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Here, we tested this hypothesis by determining whether uridine potentiates glucose-stimulated insulin secretion (GSIS) in mouse and human islets and by identifying uridine phosphorylase 1 (UPP1), the principal enzyme responsible for systemic uridine catabolism, as a key mediator of this effect.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Whole-body\n                    <jats:italic>Upp1<\/jats:italic>\n                    knockout (KO) and \u03b2-cell-specific\n                    <jats:italic>Upp1<\/jats:italic>\n                    knockout (KO\n                    <jats:sup>\u03b2<\/jats:sup>\n                    ) mice were used to determine the requirement for UPP1 in uridine-potentiated glucose-stimulated insulin secretion (GSIS) and glucose-stimulated MAPK activation. Leptin-deficient and diet-induced obese mouse models were used to assess the impact of obesity on uridine responsiveness. UPP1 protein abundance and subcellular localization were examined in islets from obese mice and human donors spanning a range of glycemic control. Integrated single-nucleus RNA sequencing and ATAC sequencing were performed on wild-type and\n                    <jats:italic>Upp1<\/jats:italic>\n                    KO mouse islets to characterize \u03b2-cell molecular remodeling associated with UPP1 deficiency and altered responses to uridine.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Uridine potentiated GSIS in islets from chow-fed and high-fat diet-fed mice, but not in leptin-deficient obese mice. Uridine also potentiated GSIS in human islets, although this effect progressively declined with worsening glycemic control. In mouse islets, uridine potentiation was accompanied by transient activation of the MAPK pathway. Both uridine-potentiated GSIS and uridine-enhanced glucose-stimulated MAPK activation were abolished in islets from\n                    <jats:italic>Upp1<\/jats:italic>\n                    KO and KO\n                    <jats:sup>\u03b2<\/jats:sup>\n                    mice. The requirement for a transient MAPK signaling was further supported by pharmacological inhibition of MEK and constitutive activation of MEK1. Leptin-deficient islets exhibited impaired glucose-induced MAPK activation together with increased UPP1 protein expression. In human islets, UPP1 protein abundance positively correlated with donor HbA\n                    <jats:sub>1c<\/jats:sub>\n                    and displayed heterogeneous subcellular localization. Integrated single-nucleus multiomic analysis identified UPP1 as an important regulator of \u03b2-cell identity, function, and transcriptional responses to uridine.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings establish UPP1 as a key regulator linking pyrimidine metabolism to \u03b2-cell function and identify impaired uridine responsiveness as a potential contributor to and\/or consequence of \u03b2-cell dysfunction during the progression of T2D.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in Context<\/jats:title>\n                  <jats:p>\n                    What is already known about this subject?\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Circulating uridine concentrations are elevated in obesity and type 2 diabetes (T2D)<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Uridine phosphorylase 1 (UPP1) is the principal enzyme responsible for uridine catabolism and plays a key role in regulating systemic uridine homeostasis.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                  <jats:p>\n                    What is the key question?\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Does uridine regulate pancreatic \u03b2-cell function, what role does UPP1 play in mediating this effect, and how is this pathway altered during obesity and the progression of T2D?<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                  <jats:p>\n                    What are the new findings?\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Uridine potentiates glucose-stimulated insulin secretion (GSIS) in a UPP1-dependent manner, accompanied by transient activation of the MAPK signaling pathway.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Uridine potentiation of GSIS is preserved in diet-induced obesity but abolished in leptin-deficient obesity, and progressively declines in human islets with worsening glycemic control.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Disrupted MAPK pathway and aberrant increased UPP1 protein expression are associated with impaired uridine potentiation of GSIS in obesity and T2D, whereas genetic deletion of\n                          <jats:italic>Upp1<\/jats:italic>\n                          affects \u03b2-cell identity, \u03b2-cell function, and the transcriptional responses to uridine.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                  <jats:p>\n                    How might this impact clinical practice in the foreseeable future?\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>These findings identify UPP1 as a previously unrecognized regulator of \u03b2-cell function that links pyrimidine metabolism to insulin secretion. Targeting the UPP1\u2013uridine pathway may represent a new strategy to preserve \u03b2-cell function or improve insulin secretory capacity during the progression of T2D.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.24.754194","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:50:25Z","timestamp":1790592625000},"source":"Crossref","is-referenced-by-count":0,"title":["Role of Uridine Phosphorylase 1 (UPP1) in Pancreatic \u03b2-Cell Physiology and Its Dysregulation in Obesity and Type 2 Diabetes"],"prefix":"10.64898","author":[{"given":"Yunqian","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Diabetes and Cancer Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Cancer 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