TRANSLATIONAL PHYSIOLOGY Short-term intermittent exposure to diazoxide improves functional performance of -cells in a high-glucose environment

Yoshikawa, Hiroyasu, Zuheng Ma, Anneli Björklund, and Valdemar Grill. Short-term intermittent exposure to diazoxide improves functional performance of -cells in a high-glucose environment. Am J Physiol Endocrinol Metab 287: E1202–E1208, 2004. First published August 3, 2004; doi:10.1152/ajpendo.00255.2004.—Prolonged periods of “ -cell rest” exert beneficial effects on insulin secretion from pancreatic islets subjected to a high-glucose environment. Here, we tested for effects of short-term intermittent rest achieved by diazoxide. Rat islets were cultured for 48 h with 27 mmol/l glucose alone, with diazoxide present for 2 h every 12 h or with continuous 48-h presence of diazoxide. Both protocols with diazoxide enhanced the postculture insulin response to 27 mmol/l glucose, to 200 mol/l tolbutamide, and to 20 mmol/l KCl. Intermittent diazoxide did not affect islet insulin content and enhanced only KATP-dependent secretion, whereas continuous diazoxide increased islet insulin contents and enhanced both KATP-dependent and -independent secretory effects of glucose. Intermittent and continuous diazoxide alike increased postculture ATP-to-ADP ratios, failed to affect [C]glucose oxidation, but decreased oxidation of [C]oleate. Neither of the two protocols affected gene expression of the ion channel-associated proteins Kir6.2, sulfonylurea receptor 1, voltagedependent calcium channel1, or Kv2.1. Continuous, but not intermittent, diazoxide decreased significantly mRNA for uncoupling protein-2. A 2-h exposure to 20 mmol/l KCl or 10 mol/l cycloheximide abrogated the postculture effects of intermittent, but not of continuous, diazoxide. Intermittent diazoxide decreased islet levels of the SNARE protein SNAP-25, and KCl antagonized this effect. Thus short-term intermittent diazoxide treatment has beneficial functional effects that encompass some but not all characteristics of continuous diazoxide treatment. The results support the soundness of intermittent -cell rest as a treatment strategy in type 2 diabetes.