Related Experiment Video

Updated: Aug 20, 2026

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
08:32

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain

Published on: January 4, 2018

A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects

Sajjad A Qureshi1, Mari Rios Candelore, Dan Xie

  • 1Department of Metabolic Disorder and Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey, USA. sajjad_a_qureshi@merck.com

Diabetes
|November 25, 2004
PubMed

Insights

Compound 1 effectively blocks the glucagon receptor, inhibiting glucose production in liver cells and reducing glucose levels in vivo. This discovery offers a potential new strategy for managing diabetes.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Metabolic Diseases

Background:

  • Glucagon is crucial for glucose homeostasis, particularly during fasting, by stimulating hepatic glucose production.
  • Elevated glucagon levels or glucagon-to-insulin ratios are observed in diabetes, contributing to hyperglycemia.
  • Targeting the glucagon receptor presents a therapeutic strategy for glycemic control by reducing hepatic glucose output.

Purpose of the Study:

  • To discover and characterize a novel glucagon receptor antagonist.
  • To evaluate the efficacy of the antagonist in blocking glucagon-mediated effects in vitro and in vivo.
  • To assess the potential of this antagonist for glycemic control.

Main Methods:

  • In vitro assays measuring glucagon binding inhibition and adenylyl cyclase stimulation in cells expressing the human glucagon receptor.
  • Experiments using primary human hepatocytes to assess blockade of glucagon-induced glycogenolysis.
  • In vivo studies in perfused mouse liver and humanized mice to evaluate the compound's effect on glucose and glycogen metabolism following glucagon administration.

Main Results:

  • Compound 1 demonstrated potent inhibition of 125I-labeled glucagon binding to the human glucagon receptor (IC50 = 181 ± 10 nmol/L).
  • Compound 1 acted as a competitive antagonist, increasing the EC50 for glucagon-stimulated adenylyl cyclase activity (KDB = 81 ± 11 nmol/L) and blocking glucagon-mediated glycogenolysis in hepatocytes and perfused mouse liver.
  • In humanized mice, Compound 1 successfully inhibited the glucose-elevating effects of exogenous glucagon.

Conclusions:

  • Compound 1 is a potent and effective glucagon receptor antagonist.
  • It successfully blocks key glucagon-mediated metabolic effects, including hepatic glucose production, both in vitro and in vivo.
  • These findings support the therapeutic potential of Compound 1 for managing hyperglycemia in conditions like diabetes.

More Related Videos

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion07:30

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

Published on: May 10, 2018

Related Concept Videos

Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Oral Hypoglycemic Agents: Glinides01:06

Oral Hypoglycemic Agents: Glinides

Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively manages...
Oral Hypoglycemic Agents: α-Glucosidase Inhibitors01:19

Oral Hypoglycemic Agents: α-Glucosidase Inhibitors

α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
Acarbose and miglitol are typically...
Hypoglycemia and Glucagon01:15

Hypoglycemia and Glucagon

Without prolonged fasting, healthy individuals maintain blood glucose levels above 3.5 mM due to a well-adapted neuroendocrine counterregulatory system that effectively prevents acute hypoglycemia, a potentially life-threatening condition. The primary clinical scenarios for hypoglycemia encompass diabetes treatment, inappropriate production of endogenous insulin or insulin-like substances by tumors, and the use of glucose-lowering agents in non-diabetic individuals. Notably, hypoglycemia in the...
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...