Inactivation of muscle insulin and IGF-I receptors and insulin responsiveness.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
Thus, abrogation of insulin-stimulated glucose uptake in skeletal muscle, at least in mice, may lead to severe insulin resistance and diabetes.
Le Roith
Derek
D
Clinical Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892-1758, USA. derek@helix.nih.gov
Kim
Hyunsook
H
Fernandez
Ana M
AM
Accili
Domenici
D
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000503:physiopathology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*
D007328:Insulin; D017526:Receptor, IGF Type 1; D005947:Glucose