Rosiglitazone (BRL 49653) Enhances Insulin Secretory Response via Phosphatidylinositol 3-Kinase Pathway
- Chi Yang1,
- Tien-Jyun Chang23,
- Jen-Chieh Chang1,
- Min-Wei Liu2,
- Tong-Yuan Tai2,
- Walter H. Hsu4 and
- Lee-Ming Chuang23
- 1Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
- 2Department of Internal Medicine, National Taiwan University Medical College, Taipei, Taiwan
- 3Graduate Institute of Clinical Medicine, National Taiwan University Medical College, Taipei, Taiwan
- 4Department of Biomedical Sciences, Iowa State University, Ames, Iowa
Abstract
To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045–4.5 μmol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 μmol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.
Footnotes
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Address correspondence and reprint requests to Dr. Lee-Ming Chuang, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Rd., Taipei, Taiwan. E-mail: leeming{at}ha.mc.ntu.edu.tw.
Received for publication 21 February 2001 and accepted in revised form 13 August 2001.
ANOVA, analysis of variance; AUC, area under the curve; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator–activated receptor; PPRE, peroxisomal proliferator response element; RIA, radioimmunoassay; RSG, rosiglitazone; TZD, thiazolidinedione.
