Protein Phosphatase 5, a Novel Member of the Insulin Signaling Cascade, is Dysregulated in Myoblasts from Human Subjects With Insulin Resistance for Glucose

When insulin binds to the insulin receptor, NADPH oxidase 4 (NOX4) generates a transient burst of superoxide that facilitates normal signal transduction by disabling PTPase gene family members. We recently reported that(1) NOX4 strongly associates with protein phosphatase-5 (PPP5C);(2) PPP5C protein is fi ve-fold overexpressed in type 2 diabetic db/db livers compared to db/m controls; and(3) Normal expression of PPP5C is needed for insulininduced phosphorylations of specifi c activation sites on AKT and ERK.-Here, we examine PPP5C regulation in humans with different degrees of insulin sensitivity for glucose metabolism (IS-g). In the Singapore Adult Metabolism Study (SAMS), 100 male ethnic Chinese subjects were recruited with BMIs of 23-30 kg/m2, 21-40 years old, in good health, on no medications. Subjects were ranked by degree of IS-g, based on euglycemic hyperinsulinemic clamps.-Four subjects in the bottom and top 5% for IS-g were selected for further study. BMIs (26.1±2.5 vs. 21.7±2.3 kg/m2, mean±SEM, n=4, P<0.05) and insulin sensitivity indices (4.3±1.5 vs. 18.8±7.5 mg/min per kg of fat-free mass, P<0.001) differed signifi cantly. After 6 passages, vastus lateralis myoblasts from subjects with poor IS-g exhibited impaired insulin-stimulated phosphorylation of AKT at Ser-473 compared to cells from subjects with robust IS-g, indicating persistent insulin resistance of that pathway. Importantly, PPP5C levels by immunoblot were doubled in myoblasts from subjects with poor IS-g versus those with robust IS-g (22.2±3.2 vs. 10.09±2.8 gray values above baseline, P<0.03).-Overall, our results demonstrate signifi cant dysregulation of PPP5C expression in muscle cells from individuals with poor IS-g. This result, in combination with our prior work showing that PPP5C controls pathway-specifi c insulin responses, suggests a role for PPP5C overexpression in the etiology of insulin resistance for glucose in humans.

Diabetes

Diabetes

61

0012-1797

N/A

Supp 1

1