Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/ lipid homeostasis

Type 2 diabetes (T2D) is a chronic, burdensome disease that is characterized by disordered insulin sensitivity and disturbed glucose/lipid homeostasis. Berberine (BBR) has multiple therapeutic actions on T2D, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity and energy expenditure. Recently, the function of BBR on fibroblast growth factor 21 (FGF21) has been identified. However, if BBR ameliorates T2D through FGF21, the underlying mechanisms remain unknown. Herein, we used T2D wild type (WT) and FGF21 global knockout (FKO) mice [mouse T2D model: established by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection], and hepatocyte-specific peroxisome proliferator activated receptor gamma (PPAR gamma) deficient (PPAR gamma(HepKO)) mice, and cultured human liver carcinoma cells line, HepG2 cells, to characterize the role of BBR in glucose/lipid metabolism and insulin sensitivity. We found that BBR activated FGF21 expression by up regulating PPAR gamma expression at the cellular level. Meanwhile, BBR ameliorated glucosamine hydrochloride (Glcn)-induced insulin resistance and increased glucose transporter 2 (GLUT2) expression in a PPAR gamma/FGF21-dependent manner. In T2D mice, BBR up-regulated the expression of PPAR gamma, FGF21 and GLUT2 in the liver, and GLUT2 in the pancreas. BBR also reversed T2D-induced insulin resistance, liver lipid accumulation, and damage in liver and pancreas. However, FGF21 deficiency diminished these effects of BBR on diabetic mice. Altogether, our study demonstrates that the therapeutic effects of BBR on T2D were partly accomplished by activating PPAR gamma-FGF21-GLUT2 signaling pathway. The discovery of this new pathway provides a deeper understanding of the mechanism of BBR for T2D treatment.

Automated summary

This study found that berberine (BBR) improved the treatment of type 2 diabetes (T2D) by activating the PPARγ-FGF21-GLUT2 signaling pathway.