Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes. Issue 5 (6th March 2020)

• Record Type: Journal Article
• Authors: Lytrivi, Maria; Castell, Anne-Laure; Poitout, Vincent; Cnop, Miriam
• Is Part Of: Journal of molecular biology. Volume 432:Issue 5(2020)
• Page Start: 1514
• Page End: 1534
• Publication Date: 2020-03-06
• Subjects: Pancreatic β-cell -- Islet -- Insulin -- Lipotoxicity -- Palmitate; ACC acetyl-coA carboxylase -- BMI body mass index -- BSA bovine serum albumin -- ER endoplasmic reticulum -- FFA free fatty acid -- GSIS glucose-stimulated insulin secretion -- GWAS genome-wide association study -- JNK c-Jun N-terminal kinase -- LPL lipoprotein lipase -- PBA 4-phenyl butyric acid -- PKC protein kinase C -- PPARγ peroxisome proliferator–activated receptor γ -- ROS reactive oxygen species -- T2D type 2 diabetes -- UCP2 uncoupling protein-2 -- ZDF Zucker diabetic fatty; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2019.09.016
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: Prolonged exposure to elevated FFA and glucose levels contributes to β-cell demise. Human and genetic studies support the relevance of lipotoxicity for T2D. Mimicking prevailing in situ islet FFA levels in in vitro experiments is challenging. Glucolipotoxicity impairs key steps in insulin biosynthesis and release. FFAs elicit ER and oxidative stress and impair autophagy, causing β-cell apoptosis.