Amylin-mediated reduction in insulin sensitivity corresponds to reduced insulin receptor kinase activity in the rat in vivo☆

Abstract 

Studies were undertaken to elucidate further the mechanism whereby the pancreatic peptide amylin induces insulin resistance. Sixteen male Sprague-Dawley rats underwent hyperinsulinemic (14 pmol/kg/min, 0 to 120 minutes) euglycemic clamps in the presence or absence of amylin (500 pmol/kg/min, 60 to 120 minutes). Amylin induced insulin resistance at both the hepatic level (mean ± SE: hepatic glucose output [HGO] with amylin 1.4 ± 0.2 v without amylin −1.9 ± 0.3 mmol/kg/h, P < .001) and peripheral level (glucose disposal [R_d] with amylin 5.0 ± 0.2 v without amylin 8.5 ± 0.6 mmol/kg/h, P < .001). Serum insulin levels were similar in the presence or absence of amylin alone (661 ± 89 v 636 ± 50 pmol/L, respectively, P = NS), but were significantly less when somatostatin (SRIF) was simultaneously infused (408 ± 15 pmol/ L, P < .02 v the other two groups). This suggests that endogenous insulin production was not suppressed by amylin under these study conditions. Similar findings were obtained in 18 animals in the absence of exogenous insulin infusion. In vitro kinase activity toward histone of skeletal muscle insulin receptors (IRs) activated by insulin in vivo was reduced in the presence of amylin to 6.0 ± 0.8 versus 9.1 ± 1.2 fmol phosphate into histone (insulin-infused) and 3.9 ± 0.7 versus 6.9 ± 1.4 (non-insulin-infused; P < .03 by ANOVA). Serum calcium was significantly decreased in amylin-treated animals (1.93 ± 0.04 v 2.30 ± 0.05 mmol/L, P < .001). The ability of insulin to promote R_d was decreased in the presence of amylin (12.0 ± 1.4 v 19.7 ± 2.7 mmol/ kg/h per nmol/L insulin, P < .03), but the relationship between IR kinase activity and R_d was similar in the presence or absence of amylin (0.9 ± 0.1 v 1.1 ± 0.1 mmol/kg/h per fmol PO₄, P = NS). The data suggest that in vivo amylin may induce insulin resistance at or proximal to IR kinase.

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