Abstract
The pathophysiology of type 2 diabetes mellitus (T2DM) is characterized by not only insulin resistance, but also the abnormal regulation of glucagon secretion, suggesting that antagonizing the glucagon-induced signaling pathway has therapeutic potential in the treatment of T2DM. Although various Kampo medicines (traditional herbal medicines) are often utilized to ameliorate the symptoms of T2DM, their effects on glucagon signaling have not yet been clarified. In the present study, we examined the effects of nine types of representative Kampo formulations prescribed for T2DM on glucagon-induced CREB activation in HEK293T cells stably expressing glucagon receptor (Gcgr) and a hepatic cell line HepG2. Among these Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan significantly suppressed the glucagon-induced transactivation of the cAMP-responsive element (CRE)-binding protein (CREB) by inhibiting its interaction with CREB-binding protein (CBP), which led to a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) mRNA. Furthermore, among the crude drugs commonly contained in these three Kampo medicines, Rehmannia Root (Jio), Moutan Bark (Botampi), and Cornus Fruit (Shanzhuyu) exerted inhibitory effects on glucagon-induced CREB activation. Collectively, the present results provide a novel mechanism, the inhibition of glucagon signaling, by which Rokumigan, Hachimijiogan, and Goshajinkigan improve the symptoms of T2DM.
Highlights
Glucagon is best known as the counter-regulatory hormone to insulin, and normal glucose homeostasis depends largely on the balanced secretion of insulin and glucagon from pancreatic beta and alpha cells, respectively
The treatment with the 6 other types of Kampo drugs had no effect on glucagon-induced phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression (Figure 4). These results suggest that the ability of Rokumigan, Hachimijiogan, and Goshajinkigan to ameliorate diabetes-related conditions is due to their inhibitory effects on glucagon-induced CREB activation
We found that Rokumigan, Hachimijiogan, and Goshajinkigan inhibited the glucagon-induced activation of CREB, leading to the inhibited expression of PEPCK mRNA, which is important in gluconeogenesis (Figure 10)
Summary
Glucagon is best known as the counter-regulatory hormone to insulin, and normal glucose homeostasis depends largely on the balanced secretion of insulin and glucagon from pancreatic beta and alpha cells, respectively. Glucagon, secreted in response to low plasma glucose concentrations, plays a central role in the maintenance of fasting glycemic levels through its stimulatory effects on hepatic glucose production [1, 2, 3]. Glucagon exerts its effects through the activation of the glucagon receptor (Gcgr), a member of the class II G protein-coupled receptor superfamily [4]. The expression of PEPCK is regulated by the transcription factor, cAMP-responsive element (CRE)-binding protein (CREB). CREB is phosphorylated by PKA and the coactivator CBP augments the activity of phosphorylated CREB to activate the transcription of the Pck gene encoding PEPCK [9, 10, 11, 12]
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