Insulin-inducible changes in the relative ratio of PTP1B splice variants

The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a m odulator of insulin and IGF-I signaling, is reduced in obese nondiabetic su bjects and in subjects with type 2 diabetes in comparison with leaner, nond iabetic controls. PTP1B mRNA, like many other signaling molecules, includin g the insulin receptor, is alternatively spliced. Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin i n vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. This was tested in 21 nondiabetic Pima Indians, a population at increased risk for obesity and type 2 diabetes. The relative ratio of the PTP1B splice variants was quant ified using RT-PCR of total RNA extracted from fractionated monocytes. The ratio of the splice variants was positively correlated with fasting plasma insulin concentration (r = 0.757; P = 0.0001), 2-h plasma insulin concentra tion following an oral glucose tolerance test (r 0.614; P = 0.01, n = 16), and percentage of body fat (r = 0.746; P = 0.0001). These data indicate tha t variability in the ratio of the two splice variants is due, in part, to i n vivo levels of chronic hyperinsulinemia. This simple, noninvasive assay i s therefore a potential biomarker for chronic hyperinsulinemia, similar to the HbAlc assay in use to monitor glucose management in diabetic patients. (C) 1999 Academic Press.