Okadaic Acid, Vanadate, and Phenylarsine Oxide Stimulate 2-Deoxyglucose Transport in Insulin-Resistant Human Skeletal Muscle

Abstract

In response to insulin, several proteins are phosphorylated on tyrosine and on serine/threonine residues. Decreased phosphorylation of signaling peptides by a defective insulin receptor kinase may be a cause of insulin resistance. Accordingly, inhibition of the appropriate phosphatases might increase the phosphorylation state of these signaling peptides and thereby elicit increased glucose transport. The purpose of this study was to examine the effect of the serine/threonine phosphatase inhibitor okadaic acid and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate on 2-deoxyglucose transport in insulin-resistant human skeletal muscle. All three phosphatase inhibitors stimulated 2-deoxyglucose transport in insulin-resistant skeletal muscle. These data suggest that these compounds have bypassed a defect in at least one of the signaling pathways leading to glucose transport. Furthermore, maximal transport rates induced by the simultaneous presence of insulin and phosphatase inhibitor in insulin-resistant muscle were equal to insulin-stimulated rates in lean control subjects. However, both vanadate alone and vanadate plus insulin stimulated 2-deoxyglucose transport significantly more in insulin-sensitive tissue than in insulin-resistant tissue. These results demonstrate that although vanadate is able to stimulate glucose transport in insulin-resistant muscle, it is not able to normalize transport to the same rate achieved in insulin-sensitive muscle.

Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes

“…In muscle of type 2 diabetic subjects, the expression of the GLUT4 gene is normal; impaired insulin action on glucose uptake most likely results from altered trafficking or impaired function of GLUT4 (6). Because glucose transport in response to other stimuli that use different signaling pathways is normal in muscle of type 2 diabetic subjects (7,8), the resistance to insulin stimulation may be due to impaired insulin signal transduction (9). Although there is growing information about the proximal steps in insulin signaling (10,11), the more distal pathways involved in insulin-stimulated glucose uptake are still unclear.…”

Classical PKC is not associated with defective insulin signaling in patients with impaired glucose tolerance

“…Recent reports indicate that the GLUT4 expression level does not differ between diabetic and non-diabetic patients, yet normal translocation of GLUT4 in the muscle of T2DM patients does not occur with insulin [18][19][20]. Therefore, we hypothesized that defects in the early steps of the insulin signaling cascade lead to the impaired glucose transport and may play a key role in the pathogenesis of insulin resistance.…”

Insulin-Mimetic Action of Vanadate

“…Our present results are in agreement with data in the literature that show vanadate does not alter basal and insulin-stimulated receptor kinase activities, 19 suggesting that the corrective effect of vanadate on magnesium and glucose metabolism may be distal to insulin receptor kinase activity, which is a magnesium-dependent enzyme. 13,19 Interestingly, the phosphatases that are inhibited by vanadate are all magnesium independent. We suggest, therefore, that the magnesium dependency of insulin-dependent kinases may account for the blunting of insulin action in magnesium-depleted cells (Figures 3 and Figure 4A) and may also explain the dissociation of vanadate action from cellular magnesium content ( Figure 4B).…”

“…6,7,11 The insulin-mimetic action of vanadate on glucose homeostasis and peripheral tissues has been well established both in vitro and in vivo. 1,2,[12][13][14][15][16] In animal models of diabetes, vanadate treatment decreases hyperglycemia and insulin levels and improves tolerance to oral glucose. 15 In humans, vanadate increases nonoxidative glucose disposal, as measured by indirect calorimetry, and decreases insulin requirements in diabetic patients, suggesting that it may have a potential role as adjunctive therapy in patients with diabetes mellitus.…”