Induction of Insulin Resistance In Vivo by Amylin and Calcitonin Gene–Related Peptide

During hyperinsulinemic glucose-clamp studies, intravenous infusion of calcitonin gene-related peptide (CGRP) in rats antagonized the ability of insulin to stimulate peripheral glucose disposal by 52% (196 ± 7.2 vs. 105 ± 10.5 μmol · kg⁻¹ · min⁻¹, P < 0.05) and to inhibit hepatic glucose output by 54% (P < 0.01). CGRP also inhibited the in vitro effects of insulin to stimulate hexose uptake in cultured BC₃H1 myocytes at all insulin concentrations studied. Amylin is a peptide isolated from amyloid deposits in pancreatic islets of type II (non-insulin-dependent) diabetic subjects, is present in normal β-cells, and bears a striking homology to CGRP. When synethetic human amylin was infused during clamp studies, it inhibited the ability of insulin to stimulate glucose disposal by 56% (96.9 ± 9.4 vs. 42.4 ± 5.0 μmol · kg⁻¹ · min⁻¹, P < 0.05) and to suppress hepatic glucose output by 64%. Therefore, amylin and CGRP can cause insulin resistance in vivo and may be implicated in insulinresistant states such as type II diabetes mellitus.