Antidiabetic effects of betulinic acid mediated by the activation of the AMP-activated protein kinase pathway

Abstract

Betulinic acid (BA) is a naturally arising pentacyclic triterpenoid that has anti-malarial, anti-retroviral, anti-inflammatory, and anti-cancer biological effects. More recently, it has been reported to possess anti-obesity activity mediated by the activation of AMP-activated protein kinase (AMPK). We further investigated antidiabetic activity of BA in mouse tissues at the cellular and systemic levels. We found that BA stimulated AMPK in a similar fashion to the known AMPK activators, such as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin. Notably, the level of glucose uptake by BA was not altered by wortmannin, suggesting that this activation did not depend on phosphoinositide 3-kinase. Furthermore, BA diminished blood glucose levels in alloxane-treated ICR mice and in untreated mice during the glucose tolerance test. BA also stimulated mRNA expression of glucose transporter 4, which could partly explain increased glucose uptake. BA also increased AS160 phosphorylation by insulin-independent mechanisms in the extensor digitorum longus muscle. These results indicate that BA may serve as a promising therapeutic agent for diabetes by activating AMPK, like metformin. Notably, BA also enhanced mouse endurance capacity, indicating that it also affects metabolic regulation in addition to its antidiabetic activity.

Plants Secondary Metabolites as Blood Glucose-Lowering Molecules

“…It stimulates glucose uptake and modulates insulin secretion. Several alkaloids are allosteric activators of AMPK and enhance its enzymatic activity [ 45 , 49 ].…”

“…Its activation prompted upregulation of GLUT-4 and enhancement of glucose uptake, reduction in hepatic glucose production and increase fatty acid oxidation. It had been reported that triterpenes stimulate glucose uptake and glycogen synthesis through AMPK activation [ 49 , 97 ].…”

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

“…This study suggests that several targets including AMPK, NRF2, autophagy regulators and FXR are to be considered for developing novel therapies for liver cholestatis and fibrosis. Thus, betulinic acid [53] (a natural pentacyclic triterpenoid), 5-aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) [108], metformin [109,110], and GSK621 [111] are AMPK activators known for beneficial effects related to several diseases including diabetes, obesity, chronic inflammation, and cancer, and deserve to be investigated in the context of cholestasis [112]. In fact, recent studies identified the AMPK/FXR axis as having critical role in cholestatic liver injuries [113].…”

The hypoglycemic effect of freeze‐dried fermented mulberry mixed with soybean on type 2 diabetes mellitus

“…Free radicals are by‐products of metabolism that are highly toxic in high concentrations. They can cause the oxidation of amino acids, sugars, proteins, nucleic acids, and other compounds in various tissues, leading to oxidative stress and inflammation, and thus organ damage (Song et al., 2021; Wang, Wang, et al., 2018; Wang, Zhao, et al., 2018).…”