{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:22:36Z","timestamp":1768522956627,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,17]]},"group-title":"Physiology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T00:00:00Z","timestamp":1747440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Aims\/Hypothesis<\/jats:title>\n                  <jats:p>\n                    The importance for normal insulin secretion of ceramide synthesis is unclear.\n                    <jats:italic>De novo<\/jats:italic>\n                    ceramide synthesis requires serine palmitoyl transferase, SPT2, encoded by\n                    <jats:italic>Sptl2<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We generated \u03b2-cell-selective\n                    <jats:italic>Sptl2<\/jats:italic>\n                    null mice by crossing animals with\n                    <jats:italic>floxed<\/jats:italic>\n                    alleles to mice expressing\n                    <jats:italic>Cre<\/jats:italic>\n                    recombinase from the\n                    <jats:italic>Ins1<\/jats:italic>\n                    locus. Metabolic phenotyping, transcriptomic, functional analyses and histology were performed using standard approaches.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Islets from\n                    <jats:italic>Sptlc2<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:monospace>Ins1<\/jats:monospace>\n                    <\/jats:sup>\n                    mice displayed marked alterations in ceramide and sphingomyelin levels: ceramide content: p=0.016 and p=0.109; sphingomyelin content: p=0.016 and p=0.004 in\n                    <jats:italic>Sptlc2<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:monospace>Ins1<\/jats:monospace>\n                    <\/jats:sup>\n                    vs\n                    <jats:italic>Sptlc2<\/jats:italic>\n                    <jats:sup>CTL<\/jats:sup>\n                    mice under regular and high fat diet, respectively, despite compensatory increases in the expression of enzymes in the salvage and sphingomyelinase pathways. Correspondingly, profound abnormalities were observed in glucose-regulated insulin secretion and glucose tolerance\n                    <jats:italic>in vivo<\/jats:italic>\n                    , both on a regular chow and high fat diet. These changes were associated with a drastic (\u223c80%) lowering in \u03b2-cell numbers, and a more minor increase in delta cell numbers. They were also preserved in animals maintained on a ketogenic diet, consistent with a cell autonomous effect on the \u03b2-cell. Despite normal glucose-regulated intracellular calcium dynamics and insulin secretion, marked transcriptomic changes were observed in\n                    <jats:italic>Sptlc2<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:monospace>Ins1<\/jats:monospace>\n                    <\/jats:sup>\n                    mouse islets, with affected GO terms including lysosome organisation and regulation of autophagy. Consistent with roles for compromised SPT2 function in diseased \u03b2-cells,\n                    <jats:italic>Sptl2<\/jats:italic>\n                    expression in Balbc and DBA2J mouse islets was lowered by a high fat-diet. Moreover,\n                    <jats:italic>SPTLC2<\/jats:italic>\n                    mRNA tended to be lower, and\n                    <jats:italic>SPTLC1<\/jats:italic>\n                    mRNA was significantly decreased, in islets from human subjects with type 2 diabetes\n                    <jats:italic>versus<\/jats:italic>\n                    normoglycemic individuals.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Preserved\n                    <jats:italic>de novo<\/jats:italic>\n                    ceramide synthesis is required to maintain normal \u03b2-cell mass and thus insulin secretion in mice. Therapeutic approaches which seek to target this process systemically using pharmacological SPT2 inhibitors should thus be treated with caution.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>- What is already known about this subject?<\/jats:title>\n                    <jats:p>Ceramides are key components of sphingolipid metabolism.<\/jats:p>\n                    <jats:p>Excess ceramide levels contribute to lipotoxicity and \u03b2-cell apoptosis.<\/jats:p>\n                    <jats:p>\n                      \u03b1-cell-restricted deletion of\n                      <jats:italic>Cers2<\/jats:italic>\n                      , which is responsible for the synthesis of very long ceramide chains, alters the insulin content of pancreatic islets and modifies glucose tolerance. Deletion of\n                      <jats:italic>Cers 5<\/jats:italic>\n                      or\n                      <jats:italic>6<\/jats:italic>\n                      , responsible for the synthesis of the long chains, has no effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>- What is the key question?<\/jats:title>\n                    <jats:p>\n                      What is the importance of\n                      <jats:italic>de novo<\/jats:italic>\n                      ceramide synthesis in \u03b2-cells for the normal regulation of insulin production and glucose homeostasis?\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>- What are the new findings?<\/jats:title>\n                    <jats:p>\n                      Inhibition of the\n                      <jats:italic>de novo<\/jats:italic>\n                      ceramide synthesis pathway in \u03b2-cells, achieved by selective deletion of\n                      <jats:italic>Sptlc2<\/jats:italic>\n                      , encoding subunit 2 of the serine palmitoyltransferase (SPT) enzyme, induces a major alteration of glucose tolerance and insulin secretion. This is accompanied by a drastic reduction in \u03b2-cell mass and islet insulin content.\n                    <\/jats:p>\n                    <jats:p>\n                      The remaining islets of\n                      <jats:italic>Sptlc2<\/jats:italic>\n                      <jats:sup>\n                        \u0394\n                        <jats:monospace>Ins1<\/jats:monospace>\n                      <\/jats:sup>\n                      display normal glucose-regulated intracellular calcium dynamics and insulin secretion despite imbalances in ceramide and sphingomyelin levels and substantial transcriptomic changes.\n                    <\/jats:p>\n                    <jats:p>\n                      Expression of\n                      <jats:italic>SPTLC1<\/jats:italic>\n                      , which encodes the other subunit of the SPT heterodimer, is reduced in islets from humans with type 2 diabetes, and a trend is observed towards lowered\n                      <jats:italic>SPTLC2<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                    <jats:p>\n                      Taken together, these findings highlight the importance of\n                      <jats:italic>de novo<\/jats:italic>\n                      ceramide synthesis for normal \u03b2-cell survival and function\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>- How might this impact on clinical practice in the foreseeable future?<\/jats:title>\n                    <jats:p>By suppressing insulin production, global blockade or inhibition of SPT2, achieved with pharmacological approaches which seek to rescue insulin sensitivity in T2D, may be deleterious for glucose tolerance.<\/jats:p>\n                  <\/jats:sec>\n                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