Puerarin Protects Pancreatic β-Cells in Obese Diabetic Mice via Activation of GLP-1R Signaling

Abstract

Diabetes is characterized by a loss and dysfunction of the β-cell. Glucagon-like peptide 1 receptor (GLP-1R) signaling plays an important role in β-cell survival and function. It is meaningful to identify promising agents from natural products which might activate GLP-1R signaling. In this study, puerarin, a diet isoflavone, was evaluated its beneficial effects on β-cell survival and GLP-1R pathway. We showed that puerarin reduced the body weight gain, normalized blood glucose, and improved glucose tolerance in high-fat diet-induced and db/db diabetic mice. Most importantly, increased β-cell mass and β-cell proliferation but decreased β-cell apoptosis were observed in puerarin-treated diabetic mice as examined by immunostaining of mice pancreatic sections. The protective effect of puerarin on β-cell survival was confirmed in isolated mouse islets treated with high glucose. Further mechanism studies showed that the circulating level of GLP-1 in mice was unaffected by puerarin. However, puerarin enhanced GLP-1R signaling by up-regulating expressions of GLP-1R and pancreatic and duodenal homeobox 1, which subsequently led to protein kinase B (Akt) activation but forkhead box O1 inactivation, and promoted β-cell survival. The protective effect of puerarin was remarkably suppressed by Exendin(9-39), an antagonist of GLP-1R. Our study demonstrated puerarin improved glucose homeostasis in obese diabetic mice and identified a novel role of puerarin in protecting β-cell survival by mechanisms involving activation of GLP-1R signaling and downstream targets.

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

“…Puerarin([8‐(β‐ d ‐glucopyranosyl‐7‐hydroxy‐3‐(4‐hydroxyphenyl)‐4H‐1‐benzopyran‐4‐one]) is a major bioactive isoflavone compound isolated from the roots of the Pueraria lobata and has been clinically used for its protection against inflammation, oxidative stress, and mitochondrial dysfunction (Wang, Shi, et al, ; Zeng et al, ). It is reported that puerarin might be beneficial to improve lipid metabolism (Prasain, Peng, Rajbhandari, & Wyss, ), restore mitochondrial function (Song, Liu, Wang, & Wang, ), and meliorate glucose homeostasis (Yang et al, ). Deng, Wang, Sun, and Xiao () indicated that puerarin could correct lipid metabolism disorder in endothelial cells via activation of PI3K/AKT pathway.…”

Long-Lasting Effects of GSPE on Ileal GLP-1R Gene Expression Are Associated with a Hypomethylation of the GLP-1R Promoter in Female Wistar Rats

“…Moreover, the authors suggested that GSPE acts on food intake and body weight through vagal GLP-1 receptor (GLP-1R) activation on the hypothalamic centre of food intake control and GLP-1 production in the intestine [25]. Similarly, puerarin, a dietary isoflavone, improves glucose homeostasis in obese diabetic mice and protects pancreatic β-cell survival by mechanisms that involve the activation of GLP-1R signaling and downstream targets [26].…”

Antidiabetic Potential of Flavonoids from Traditional Chinese Medicine: A Review

“…Wu et al (2013) found that puerarin could exert a hypoglycemic effect by upregulating the expression of insulin receptor substrate-1 (IRS-1), insulin-like growth factor-1 (IGF-1), and PPARα. Yang et al (2016) found that puerarin could activate the AKT pathway downstream of the insulin receptor, promote GSK-3β phosphorylation, and reduce the expression of uncoupling protein 2 (UCP2) mRNA, thereby reducing blood glucose levels, protecting pancreatic β-cells, and improving liver function. Mechanistic studies have shown that puerarin could upregulate the expression of GLP-1R and PDX-1, enhance GLP-1R signaling, and cause activation of PKB and inactivation of FOXO1, thereby promoting β-cell proliferation and reducing β-cell apoptosis.…”