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Disruption of IRS-2 causes type 2 diabetes in mice
D J Withers1, J S Gutierrez, H Towery
1Howard Hughes Medical Institute, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
Insights
Insulin receptor substrate-2 (IRS-2) is crucial for maintaining normal glucose levels. IRS-2 deficiency in mice leads to insulin resistance and impaired pancreatic beta-cell function, contributing to type 2 diabetes.
Area of Science:
- Molecular biology
- Endocrinology
- Metabolic diseases
Background:
- Type 2 diabetes involves impaired insulin action and secretion.
- The precise molecular cause remains unclear.
- Insulin-receptor substrates (IRS proteins) mediate insulin signaling.
Purpose of the Study:
- To investigate the role of IRS-2 in glucose homeostasis.
- To determine if IRS-2 dysfunction contributes to type 2 diabetes pathophysiology.
Main Methods:
- Generation and analysis of IRS-2-deficient mice.
- Assessment of insulin signaling in peripheral tissues (liver, skeletal muscle).
- Evaluation of pancreatic beta-cell function and insulin secretion.
Main Results:
- IRS-2 deficiency caused insulin resistance in liver and skeletal muscle.
- Pancreatic beta-cell function was impaired in IRS-2-deficient mice.
- Mice exhibited progressive glucose intolerance due to lack of beta-cell compensation.
Conclusions:
- IRS-2 plays a critical role in both insulin sensitivity and beta-cell compensation.
- IRS-2 dysfunction is implicated in the development of type 2 diabetes.
- Targeting IRS-2 may offer therapeutic potential for type 2 diabetes.