Related Experiment Video
Updated: Jun 23, 2026
11:10
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
Muscle-specific Pparg deletion causes insulin resistance
Andrea L Hevener1, Weimin He, Yaacov Barak
1Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093, USA.
Nature Medicine
|November 20, 2003
Summary
Muscle PPAR-gamma is crucial for insulin sensitivity. Disrupting this gene in mice caused glucose intolerance and insulin resistance, unaffected by thiazolidinediones (TZDs).
Area of Science:
- Metabolic diseases
- Molecular endocrinology
- Skeletal muscle physiology
Background:
- Thiazolidinediones (TZDs) are insulin-sensitizing drugs that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma).
- PPAR-gamma is highly expressed in adipose tissue, but skeletal muscle is key for glucose disposal.
- The role of muscle PPAR-gamma in insulin action and TZD efficacy is not fully understood.
Purpose of the Study:
- To investigate the function of PPAR-gamma specifically in mouse skeletal muscle.
- To determine the impact of muscle-specific PPAR-gamma deficiency on glucose metabolism and insulin sensitivity.
- To assess the role of muscle PPAR-gamma in mediating the effects of TZDs.
Main Methods:
- Utilized the Cre-loxP system for targeted knockout of the Pparg gene in mouse skeletal muscle.
- Employed the hyperinsulinemic-euglycemic clamp technique to measure in vivo insulin-stimulated glucose disposal rate (IS-GDR).
- Administered TZD treatment to assess its effect on glucose disposal in mice with muscle-specific PPAR-gamma deficiency.
Main Results:
- Mice with targeted disruption of PPAR-gamma in skeletal muscle exhibited glucose intolerance and progressive insulin resistance by 4 months of age.
- The in vivo IS-GDR was significantly reduced by approximately 80% in these mice.
- TZD treatment did not improve the impaired glucose disposal rate in mice lacking muscle PPAR-gamma.
Conclusions:
- Muscle PPAR-gamma plays a critical role in maintaining skeletal muscle insulin action.
- Muscle-specific PPAR-gamma deficiency contributes to the etiology of insulin resistance.
- Muscle PPAR-gamma is essential for the therapeutic action of TZDs in improving insulin sensitivity.
Related Concept Videos
01:58Cell Specific Gene Expression
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
01:28Insulin: 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 this inhibition is released...
01:24Glucagon-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...
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...
01:26Type II Diabetes I: Introduction
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, in which target tissues such as the liver, muscle, and adipose tissue respond poorly to insulin. It is also associated with inadequate compensatory insulin secretion, where pancreatic β-cells fail to produce sufficient insulin. Together, these abnormalities lead to persistent hyperglycemia.EtiologyT2DM develops through a complex interaction of genetic predisposition and environmental or...
01:24Type II Diabetes II: Pathophysiology
PathophysiologyType 2 diabetes mellitus (T2DM ) is a chronic metabolic disorder characterized by insulin resistance and progressive pancreatic β-cell dysfunction, leading to impaired glucose homeostasis. It results from interactions among genetic predisposition, environmental factors, and metabolic stressors, such as overnutrition and a sedentary lifestyle.Insulin Resistance and Glucose DysregulationEarly T2DM involves insulin resistance in skeletal muscle, adipose tissue, and the liver.