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KMID : 0380020060210060466
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Korean Journal of Biotechnology and Bioengineering
2006 Volume.21 No. 6 p.466 ~ p.473
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Mechanisms of Insulinotropic Effect of YHB-2017 [Genistein] Isolated from Fermentation Broths of Streptomyces sp.
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Kwag Won-Jae
Choe Tae-Boo
Park You-Hoi
Park Jun-Chul
Lee Byung-Kyu
Kang Yup
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Abstract
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Impaired insulin secretion from pancreatic beta-cells in response to glucose is an important feature in the pathology of non-insulin-dependent diabetes mellitus (NIDDM). In the course of screening for useful insulin secretagogues, we have isolated and identified YHB-2017 (Genistein) as a insulin secretion potentiator from fermentation broths of our in-house microbial library. The insulinotropic activity of YHB-2017 in isolated rat pancreatic islets was exerted only at high concentration of glucose (8.3-16 mM) but not at low concentration of glucose (3.3-5.5 mM). Also, in perifusion study with isolated rat pancreatic islets, YHB-2017 stimulated insulin secretion in a time-dependent manner when YHB-2017 was added to KRB buffer containing 16 mM glucose. In the presence of diazoxide and 35 mM KCI, which stimulates maximum influx independently of KATP channel, YHB-2017 enhanced KATP channel-independent insulin secretion at high concentration glucose (16 mM). To elucidate the mechanisms of the glucose-dependent potentiation effect of YHB-2017, pharmacologic inhibitors for protein kinase A, protein kinase C and calcium/calmodulin kinase II were pre-treated and then the potentiation effect of YHB-2017 on insulin secretion was investigated. Pre-treatment of H89 as a PKA inhibitor had a significant inhibitory effect on YHB-2017-induced potentiation effect. Furthermore, western immunoblotting analyses revealed that YHB-2017 increased phosphorylation of PKA substrates and cAMP response element-binding protein (CREB) under high concentration of glucose. These results demonstrated that the insulinotropic effect of YHB-2017 is mediated through PKA signal pathway and activated amplifying channel-independent insulin secretion pathway.
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KEYWORD
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Insulin secretion, beta-cell, insulinotropic activity, genistein, PKA substrate phosphorylation
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