Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis

Abstract

Berberine (BER), a natural product and active ingredient of genera Berberis and Coptis, has been demonstrated to possess anti-diabetic activities. However, the poor bioavailability of this agent greatly limits its clinical application. In our previous study, we demonstrated that co-administration of sodium caprate, an absorption enhancer, with BER could significantly increase the bioavailability of BER without any serious mucosal damage. Here, we investigated the effects of BER on AMP-activated protein kinase (AMPK)/gluconeogenesis pathway and the effects of sodium caprate on hypoglycemic action of BER. The ability of BER co-administered with sodium caprate to reduce insulin resistance was investigated in diabetic rat model induced by high-fat diet and low dose STZ. Western blot was performed to evaluate effects of BER on AMPK signaling proteins involved in hepatic gluconeogenesis in diabetic rat and HepG2 hepatocytes. BER reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in diabetic rats. Similarly, BER reduced plasma triglycerides and improved insulin action in diabetic rats. BER down-regulated the elevated expressions of gluconeogenesis key enzymes PEPCK and G6Pase, inhibited the translocation of TORC2 from cytoplasm to nucleus and increased AMPK activity in liver tissues. The effect of BER was higher when co-administered with sodium caprate. BER treatment resulted in reduced glucose production in HepG2 hepatocytes. BER increased AMPK activity, reduced the expression of PEPCK, and the nuclear transcription factors PGC-1, HNF-4α and FOXO1. The effect of BER on gluconeogenesis could be partly blocked by AMPK inhibitor, Compound C. BER could suppress hepatic gluconeogenesis in rat model of diabetes at least in part via stimulation of AMPK activity and this action of BER is augmented by sodium caprate.

Modulatory effect of berberine on adipose tissue PPARγ, adipocytokines and oxidative stress in high fat diet/ streptozotocin-induced diabetic rats

“…In this context, Chang et al (2013) reported that BBR activates AMPK leading to increased glucose transporter-4 (GLUT4) translocation and improved insulin sensitivity in insulin resistant H9c2 cardiomyocytes. In addition, Zhang et al (2012) demonstrated that BBR improved glucose metabolism in diabetic rats by inhibition of gluconeogenesis. In insulin resistant states, BBR inhibited fork head transcription factor O1 (FOXO-1), hepatic nuclear factor 4, and PPARγ coactivator-1α, resulted in suppressed expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two rate-limiting enzymes in gluconeogenesis (Kim et al, 2009).…”

Berberine as a therapy for type 2 diabetes and its complications: From mechanism of action to clinical studies

“…It may differ from the final official version of record. and reduced left ventricular myocardium size in rats subjected to experimentally induced cardiac hypertrophy mediated by suprarenal aortic constriction (Chang et al 2012). Moreover, BBR treatment shortened the prolonged action potential duration and reversed inward rectifying potassium ion channel 2 levels to near normal in T2D diabetic rats (Wang et al 2014) .…”

“…BBR has been shown to improve glucose metabolism in diabetic rats by inhibition of gluconeogenesis (Zhang et al 2012). In insulin resistant liver and kidney BBR inhibited several transcription factors including fork head transcription factor O1, hepatic nuclear factor 4, and peroxisome proliferator-activated receptor-γ coactivator-1α, which in turn suppressed the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, two rate-limiting enzymes in gluconeogenesis.…”

Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5′monophosphate kinase: A study in vitro and in vivo

“…Fortunately, the researches focusing on the hypoglycemic mechanism showed that metabolic regulator AMPK played an important role in regulating the blood glucose level of type 2 diabetes, and there were many anti-diabetic drugs educing potency by directing the transcriptional section of the gluconeogenic program, such as berberine and metformin [15,24]. It has been documented that AMPK could control blood glucose levels by inhibiting hepatic glucose production.…”