Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

Abstract

Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for development of severe secondary complications. The incidence of T1DM has been continuously growing in the last decades, indicating an important contribution of environmental factors. Accumulating data indicates that sphingolipids may be crucially involved in T1DM development. The serum lipidome of T1DM patients is characterized by significantly altered sphingolipid composition compared to nondiabetic, healthy probands. Recently, several polymorphisms in the genes encoding the enzymatic machinery for sphingolipid production have been identified in T1DM individuals. Evidence gained from studies in rodent islets and beta-cells exposed to cytokines indicates dysregulation of the sphingolipid biosynthetic pathway and impaired function of several sphingolipids. Moreover, a number of glycosphingolipids have been suggested to act as beta-cell autoantigens. Studies in animal models of autoimmune diabetes, such as the Non Obese Diabetic (NOD) mouse and the LEW.1AR1-iddm (IDDM) rat, indicate a crucial role of sphingolipids in immune cell trafficking, islet infiltration and diabetes development. In this review, the up-to-date status on the findings about sphingolipids in T1DM will be provided, the under-investigated research areas will be identified and perspectives for future studies will be given.

Delineating mouse β-cell identity during lifetime and in diabetes with a single cell atlas

“…Multiple parallels can be drawn between NOD and db/db+mSTZ dysregulation. For example, NOD group T1-up1 also showed high expression in cell states from db/db and mSTZ datasets (Figure 6a) and partially overlapped with db/db+mSTZ upregulated genes (Supplementary Figure S13d), with the overlap containing multiple genes previously associated with diabetes (Gc, Fabp5, Spp1, and Vgf) [123][124][125][126] . NOD and db/db+mSTZ also shared similarities in downregulated genes (T1-down4 and T2-down2, Supplementary Figure S13d) that were in turn highly expressed in healthy mature cells (Figure 6b).…”

Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

“…Little is known regarding the intersection of β cell stress and pathways that lead to EV formation, although common players exist in both diabetes pathogenesis and EV biogenesis. As one example, cytokines such as IL-1β or TNFα have been shown to activate the sphingomyelin/ceramide pathway or increase ceramide content [ 124 ]. Proinflammatory cytokines also activate or upregulate SMases, leading to increased ceramide β cell content with associated ER stress, mitochondrial damage and caspase-3 activation [ 124 , 125 ].…”

“…As one example, cytokines such as IL-1β or TNFα have been shown to activate the sphingomyelin/ceramide pathway or increase ceramide content [ 124 ]. Proinflammatory cytokines also activate or upregulate SMases, leading to increased ceramide β cell content with associated ER stress, mitochondrial damage and caspase-3 activation [ 124 , 125 ]. It is conceivable that these same pathways influencing ceramide content in β cells could also affect EV biogenesis and EV properties.…”

Platelet-Derived S1P and Its Relevance for the Communication with Immune Cells in Multiple Human Diseases

“…Type 1 diabetes (T1D) is characterized by an autoimmune destruction of insulin-producing beta-cells within the pancreas by CD4+ and CD8+ T cells and by islet-infiltrating macrophages [ 87 ]. Pancreatic beta-cells show an imbalance in the enzymatic capacity of S1P formation by SphK1 and SphK2 and degradation by SPL [ 88 ]. T1D often includes average or increased HDL cholesterol (HDL-C) values.…”