Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Abstract

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3–8); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL–protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum–Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure.

Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions

“…For instance, in BALB/c primary mouse hepatocytes overexpressing Cers2 , the ratio of very long chain:long chain ceramides was increased, but despite the increase in overall ceramide abundance, insulin signal transduction was improved while markers of ER stress and gluconeogenesis were reduced (22). In addition, a recent report proposes an obesity-independent CERS2-dependent lipid signature of imbalanced very long chain:long chain ceramides as contributing to β-cell failure through impaired proinsulin processing (23). Our findings suggest that very long chain ceramide species may be neither beneficial nor deleterious within the β-cell, but future work including feeding with a ketogenic diet containing a higher fat content could be performed to determine the optimal abundance and ratio of very long acyl chain-containing lipids for normal β-cell health.…”

Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis

“…Genetic depletion of CerS2 induces the unfolded protein response and autophagy ( Spassieva et al, 2009 ), and haploinsufficiency results in steatohepatitis and insulin resistance in mouse models ( Raichur et al, 2014 ). In mouse-based studies, the maturation of insulin-containing dense-core storage granules produced by pancreatic β cells was deficient, possibly due to inefficient ER-to-Golgi trafficking of the insulin processing enzyme, PCSK1, resulting in depletion of PCSK1 from the Golgi, where insulin granules are produced ( Griess et al, 2022 ). Given that there are broad impacts of altered SPL metabolism on cellular and organismal levels, it is critical to understand how cells regulate SPL and membrane homeostasis.…”

Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under obesogenic conditions

“…For instance, in BALB/c primary mouse hepatocytes overexpressing Cers2, the ratio of very long chain:long chain ceramides was increased, but despite the increase in overall ceramide abundance, insulin signal transduction was improved while markers of ER stress and gluconeogenesis were reduced (22). In addition, a recent report proposes an obesity-independent CERS2-dependent lipid signature of imbalanced very long chain:long chain ceramides as contributing to b-cell failure through impaired proinsulin processing (23). Our findings suggest that very long chain ceramide species may be neither beneficial nor deleterious within the b-cell.…”