screening, participants were admitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.
Exendin-9,39, Then Saline	Exendin-9,39	A week or two after screening, participants were admitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.
Saline, Then Exendin-9,39	Exendin-9,39	A week or two after screening, participants were admitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.

Primary Outcome Measures

Name	Time	Method
Insulin Secretion Rate During Exendin-9,39 Infusion vs. Insulin Secretion Rate During Saline Infusion	Area under the curve was quantified at the end of the Saline Study and at the end of the Exendin-9,39 study	This is the area under the curve for insulin secretion over the duration of the hyperglycemic clamp (0 to 300 minutes during the study in the Clinical Research Unit).

Secondary Outcome Measures