Diabetes Metab J.  2019 Dec;43(6):854-866. 10.4093/dmj.2018.0179.

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

Affiliations
  • 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea. kspark@snu.ac.kr
  • 2Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
  • 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • 4Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 5Division of Nephrology, Department of Internal Medicine, Konyang University College of Medicine, Seoul, Korea.
  • 6Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.

Keyword

AMP-activated protein kinases; Endoplasmic reticulum stress; Insulin-secreting cells; Metformin; Oxidative stress; Rho-associated kinases

MeSH Terms

Adenosine Triphosphate
AMP-Activated Protein Kinases
Animals
Blotting, Western
Cell Survival
Electron Transport
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Fatty Acids, Nonesterified
Insulin
Insulin-Secreting Cells
Metformin*
Mice
NADPH Oxidase
Oxidative Stress
Phosphorylation
Polymerase Chain Reaction
Reactive Oxygen Species
rho-Associated Kinases
RNA, Messenger
AMP-Activated Protein Kinases
Adenosine Triphosphate
Fatty Acids, Nonesterified
Insulin
Metformin
NADPH Oxidase
RNA, Messenger
Reactive Oxygen Species
rho-Associated Kinases
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