Related Experiment Video

Updated: Mar 8, 2026

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
11:10

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Published on: November 16, 2011

96.0K

Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

Haruka Okamoto1, Katie Cavino1, Erqian Na1

  • 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.

Proceedings of the National Academy of Sciences of the United States of America
|January 25, 2017
PubMed

Insights

Glucagon receptor inhibition effectively treated severe insulin resistance and hyperglycemia in mice. This approach also significantly increased pancreatic beta-cell mass, offering a potential therapy for extreme insulin resistance syndromes.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Pharmacology

Background:

  • Inactivating mutations in the insulin receptor cause extreme insulin resistance, leading to difficult-to-treat hyperglycemia and increased risk of diabetes complications.
  • Current treatments for extreme insulin resistance are limited, posing significant morbidity and mortality risks.

Purpose of the Study:

  • To investigate the therapeutic potential of glucagon receptor (GCGR) inhibition in a mouse model of extreme insulin resistance.
  • To evaluate the effects of GCGR inhibition on blood glucose, ketonemia, and pancreatic islet cell mass.

Main Methods:

  • Induced severe insulin resistance, hyperglycemia, and ketonemia in mice using the insulin receptor antagonist S961.
  • Administered a monoclonal antibody targeting the glucagon receptor (GCGR) to the S961-treated mice.
  • Assessed blood glucose, β-hydroxybutyrate levels, and pancreatic β-cell and α-cell mass.

Main Results:

  • GCGR inhibition normalized blood glucose and β-hydroxybutyrate levels in the insulin-resistant mice.
  • Insulin receptor antagonism alone increased pancreatic β-cell mass threefold.
  • GCGR antibody treatment further increased β-cell mass (doubled relative to S961 alone) and expanded α-cell mass 5.7-fold.

Conclusions:

  • Glucagon receptor antibody inhibition is a promising therapeutic strategy for managing hyperglycemia and ketonemia in extreme insulin resistance syndromes.
  • GCGR inhibition significantly enhances pancreatic islet cell expansion, suggesting a role in restoring pancreatic function.
Keywords:
antibodyglucagon receptorinsulin receptor antagonistα-cell massβ-cell mass

More Related Videos

Author Spotlight: Investigating the Blood Glucose Homeostasis in Murine Brain Using a Cost-Effective Hyperglycemic And Hypoglycemic Clamp Technique07:35

Author Spotlight: Investigating the Blood Glucose Homeostasis in Murine Brain Using a Cost-Effective Hyperglycemic And Hypoglycemic Clamp Technique

Published on: January 26, 2024

2.3K
Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test OGTT and Insulin Tolerance Test ITT08:13

Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test OGTT and Insulin Tolerance Test ITT

Published on: January 7, 2018

72.2K

Related Concept Videos

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...
1.1K
Hormones Regulating Blood Glucose01:16

Hormones Regulating Blood Glucose

Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
7.8K
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...
1.1K
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

Glucose Homeostasis: Pancreatic Islets and Insulin Secretion

The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are...
2.9K
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...
827
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
5.4K