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Short-term intermit...
Short-term intermittent exposure to diazoxide improves functional performance of beta-cells in a high-glucose environment
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Yoshikawa, H (författare)
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- Ma, ZH (författare)
- Karolinska Institutet
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- Bjorklund, A (författare)
- Karolinska Institutet
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Grill, V (författare)
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(creator_code:org_t)
- American Physiological Society, 2004
- 2004
- Engelska.
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:6, s. E1202-E1208
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- Prolonged periods of “β-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 μmol/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 [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, sulfonylurea receptor 1, voltage-dependent calcium channel-α1, 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 μmol/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 β-cell rest as a treatment strategy in type 2 diabetes.
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