Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

J Mol Biol. 2020 Mar 6;432(5):1514-1534. doi: 10.1016/j.jmb.2019.09.016. Epub 2019 Oct 16.


The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.

Keywords: Insulin; Islet; Lipotoxicity; Palmitate; Pancreatic β-cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autophagy
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / metabolism
  • Endoplasmic Reticulum Stress
  • Fatty Acids, Nonesterified / metabolism
  • Fatty Acids, Nonesterified / toxicity*
  • Glucagon-Like Peptide-1 Receptor / analysis
  • Glucagon-Like Peptide-1 Receptor / therapeutic use
  • Glucose / metabolism
  • Glucose / toxicity*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Inflammation
  • Insulin / biosynthesis
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Metformin / pharmacology
  • Mitochondria / pathology
  • Oxidative Stress
  • Signal Transduction
  • Thiazolidinediones / pharmacology


  • Fatty Acids, Nonesterified
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Thiazolidinediones
  • Metformin
  • Glucose