Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action

• Published in: Diabetes & metabolism journal Vol. 43; no. 6; pp. 854 - 866
• Main Authors: Kim, Hong Il, Lee, Ji Seon, Kwak, Byung Kook, Hwang, Won Min, Kim, Min Joo, Kim, Young Bum, Chung, Sung Soo, Park, Kyong Soo
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Diabetes Association 01.12.2019; 대한당뇨병학회
• Subjects: Original; 내과학; AMP-activated protein kinases; Oxidative stress; Rho-associated kinases; Metformin; Insulin-secreting cells; Endoplasmic reticulum stress
• ISSN: 2233-6079; 2233-6087
• DOI: 10.4093/dmj.2018.0179

Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress. NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis. We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK. This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.