The inability of insulin to stimulate glucose transport in muscle of obese individuals raises the question as to whether this effect is caused by a defect in the glucose-transport system (i.e., glucose transporter 4 [GLUT4] translocation and activation) or in the insulin signaling system (i.e., insulin-signal transduction). To differentiate between these alternative mechanisms for insulin resistance, a number of experiments have been conducted to test whether glucose transport could be stimulated in insulin-resistant muscle if a signal other than insulin were presented. Exercise and muscle contraction have been shown to stimulate glucose transport by causing translocation of glucose transporters to the cell surface, analogous to the stimulation by insulin.36 Maximal stimulation of transport by insulin and exercise are additive, suggesting that the two stimuli act through different signaling pathways. Several groups have investigated stimulation of glucose transport in the insulin-resistant muscle of obese rats and have observed normal stimulation by muscle contraction, even though insulin stimulation was severely impaired.1628 Kennedy et al.60 confirmed this finding in human subjects. This suggests that the glucose-transport system, (i.e., translocation and activation of glucose transporters) can respond if an alternative signal is transmitted.
In our in vitro human-muscle preparations we have not been able to study muscle contraction, but stimulation of transport by hypoxia occurs by the same signaling pathway as contraction; stimulation by insulin and hypoxia are additive, but stimulation by contraction and hypoxia are not additive.20 The finding that stimulation of transport by hypoxia was normal in muscle of obese patients seems to confirm that the glucose-transport system is intact in insulin-resistant muscle.7 Likewise, we have observed that stimulation of transport by alkaline conditions was normal in muscle of obese patients,19 suggesting that several stimuli can stimulate transport in insulin-resistant muscles.
Another line of evidence that a defect in insulin signaling causes insulin resistance comes from our experiments with serine/threonine and tyrosine protein phosphatase inhibitors. These experiments were based on the fact that insulin initiates a cascade of tyrosine and serine/threonine kinase activations. Therefore, inhibiting the opposing phosphatases mimics insulin action, but without the need for the defective step in the signaling pathway. The serine/threonine phosphatase inhibitor, okadaic acid, and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate all produced robust stimulation of glucose transport in insulin-resistant muscle of obese patients.19
A more direct set of observations that demonstrate a defect in the insulin-signaling pathway of insulin-resistant muscle come from studies in which the early steps in the signaling pathway were measured in normal and insulin-resistant muscle. Goodyear et al.38 found that autophosphorylation of the insulin receptor, phosphorylation of IRS-I, and activation of PI 3-kinase were all depressed in incubated human muscle from obese, insulin-resistant patients. Brozinick et al.17 demonstrated that protein kinase B (PKB/Akt) activation is also depressed in insulin-resistant muscle of obese individuals.
Further evidence that the proximal steps in insulin signaling are depressed in obesity is demonstrated by the experiments of Leng et al.65 They found that in muscle of lean animals both insulin and muscle contraction activate the enzymes of the MAP kinase pathway (c-Jun NH2-terminal kinase [JNK], p38 MAPK, and extracellular signal-related kinase [ERK 1 and 2]). Insulin stimulation of the MAPK enzymes was blunted in obese muscle, but contraction caused a normal response. This seems to suggest that the distal-signaling proteins respond normally if stimulated, and the depressed-insulin response in obese muscle was due to defects in the proximal steps.
The insulin receptor tyrosine-kinase activity is depressed in muscle of obese individuals.4'537677 In Pima Indians, insulin receptor autophosphorylation correlated well with glucose disposal,109 and the correlations were also found in cultured myoblasts.110 The mechanism that decreases insulin receptor tyrosine kinase activity has been investigated. We observed that removing phosphates from the receptors of obese individuals with alkaline phosphatase restored tyrosine-kinase activity,53112 suggesting that phosphorylation of insulin receptors on serine or threonine residues might be the cause of inactivation. Hyperphosphorylation and inactivation of the insulin receptor has also been observed in insulin-resistant muscle of patients with polycystic-ovary syndrome30 and gestational diabetes. 97
Serine/threonine phosphorylation of IRS-1 may also be a potential mechanism for the inactivation of insulin-signal transduction.111Infusing rats with fatty acids for 3-4 hours caused decreased insulin receptor and IRS-1 tyrosine phosphorylation in response to insulin. IRS-1 was phosphorylated on serine 307 which makes it a less favorable substrate for the insulin receptor kinase.48
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