Molecular mechanisms of lipotoxicity-induced pancreatic ß-cell dysfunction.

ABSTRACT

Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in ß-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-ß-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and ß-cell dedifferentiation. Finally therapeutic strategies for the ß-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.