Inactivation of muscle insulin and IGF-I receptors and insulin responsiveness
Derek Le Roith1, Hyunsook Kim, Ana M Fernandez
1Clinical Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892-1758, USA. derek@helix.nih.gov
Purpose Of Review:
This review will outline the recent advances in the area of insulin-stimulated skeletal muscle glucose uptake and its effect on whole body glucose homeostasis, using gene-deletion and transgenic mouse models.
Recent Findings:
Insulin resistance is often the first abnormality detected in cases of type 2 diabetes, and is seen at the level of the peripheral tissues especially muscle. Both the insulin receptor and the insulin-like growth factor I receptor are capable of stimulating glucose uptake into skeletal muscle. One model involves the gene deletion of muscle glucose transport protein 4, which leads to severe insulin resistance and hyperglycemia, and a second model using a transgenic approach abrogates the function of the insulin-like growth factor I receptor and the insulin receptor resulting in severe insulin resistance and progression to diabetes. Both models demonstrate that abrogation of the insulin-like growth factor I receptor and the insulin receptor or a common signalling pathway must be inhibited to cause sufficient insulin resistance to lead to type 2 diabetes; with either glucotoxicity or lipotoxicity being involved in the progression from severe to resistance to full-blown type 2 diabetes.
Summary:
Thus, abrogation of insulin-stimulated glucose uptake in skeletal muscle, at least in mice, may lead to severe insulin resistance and diabetes.
Insights
Impaired insulin-stimulated skeletal muscle glucose uptake in mice leads to severe insulin resistance and type 2 diabetes. This highlights the critical role of muscle glucose transport in maintaining whole-body glucose homeostasis.
Area of Science:
- Metabolic research
- Endocrinology
- Molecular biology
Background:
- Insulin resistance is a key feature of type 2 diabetes, primarily affecting peripheral tissues like skeletal muscle.
- Skeletal muscle glucose uptake is regulated by both the insulin receptor and insulin-like growth factor I receptor.
Purpose of the Study:
- To review advances in understanding insulin-stimulated skeletal muscle glucose uptake.
- To examine the impact on whole-body glucose homeostasis using mouse models.
Main Methods:
- Utilized gene-deletion mouse models targeting muscle glucose transport protein 4.
- Employed transgenic mouse models to abrogate insulin-like growth factor I receptor and insulin receptor function.
Main Results:
- Gene deletion of muscle glucose transport protein 4 induced severe insulin resistance and hyperglycemia.
- Abrogation of insulin-like growth factor I receptor and insulin receptor signaling led to severe insulin resistance and diabetes progression.
- Common signaling pathways, glucotoxicity, and lipotoxicity are implicated in the development of type 2 diabetes.
Conclusions:
- Disruption of insulin-stimulated glucose uptake in skeletal muscle can precipitate severe insulin resistance and diabetes in mouse models.
- These findings underscore the importance of skeletal muscle's role in glucose metabolism and diabetes pathogenesis.
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