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1 Department of Medicine, Endocrine Section, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway
2 Department of Molecular Medicine, Endocrine and Diabetics Unit, Karolinska Institute and Hospital, Stockholm, Sweden
3 Department of Medicine, Endocrine Section, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway; Department of Molecular Medicine, Endocrine and Diabetics Unit, Karolinska Institute and Hospital, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: valdemar.grill{at}medisin.ntnu.no.
Prolonged periods of "beta 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 48h with
27 mmol.L-1 glucose alone, with diazoxide present during 2h every 12h or with
continuous 48h presence of diazoxide. Both protocols with diazoxide enhanced the post-culture
insulin response to 27 mmol.L-1 glucose, to 200 µmol.L-1 tolbutamide and to 20
mmol.L-1 KCl1. 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 post-culture ATP.ADP-1 ratios,
failed to affect 14C -glucose oxidation but decreased oxidation of 14C -oleate. Neither of
the two protocols affected gene expression of the ion-channel-associated proteins Kir6.2,
SUR11, VDCC
11 or Kv2.11. Continuous but not intermittent diazoxide decreased
significantly mRNA1 for uncoupling protein 2. A 2h exposure to 20 mmol.L-1 KCl or 10
µmol.L-1 cycloheximide abrogated the post-culture 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 which encompass some but not all
characteristics of continuous diazoxide treatment. The results support the soundness of
intermittent beta cell rest as a treatment strategy in type 2 diabetes.
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