HYPERGLYCEMIA AND IMPAIRED GLUCOSE-TOLERANCE IN IGF BINDING PROTEIN-1TRANSGENIC MICE

The insulin like growth factors (IGFs) are present in the serum in ass ociation with high-affinity binding proteins (IGFBPs), which limit the hypoglycemic insulin-like actions of these growth factors. By utilizi ng the mouse phosphoglycerate kinase promoter to drive a rat genomic f ragment, we developed three transgenic mouse strains that overexpresse d IGFBP-1. Homozygous offspring demonstrated fasting hyperglycemia. Th e blood glucose values were 4.97 +/- 0.37, 4.57 +/- 0.33, and 5.58 +/- 0.50 mM for transgenic mice compared with 3.33 +/- 0.19 mM (mean +/- SE, P < 0.005) for the wild-type mice. The transgenic mice had more ma rked hyperglycemia after an intraperitoneal glucose challenge. The fas ting serum insulin levels were significantly elevated in the transgeni c mice; however, the insulin-to-glucose ratio was only modestly elevat ed in the fasting state and fell after a glucose challenge. Islet size and number were significantly increased; however, pancreatic insulin content was reduced (P < 0.05) compared with that of wild-type mice. T he glucose response to subcutaneous insulin was similar in transgenic and wild-type mice. These data demonstrate that constitutive overexpre ssion of IGFBP-1 results in impaired glucose tolerance with normal ins ulin sensitivity.