In vivo insulin resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle

Abstract

We examined the in vivo mechanisms of amylin-induced resistance in concious rats (n = 18). During 180-min euglycemic insulin-clamp (21.5 pmol.kg-1.min-1) studies, amylin (50, 200, or 500 pmol.kg-1.min-1; plasma concentration from 3 x 10(-10) to 9 x 10(-9) M) infusion determined a 19-27% reduction in glucose uptake (117.8 +/- 7.0 vs. 145.8 +/- 11.0, 107.1 +/- 9.2 vs. 145.1 +/- 6.7, and 105.0 +/- 7.2 vs. 144.4 +/- 7.0 mumol.kg-1.min-1 at 50, 200, or 500 pmol.kg-1.min-1, respectively, P less than 0.01) versus insulin alone, whereas 10-pmol.kg-1.min-1 amylin infusion (plasma concn 5 x 10(-11) M) failed to affect insulin-mediated glucose disposal. After amylin infusion, the contribution of whole-body glycolysis to overall glucose disposal increased from 43-48 to 62-79%, whereas muscle glycogen synthesis decreased significantly at all peptide concentrations greater than 3 x 10(-10) M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 +/- 0.038 mumol/g (insulin alone) to 0.350 +/- 0.018, 0.440 +/- 0.020, and 0.505 +/- 0.035 mumol/g (insulin plus amylin at 50, 200, or 500 pmol.kg-1.min-1, P less than 0.01). Suppression of hepatic glucose production by insulin was unaffected by a 50-pmol.kg-1.min-1 amylin infusion (18.5 +/- 4.3 vs. 21.7 +/- 2.9 mumol.kg-1.min-1), whereas it was slightly but significantly impaired by amylin infusion at 200 pmol.kg-1.min-1 (17.8 +/- 3.9 vs. 24.7 +/- 4.5 mumol.kg-1.min-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)