Insulin Resistance: The Muscle Scene
Skeletal muscle in T2 diabetes is resistant to insulin action. There is a 50% reduction in the ability of insulin to increase muscle glucose disposal in type 2 diabetes. This muscle insulin resistance is well established in IGT individuals as well.
Yet, muscle insulin receptors are not crucial to facilitate muscle uptake of glucose, as hyperglycaemia itself can produce glucose uptake in muscles. In keeping with this, rats with tissue specific deletion of the muscle insulin receptor have normal glucose and insulin concentrations. Mol Cell. 1998 Nov;2(5):559-69. Note that the number of insulin receptors and transporters as GLUT4 and the affinity of insulin for receptors in muscle are mostly normal despite insulin resistance. Instead multiple intracellular signalling defects have been identified as the cause of defective insulin action at the muscular level, namely:
1. Defective insulin receptor tyrosine phosphorylation so that Insulin is unable to activate the insulin receptor.
2. Defective IRS-1 (Insulin receptor substrate) phosphorylation and PI-3 (Phosphatidyl Inositol) activation by insulin.
3. Impaired ability of PI-3 to induce GLUT4 translocation.
4. Other defects as defective muscle glucose phosphorylation by hexokinase 2 are also well described in IGT and diabetes.
All these provide various areas to target with drug therapy partly due to the fact that it is not yet clear whether they are causal or merely an effect of the insulin resistance state.
Skeletal muscles, like adipose tissue, also possess lipoprotein lipase, the activity of which is normally suppressed by insulin. Metabolism. 1991 Feb;40(2):214-6. In insulin resistance, this activity is increased which could contribute to the increased muscle triglyceride content, Metabolism. 1995 Jun;44(6):786-90. with resultant muscle insulin resistance. In fact, skeletal muscle insulin sensitivity correlates closely with intramyocellular fat. Diabetologia. 2001 Jul;44(7):824-33.
Yet, muscle insulin receptors are not crucial to facilitate muscle uptake of glucose, as hyperglycaemia itself can produce glucose uptake in muscles. In keeping with this, rats with tissue specific deletion of the muscle insulin receptor have normal glucose and insulin concentrations. Mol Cell. 1998 Nov;2(5):559-69. Note that the number of insulin receptors and transporters as GLUT4 and the affinity of insulin for receptors in muscle are mostly normal despite insulin resistance. Instead multiple intracellular signalling defects have been identified as the cause of defective insulin action at the muscular level, namely:
1. Defective insulin receptor tyrosine phosphorylation so that Insulin is unable to activate the insulin receptor.
2. Defective IRS-1 (Insulin receptor substrate) phosphorylation and PI-3 (Phosphatidyl Inositol) activation by insulin.
3. Impaired ability of PI-3 to induce GLUT4 translocation.
4. Other defects as defective muscle glucose phosphorylation by hexokinase 2 are also well described in IGT and diabetes.
All these provide various areas to target with drug therapy partly due to the fact that it is not yet clear whether they are causal or merely an effect of the insulin resistance state.
Skeletal muscles, like adipose tissue, also possess lipoprotein lipase, the activity of which is normally suppressed by insulin. Metabolism. 1991 Feb;40(2):214-6. In insulin resistance, this activity is increased which could contribute to the increased muscle triglyceride content, Metabolism. 1995 Jun;44(6):786-90. with resultant muscle insulin resistance. In fact, skeletal muscle insulin sensitivity correlates closely with intramyocellular fat. Diabetologia. 2001 Jul;44(7):824-33.