MECHANISM BY WHICH CALCITONIN GENE-RELATED PEPTIDE ANTAGONIZES INSULIN ACTION INVIVO

Calcitonin gene-related peptide (CGRP) is a peptide with structural homology to amylin, which is present in nerve terminals of skeletal muscle and intestine. The effect of this peptide on in vivo insulin action was studied in conscious rats. All rats received 180 min euglycemic (5.6 mM) insulin (21.5 pmol.kg-1.min-1) clamp study in combination with [3-H-3]- and [U-C-14]glucose infusions. In the basal state, the plasma CGRP concentration was 36 +/- 5 pM, and the skeletal muscle CGRP concentration was 376 +/- 88 pmol/kg wet wt. CGRP was infused at 100 pmol.kg-1.min-1 during the last 90 min of the insulin clamp study and determined a rise in plasma concentration to 781 +/- 34 pM. Hepatic glucose production was stimulated by the infusion of CGRP (35.6 +/- 6.1 vs. 24.4 +/- 4.4-mu-mol.kg-1.min-1). During infusion of insulin alone, glucose uptake was 133.3 +/- 8.9-mu-mol.kg-1.min-1 and decreased to 105.5 +/- 12.2-mu-mol.kg-1.min-1 with CGRP. However, the whole body rates of glycolysis (H-3(2)O generation) were higher during the infusion of CGRP (83.9 +/- 6.1-mu-mol.kg-1.min-1) compared with insulin alone (72.2 +/- 7.8-mu-mol.kg-1.min-1). By contrast, CGRP determined a severe impairment in muscle glycogen synthesis (11.7 +/- 3.9 vs .47.8 +/- 5.0-mu-mol.kg-1.min-1). Skeletal muscle glucose 6-phosphate concentration was significantly increased after CGRP infusion compared with insulin alone (0.540 +/- 0.052 vs. 0.219 +/- 0.038-mu-mol/g wet wt; P < 0.01). We conclude that 1) in conscious rats, CGRP determines severe hepatic and peripheral insulin resistance, and 2) at plasma peptide concentrations that are in the physiological range for skeletal muscle, CGRP induces insulin resistance primarily through its inhibition of muscle glycogen synthesis. These results indicate that CGRP exerts potent effects on glucose metabolism and may contribute to the pathogenesis of insulin resistance.