Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by Lipotoxicity

Abstract

Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic β cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic β cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic β cells. The review highlights the role of a sphingolipid biostat on the dysregulation of β cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

“…Previous studies have reported that ceramide and oxidative stress are intimately related to cell death induction [34]. Recently, there have been reports that the development of nonalcoholic steatohepatitis or pancreatic β-cell dysfunction in patients with type 2 diabetes mellitus is associated with an increase in ROS by ceramide [35,36]. Moreover, in human myeloid leukemia U937 cells, it has been reported that ceramide elicits a direct effect on mitochondria to overproduce ROS, causing inhibition of the respiratory chain [37] and increasing permeability of the mitochondrial membrane to form ceramide channels that increase cytochrome C release [35].…”

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

“…Circulating lipids and lipid metabolism are integrally related to type-2 diabetes (T2D) and sphingolipids specifically act as mediators of fatty acid-induced b-cell dysfunction, with possible therapeutic implications. 43,44 Interestingly, we found euricoyl-sphingomyelin associated with 25(OH)D. Given its role in sphingolipid metabolism, an increase in this metabolite could lead to production of sphingolipids necessary to reduce b-cell dysfunction in T2D. A recent Mendelian randomization study demonstrated an association between genetic variants of low plasma 25(OH)D (specifically DHCR7) and T2D, suggesting a possible causal relationship between serum vitamin D and this disease.…”

Alterations in Gut Microbiota of Gestational Diabetes Patients During the First Trimester of Pregnancy

“…In contrast, enrichment of modules for sphingolipid metabolism in the GDM group may hint at a potential role of gut microbiota in inflammatory signaling (Maceyka and Spiegel, 2014), as bacterial sphingolipid production resulted in changes in host sphingolipid metabolites (Brown et al, 2019), and sphingolipid metabolism was a converging point linking excess free fatty acids and inflammation aroused by adipose-derived inflammation (Kang et al, 2013). Moreover, sphingolipid metabolism also played a crucial role in glucolipotoxicity induced apoptosis and loss of function of pancreatic β cells, contributing to the progression of insulin resistance (Kang et al, 2013;Veret et al, 2014). Consistent with the findings in T2DM and obesity (Haus et al, 2009), the link between sphingolipids, inflammation, and insulin resistance was likely responsible for GDM pathology.…”