期刊
PHYSIOLOGICAL REPORTS
卷 2, 期 5, 页码 -出版社
WILEY
DOI: 10.14814/phy2.12014
关键词
Diabetes; islet; PPAR; PI3K
类别
资金
- Stiftelsen Olle Engkvist Byggmastare
- Janne Elgqvist Family Foundation
- Swedish Society of Medicine
- Sigurd and Elsa Golje Memorial Foundation
- Svenska Diabetesstiftelsen, Magn
- Bergvall Foundation
- Stiftelsen Samariten
- Barndiabetesfonden
- Ake Wiberg's Foundation
- Torsten Soderberg's Foundations
- Ragnar Soderberg's Foundations
- Berth von Kantzow's Foundation
- Trygg-Hansas Research Foundation
- Tore Nilson's Foundation for Medical Research
- Fredrik and Inger Thuring's Foundation
- Syskonen Svensson's Fund
BLX-1002 is a novel thiazolidinedione with no peroxisome proliferator-activated receptor (PPAR) activity that has been shown to improve glycemia in type 2 diabetes without weight gain. We previously found that BLX-1002 selectively augments glucose-sensitive (but not basal) insulin secretion in normal mouse beta-cells. We have now extended these observations to other insulin secretagogues and to diabetic rat islets. To this end, dynamics of insulin secretion stimulated by glucose, GLP-1, and the sulfonylurea tolbutamide were examined in pancreatic islets from nondiabetic Wistar and type 2 diabetic Goto-Kakizaki rats ex vivo. BLX-1002 restored normal glucose-sensitive insulin secretion in otherwise glucose-blind islets from GK rats, but did not affect basal or glucose-stimulated secretion in normal Wistar rat islets. The stimulatory effect of BLX-1002 on insulin secretion at high glucose required Ca2+ and involved phosphatidylinositol 3-kinase (PI3K) activity. Consistent with its effects on insulin secretion, BLX-1002 also augmented insulin secretion and cytoplasmic-free Ca2+ concentrations ([Ca2+](i)) stimulated by high glucose, GLP-1, and tolbutamide in islets from GK, but not Wistar, rats. The inactive analog BLX-1237 had no effects. In conclusion, our findings suggest that BLX-1002 potentiates insulin secretion by different stimuli in diabetic beta-cells only, in a Ca2+-dependent manner and involving PI3K.
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