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 [3-3H]- and [U-14C]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 mumol.kg-1.min-1). During infusion in insulin alone, glucose uptake was 133.3 +/- 8.9 mumol.kg-1.min-1 and decreased to 105.5 +/- 12.2 mumol.kg-1.min-1 with CGRP. However, the whole body rates of glycolysis (3H2O generation) were higher during the infusion of CGRP (83.9 +/- 6.1 mumol.kg-1.min-1) compared with insulin alone (72.2 +/- 7.8 mumol.kg-1.min-1). By contrast, CGRP determined a severe impairment in muscle glycogen synthesis (11.7 +/- 3.9 vs. 47.8 +/- 5.0 mumol.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 mumol/g wet wt; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)