The effects of two K-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. Light- and electron-microscopy studies of sections of pancreas and islets from ob/ob and lean mice demonstrated the presence of three times more dynorphin within glucagon than somatostatin cells in ob/ob mice. These observations coincided with increased responsiveness (10- to 100-fold) of isolated islets of ob/ob mice to the insulinotropic effect of dynorphin and U 50488h. We suggest that this insulin-resistant glucose-insensitive mouse model of obesity and non-insulin-dependent diabetes has increased sensitivity to K-agonists, probably acting peripherally and independently to mediate hyperglycemic and hyperinsulinemic responses.
Increased Sensitivity to Insulin-Releasing and Glucoregulatory Effects of Dynorphin A 1–13 and U 50488h in ob/ob Versus Lean Mice
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Xavier Z Khawaja, Irene C Green, Julian R Thorpe, Clifford J Bailey; Increased Sensitivity to Insulin-Releasing and Glucoregulatory Effects of Dynorphin A 1–13 and U 50488h in ob/ob Versus Lean Mice. Diabetes 1 October 1990; 39 (10): 1289–1297. https://doi.org/10.2337/diab.39.10.1289
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