Increased sensitivity to insulin-releasing and glucoregulatory effects of dynorphin A1-13 and U 50488h in ob/ob versus lean mice.

Abstract

The effects of two kappa-opiate agonists, U 50488h and dynorphin A1-13, on plasma insulin and glucose concentrations in vivo and insulin release in vitro were tested in fasted genetically obese (ob/ob) and lean (+/+) mice at 12-15 wk of age. Fasting plasma insulin concentrations in ob/ob and lean mice were 1.22 +/- 0.10 and 0.23 +/- 0.05 nM, and plasma glucose levels were 6.90 +/- 0.84 and 4.70 +/- 0.29 mM, respectively. Administration of U 50488h (1 mg/kg body wt i.p.) to ob/ob mice dramatically raised plasma insulin by 670 and 790 pM at 15 and 30 min. Plasma glucose was raised from 5 min onward to a maximum increment of 4.2 mM above baseline. These effects were blocked by simultaneous administration of naloxone (10 mg/kg). A higher dose of U 50488h (10 mg/kg body wt i.p.) was required to produce significant increases in lean mouse plasma insulin (81 pM at 15 min) and glucose (0.7, 1.1, and 1.7 mM at 5, 15, and 30 min, respectively). Dynorphin (1 mg/kg body wt i.p.) raised plasma insulin in ob/ob mice by 380 and 410 pM at 15 and 30 min and raised plasma glucose by 1.6 mM at 15 min. In lean mice, the same dose of dynorphin had no effect on plasma insulin concentrations but induced a small rise in glucose. In ob/ob mice, the agonist-induced rise in glucose did not cause the insulin response, because insulin levels were not elevated by a glucose challenge.(ABSTRACT TRUNCATED AT 250 WORDS)