Berberine Attenuates Hyperglycemia by Inhibiting the Hepatic Glucagon Pathway in Diabetic Mice

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.

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

“…It has been shown to inhibit MPT pore opening [ 247 ]. On the other hand, the plant alkaloid berberine, used in traditional Chinese medicine and possessing antidiabetic properties [ 248 ], causes an inhibition of mitochondrial respiration and a decrease on Ca 2+ loading capacity through induction of the mitochondrial permeability transition [ 249 ]. All this suggests that it is necessary to carefully approach the issue of diabetes mellitus therapy through the modulation of MPT pore activity.…”

Prebiotic Effect of Berberine and Curcumin Is Associated with the Improvement of Obesity in Mice

“…Berberine is another interesting prebiotic candidate. It is a natural isoquinoline-type alkaloid originally isolated from Coptis chinensis , with a long history of Chinese medicinal application [ 27 ]. Berberine suppresses proinflammatory responses by inhibiting mitogen-activated protein kinase signaling and cellular reactive oxygen species production [ 28 ].…”

Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation

“…Notably, results of various research reports suggest that JDTL active ingredients may regulate glucose levels. For example, bioactive components of Coptidis Rhizoma have been shown to improve disordered glucose and lipid metabolism in T2DM animal models by acting on a variety of signaling pathways to ultimately reduce effects of glucose toxicity [ 21 , 22 ]. Meanwhile, huangqi polysaccharides have been used to prevent and treat T2DM, due to their abilities to enhance immunity and improve insulin sensitivity [ 23 ].…”