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.

• Authors: Ying Zhong, Jing Jin, Peiyu Liu, Yu Song, Hui Zhang, Liang Sheng, Huifang Zhou, Bijie Jiang
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 6210526 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 31976031 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Ying Zhong et al.

Chemical References

• Berberine
• Glucagon

Topics

• Animals
• Berberine (pharmacology)
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Glucagon (metabolism)
• Hyperglycemia (drug therapy, metabolism, pathology)
• Liver (metabolism, pathology)
• Mice
• Mice, Obese
• Signal Transduction (drug effects)