Deoxysphingolipids, Novel Biomarkers for Type 2 Diabetes, Are Cytotoxic for Insulin-Producing Cells

Abstract

Irreversible failure of pancreatic β-cells is the main culprit in the pathophysiology of diabetes, a disease that is now a global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as a novel biomarker for the disease. In this study, we analyzed whether deoxysphingolipids directly compromise the functionality of insulin-producing Ins-1 cells and primary islets. Treatment with 1-deoxysphinganine induced dose-dependent cytotoxicity with senescent, necrotic, and apoptotic characteristics and compromised glucose-stimulated insulin secretion. In addition, 1-deoxysphinganine altered cytoskeleton dynamics, resulting in intracellular accumulation of filamentous actin and activation of the Rho family GTPase Rac1. Moreover, 1-deoxysphinganine selectively upregulated ceramide synthase 5 expression and was converted to 1-deoxy-dihydroceramides without altering normal ceramide levels. Inhibition of intracellular 1-deoxysphinganine trafficking and ceramide synthesis improved the viability of the cells, indicating that the intracellular metabolites of 1-deoxysphinganine contribute to its cytotoxicity. Analyses of signaling pathways identified Jun N-terminal kinase and p38 mitogen-activated protein kinase as antagonistic effectors of cellular senescence. The results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulin-producing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic β-cells. Thus, targeting deoxysphingolipid synthesis may complement the currently available therapies for diabetes.

Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?

“…30 Elevated plasma 1-deoxySLs were also found in patients with metabolic diseases such as the MetS and T2DM and might be directly involved in the development of insulin resistance. 20 However, the increased 1-deoxySL formation in metabolic diseases is not caused by mutations in SPT but is associated with a derailed carbohydrate and fatty acid metabolism. In several previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglyceride levels, which raised the question whether increased TG levels are confounders for elevated 1-deoxySL.…”

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

“…In addition, 1-deoxySLs were shown to be elevated under Taxol treatment and might contribute to Taxol-induced peripheral neuropathy (13). Furthermore, 1-deoxySLs were found to be increased in patients with nonalcoholic steatohepatitis (14) and to interfere with the function and survival of pancreatic -cells (15). Elevated 1-deoxySL plasma levels are also predictive for the risk to develop T2D (6).…”

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

“…The development sphinganine is acylated to dihydroceramides that in turn are desaturated to ceramides; therefore, these dihydrosphingolipids typically refl ect the status of de novo sphingolipid biosynthesis rather than turnover ( 54 ). Elevations in 1-deoxy-sphingolipids are also refl ective of altered biosynthesis because they are produced when there is a shift in the availability of alanine versus serine, as both are utilized by serine palmitoyltransferase ( 54 ), and have been associated with diabetes ( 55 ). The mRNA level of SPTLC1 is unchanged and SPTLC2 was not detected in transcriptomic data.…”