Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia.

Maddux BA, Chang YN, Accili D, McGuinness OP, Youngren JF, Goldfine ID
Am J Physiol Endocrinol Metab. 2006 290 (4): E746-9

PMID: 16278247 · DOI:10.1152/ajpendo.00298.2005

The ectoenzyme PC-1 is an insulin receptor inhibitor that is elevated in cells and tissues of humans with type 2 diabetes (T2D). We have recently shown that acute PC-1 overexpression in liver causes insulin resistance and glucose intolerance in mice (3), but the chronic effects of PC-1 overexpression on these functions are unknown. Herein we produced transgenic mice overexpressing the potent q allele of human PC-1 in muscle and liver. Compared with controls, these mice had 2- to 3-fold elevations of PC-1 content in liver and 5- to 10-fold elevations in muscle. In the fed state, the PC-1 animals had 100 mg/dl higher glucose levels and sixfold higher insulin levels compared with controls. During glucose tolerance tests, these PC-1 animals had peak glucose levels that were >150 mg/dl higher than controls. In vivo uptake of 2-deoxy-d-glucose in muscle during insulin infusion was decreased in the PC-1 animals. These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and hyperglycemia and suggest that animals with overexpression of human PC-1 in insulin-sensitive tissues may be important models to investigate insulin resistance.

MeSH Terms (19)

Animals Blotting, Western Enzyme-Linked Immunosorbent Assay Female Glucose Glucose Tolerance Test Humans Hyperglycemia Hyperinsulinism Insulin Insulin Resistance Liver Male Mice Mice, Inbred C57BL Mice, Transgenic Muscle, Skeletal Phosphoric Diester Hydrolases Pyrophosphatases

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