Related Experiment Video

Updated: Jul 31, 2025

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

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Published on: November 16, 2011

94.6K

Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice

Stavroula Bitsi1, Liliane El Eid1, Yusman Manchanda1

  • 1Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

Science Advances
|May 3, 2023
PubMed

Insights

β-arrestin 2 knockout mice show altered responses to GLP-1R agonists, impacting type 2 diabetes drug development. These findings reveal key mechanisms in receptor regulation for improved therapeutic design.

Area of Science:

  • Endocrinology
  • Molecular Pharmacology
  • Cell Biology

Background:

  • The glucagon-like peptide-1 receptor (GLP-1R) is a key target for type 2 diabetes treatments.
  • β-arrestins are crucial regulators of GLP-1R signaling, mediating desensitization and independent signaling pathways.

Purpose of the Study:

  • To investigate the in vivo role of β-arrestin 2 in regulating GLP-1R responses to agonists.
  • To explore the impact of β-arrestin 2 deficiency on glycemic control and GLP-1R signaling.

Main Methods:

  • Utilized adult β cell-specific β-arrestin 2 knockout (KO) mice.
  • Administered pharmacological GLP-1R agonists (exendin-4, semaglutide, tirzepatide) and assessed glycemic responses.
  • Analyzed cyclic adenosine 5'-monophosphate (cAMP) production and GLP-1R desensitization in KO islets.

Main Results:

  • KO mice exhibited sex-dimorphic, attenuated acute glycemic responses to GLP-1R agonists, which improved over time.
  • Impaired acute cAMP increases and reduced GLP-1R desensitization were observed in KO islets.
  • Reduced desensitization correlated with impaired receptor recycling, lysosomal targeting, and ubiquitination, alongside increased trans-Golgi network signaling.

Conclusions:

  • β-arrestin 2 plays a critical role in modulating GLP-1R agonist efficacy and desensitization.
  • Understanding β-arrestin 2's function provides insights into GLP-1R desensitization mechanisms.
  • These findings have implications for designing more effective GLP-1R-based therapies for type 2 diabetes.

More Related Videos

Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets10:09

Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets

Published on: May 11, 2015

9.5K
Imaging Calcium Dynamics in Subpopulations of Mouse Pancreatic Islet Cells08:03

Imaging Calcium Dynamics in Subpopulations of Mouse Pancreatic Islet Cells

Published on: November 26, 2019

8.3K

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...
373
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...
194
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...
218
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...
1.3K
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...
3.6K
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...
306