Ptpn2 is a pro-inflammatory cytokine regulator and novel player in the endoplasmic reticulum stress response in beta cells

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The Nova1-Bim axis in pancreatic beta-cells does not impact glucose homeostasis in obesity and multiple low-dose streptozotocin-induced diabetes

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Nova1 or Bim Deficiency in Pancreatic β-Cells Does Not Alter Multiple Low-Dose Streptozotocin-Induced Diabetes and Diet-Induced Obesity in Mice.

The loss of functional pancreatic β-cell mass is an important hallmark of both type 1 and type 2 diabetes. The RNA-binding protein NOVA1 is expressed in human and rodent pancreatic β-cells. Previous in vitro studies indicated that NOVA1 is necessary for glucose-stimulated insulin secretion and its deficiency-enhanced cytokine-induced apoptosis. Moreover, Bim, a proapoptotic protein, is differentially spliced and potentiates apoptosis in NOVA1-deficient β-cells in culture. We generated two novel mouse models by Cre-Lox technology lacking Nova1 (βNova1-/-) or Bim (βBim-/-) in β-cells. To test the impact of Nova1 or Bim deletion on β-cell function, mice were subjected to multiple low-dose streptozotocin (MLD-STZ)-induced diabetes or high-fat diet-induced insulin resistance. β-cell-specific Nova1 or Bim deficiency failed to affect diabetes development in response to MLD-STZ-induced β-cell dysfunction and death evidenced by unaltered blood glucose levels and pancreatic insulin content. In addition, body composition, glucose and insulin tolerance test, and pancreatic insulin content were indistinguishable between control and βNova1-/- or βBim-/- mice on a high fat diet. Thus, Nova1 or Bim deletion in β-cells does not impact on glucose homeostasis or diabetes development in mice. Together, these data argue against an in vivo role for the Nova1-Bim axis in β-cells.info:eu-repo/semantics/publishe

Single-cell sequencing reveals preserved pancreatic islet cell identity by administration of metabolite-based diet in autoimmune diabetes

Background and aims: An altered gut bacterial composition is associatedwith the pathogenesis of type 1 diabetes (T1D) and short-chain fatty acids(SCFA) are known play a pivotal role in maintaining gut homeostasis. Aspecial diet based on high-amylose maize-resistant starch modified withacetate and butyrate metabolites (HAMSAB) provided protection fromautoimmune diabetes in the NOD mouse model. We recently tested theHAMSAB diet in patients with established T1D showing improvement inglucose control. Based on these findings, we studied the molecular mechanisms and effects of SCFA in pre-diabetic pancreatic islets.Materials and methods: EndoC-βH1 and INS-1E β-cell lines weretreated with acetate (250μM), butyrate (10μM) and/or IFN-γ (1,000U/mL) + IL-1β (50U/mL). The cell viability was analyzed using SYTOX™Green Nucleic Acid Stain assay. five-week-old female NOD mice werefed with HAMSAB or HAMS control diet for five consecutive weeks.The pancreata were harvested, islets isolated using collagenase, anddispersed into single cells by trypsin. Single-cell RNA (scRNA)-sequencing was performed with 10x Chromium. The raw counts were analyzedusing RStudio with the Seurat package. The cells were filtered based onRNA features, counts, and mitochondrial percentage and annotated bytheir principal component analysis using UMAP.Results: Physiological concentrations of acetate and/or butyrate showedminimal effects on pro-inflammatory cytokine-induced cell death inEndoC-βH1 and INS-1E β-cell lines, suggesting that improved β-cellfunction is not due to SCFA-induced β-cell survival. To study the effectof the gut metabolites in the endocrine cells, we performed scRNA-seq inpancreatic islets isolated from pre-diabetic NOD mice fed HAMSAB orHAMS diets for five weeks. scRNA-seq analysis mapped the geneexpression profiles of 4,301 and 4,113 individual islet cells fromHAMSAB or HAMS fed mice, respectively. Cells were annotated into12 clusters: 5 immune and 7 pancreatic endocrine cell types. The scRNAseq dataset indicated that T-cells, B-cells, macrophages, and dendritic cellsubsets infiltrated the islets of Langerhans from both HAMSAB andHAMS-fed mice. Interestingly, HAMSAB reduced the number ofCD8+ cytotoxic cells, in line with previously described tolerogeniceffects. Moreover, subclustering and differential gene expression analysisindicated that HAMSAB enhances β-cell function and decreases theirstress response. In addition, the HAMSAB preserved the identity of endocrine cells evaluated by decreased dedifferentiated poly-hormonal (Ins+Gluc, Ins+Sst) cells expressing endocrine progenitor genes (MafA, Nfix)in mice fed this diet.Conclusion: The HAMSAB diet prevents diabetes development in NODmice, at least in part, by enhancing β-cell function and preserving cellidentity of endocrine cells under inflammatory-mediated autoimmunestress.info:eu-repo/semantics/publishe

PTPN2 regulates the interferon signalling in pancreatic beta-cells and its expression correlates with therapy outcome in autoimmune diabetes

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STAT3 Regulates Mitochondrial Gene Expression in Pancreatic Beta-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

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HAMSAB diet ameliorates dysfunctional signaling in pancreatic islets in autoimmune diabetes

Summary: An altered gut microbiota is associated with type 1 diabetes (T1D), affecting the production of short-chain fatty acids (SCFA) and glucose homeostasis. We previously demonstrated that enhancing serum acetate and butyrate using a dietary supplement (HAMSAB) improved glycemia in non-obese diabetic (NOD) mice and patients with established T1D. The effects of SCFA on immune-infiltrated islet cells remain to be clarified. Here, we performed single-cell RNA sequencing on islet cells from NOD mice fed an HAMSAB or control diet. HAMSAB induced a regulatory gene expression profile in pancreas-infiltrated immune cells. Moreover, HAMSAB maintained the expression of β-cell functional genes and decreased cellular stress. HAMSAB-fed mice showed preserved pancreatic endocrine cell identity, evaluated by decreased numbers of poly-hormonal cells. Finally, SCFA increased insulin levels in human β-like cells and improved transplantation outcome in NOD/SCID mice. Our findings support the use of metabolite-based diet as attractive approach to improve glucose control in T1D

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic Beta-Cells in Autoimmune Diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from early onset non-obese diabetic (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.info:eu-repo/semantics/publishe

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from nonobese mice with early-onset diabetes (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia, and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression toward autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER stress-induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from nonobese mice with early-onset diabetes (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia, and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression toward autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER stress-induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes