Bidirectional regulation of adenosine 5′‐monophosphate–activated protein kinase activity by berberine and metformin in response to changes in ambient glucose concentration

Abstract

Both berberine and metformin are well‐known antihyperglycemic agents for diabetes treatment. Adenosine monophosphate (AMP)‐activated protein kinase (AMPK) activation is often considered as the most important molecular mechanism although the mechanism has been challenged recently. Up to now, when the ambient glucose level changes dynamically, the interaction between AMPK activity and the glucose‐lowering effects of the agents remains largely unknown. To address this issue, HepG2 hepatocytes and C2C12 myotubes were preincubated at normal (5.6 mM), moderate (15 mM), or high (30 mM) glucose concentrations followed by moderate‐glucose incubation plus berberine or metformin treatment. Preincubation at high glucose concentration followed by moderate‐glucose incubation activated the AMPK pathway, but the activation was abolished with berberine or metformin treatment. In contrast, alteration from normal glucose to moderate glucose concentration in the medium suppressed AMPK activity, which was activated by berberine or metformin. Both metformin and berberine decreased the intercellular adenosine triphosphate content, enhanced glucose consumption, and lactate release under all three preincubation glucose concentrations regardless of AMPK activity. In conclusion, AMPK activated by glucose reduction is inhibited by berberine or metformin. The elevation of glucose level led to suppressed AMPK activity, which was activated with the addition of agents. The potent glucose‐lowering effects with minimal hypoglycemia of berberine and metformin may be partially due to their bidirectional regulation of the AMPK signaling pathway. Berberine and metformin promote glucose metabolism via stimulation of glycolysis, which may not be related to AMPK activity.

Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment

“…us, AMPK activation may be caused by the increase in the AMP/ATP ratio due to mitochondrial inhibition [61]. In contrast, other scholars found that BBR stimulated glycolysis and improved sugar metabolism via inhibiting mitochondrial respiratory chain complex I, which did not depend on AMPK activation, in case of nonhypoglycemia [62,63].…”

Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics

“…In vitro and in vivo studies have highlighted that BBR contributed to its therapeutic activities via variety of mechanisms and signaling pathways, including improving IR, activating AMPK, modulating gut microbiota, reducing gluconeogenesis in liver and enhancing glycolysis in peripheral tissues 217, 222-224. Although many studies have shown that BBR is an AMPK activator 30, 225, 226, in HepG2 and C2C12 cells BBR promoted glucose metabolism by stimulating glycolysis, and this effect may be independent of AMPK activity 227. A recent study has shown that BBR (150 mg/kg/d, p.o.…”

The mechanism of berberine alleviating metabolic disorder based on gut microbiome

“…Meanwhile, numerous experimental studies have shown that BBR ameliorate body metabolic dysfunction through multiple mechanisms ( Yin et al., 2012 ; Ilyas et al., 2020 ). In terms of glucose metabolism, BBR strengthened autophagy and protected from high glucose-related injury in podocytes by promoting the AMPK activation, at the same time, the bidirectional regulation of AMPK activity can reduce the risk of hypoglycemia caused by berberine ( Xiao et al., 2018 ). BBR also through TLR4/MyD88/NF-κB signaling pathway improves gut-derived hormones ( Gong et al., 2017a ), alleviate inflammation by reducing the exogenous antigen load in the host ( Zhang et al., 2012 ).…”