Abstract
Dysregulated glucagon drives hyperfunction in hepatic glucose output, which is the main cause of persistent hyperglycemia in type 2 diabetes. Berberine (Zhang et al., 2010) has been used as a hypoglycemic agent, yet the mechanism by which BBR inhibits hepatic gluconeogenesis remains incompletely understood. In this study, we treated diabetic mice with BBR, tested blood glucose levels, and then performed insulin, glucose lactate, and glucagon tolerance tests. Intracellular cAMP levels in hepatocytes were determined by ELISA, hepatic gluconeogenetic genes were assayed by RT-qPCR, and the phosphorylation of CREB, which is the transcriptional factor controlling the expression of gluconeogenetic genes, was detected by western blot. BBR reduced blood glucose levels, improved insulin and glucose tolerance, and suppressed lactate- and glucagon-induced hepatic gluconeogenesis in ob/ob and STZ-induced diabetic mice. Importantly, BBR blunted glucagon-induced glucose production and gluconeogenic gene expression in hepatocytes, presumably through reducing cAMP, which resulted in the phosphorylation of CREB. By utilizing a cAMP analogue, adenylate cyclase (AC), to activate cAMP synthetase, and an inhibitor of the cAMP degradative enzyme, phosphodiesterase (PDE), we revealed that BBR accelerates intracellular cAMP degradation. BBR reduces the intracellular cAMP level by activating PDE, thus blocking activation of downstream CREB and eventually downregulating gluconeogenic genes to restrain hepatic glucose production.
Highlights
Berberine (BBR), an isoquinoline-type alkaloid originally isolated from Coptis chinensis with a long history of Chinese medicinal application, has been shown to reduce blood glucose levels in diabetes [1, 2]
Hepatic gluconeogenesis is physiologically initiated by glucagon, which activates adenylyl cyclase (AC) to increase the cytosol cyclic AMP level via its receptor on the hepatocyte plasma membrane. cAMP stimulates PKA to phosphorylate cyclic AMP response element binding (CREB), a transcriptional factor that regulates gluconeogenetic genes such as phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pc), and
The results showed that glucagon dramatically increased cAMP levels in hepatocytes and the liver, and they were significantly reduced by BBR (Figures 4(a) and 4(b)), suggesting that cAMP is involved in the regulation of CREB phosphorylation by BBR
Summary
Berberine (BBR), an isoquinoline-type alkaloid originally isolated from Coptis chinensis with a long history of Chinese medicinal application, has been shown to reduce blood glucose levels in diabetes [1, 2]. Hepatic gluconeogenesis is physiologically initiated by glucagon, which activates adenylyl cyclase (AC) to increase the cytosol cyclic AMP (cAMP) level via its receptor on the hepatocyte plasma membrane. An abnormally elevated glucagon level and increased hepatic glucagon sensitivity are the primary reasons for hyperglycemia in type 2 diabetic patients [13, 14]. It was confirmed that BBR targets the glucagon signaling pathway. BBR decreases glucagonstimulated cAMP levels by activating phosphodiesterase (PDE), the catabolic enzyme of cAMP, which inhibits hepatic gluconeogenesis. These molecular mechanisms by which BBR operates might provide new strategies to prevent diabetes and related metabolic complications
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