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Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet [beta] cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans., Introduction Diabetes mellitus (DM) is a metabolic disorder that affects around 463 million individuals globally (1). DM is one of the most significant worldwide health issues, diminishing quality of life [...]

Diabetes mellitus (DM) is a type of metabolic disorder characterized by long- term hyperglycemia. Accumulating evidence shows that long noncoding RNAs (lncRNAs) play significant roles in the occurrence and development of DM. This study intended to investigate the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in rat insulinoma (INS-1) cells damaged by streptozotocin (STZ) and to identify the potential mechanisms. Firstly, PVT1 expression in INS-1 cells was assessed using RT-qPCR after STZ stimulation. After PVT-knockdown, cell apoptosis, the contents of oxidative stress related markers, and changes in insulin secretion were detected. Results indicated that PVT1 was remarkably upregulated after STZ stimulation. PVT1-knockdown inhibited STZ-induced oxidative stress and apoptosis of INS-1 cells. Moreover, the insulin secretory capacity was notably elevated following PVT1 silencing. Subsequently, a luciferase reporter assay verified that miR181a-5p was directly targeted by PVT1. The rescue assays revealed that miR-181a-5p inhibitor dramatically abrogated the effects of PVT1 silencing on oxidative stress, apoptosis, and insulin secretion. Taken together, these findings demonstrated that PVT1-knockdown could ameliorate STZ-induced oxidative stress and apoptosis and elevate insulin secretory capacity in pancreatic [beta] cells by regulating miR-181a-5p, suggesting a promising biomarker in DM diagnosis and treatment. Key words: diabetes mellitus, PVT1, pancreatic [beta] cell, apoptosis, oxidative stress, insulin secretion. Le diabete sucre (DS) est un type de trouble metabolique caracterise par une hyperglycemie de longue duree. Nous assistons a l'accumulation de donnees montrant que les ARN non codants longs (ARNncl) jouent des roles importants dans la survenue et l'evolution du DS. Cette etude portait sur le role de la translocation variante de l'ARNncl de plasmocytome (ou PVT1 pour << plasmacytoma variant translocation 1 >>) dans des cellules d'insulinome (INS-1) de rat endommagees par la streptozotocine (STZ) et sur la caracterisation des modes d'action eventuels. Nous avons d'abord evalue l'expression de la PVT1 dans les cellules INS-1 a l'aide de la technique de PCR quantitatif en temps reel apres stimulation par la STZ. Apres la repression (<< knockdown >>) de la PVT1, nous avons tente de deceler l'apoptose cellulaire, les taux des marqueurs lies au stress oxydatif et les variations de la secretion d'insuline. Les resultats ont montre que la PVT1 etait remarquablement regulee a la hausse apres la stimulation par la STZ. La repression de la PVT1 permettait d'inhiber le stress oxydatif et l'apoptose engendres par la STZ dans les cellules INS-1. En outre, la capacite de secreter de l'insuline etait nettement a la hausse a la suite de la repression de la PVT1. Subsequemment, a l'aide des epreuves par la luciferase, nous avons verifie que le miR-181a-5p etait cible directement par la PVT1. Les tests de mobilisation ont revele que l'inhibiteur du miR-181a-5p annulait de maniere impressionnante les effets de la repression de la PVT1 sur le stress oxydatif, l'apoptose et la secretion d'insuline. Dans leur ensemble, ces resultats ont montre que la repression de la PVT1 pourrait permettre d'attenuer le stress oxydatif et l'apoptose engendres par la STZ, ainsi que de faire augmenter la capacite les cellules pancreatiques [beta] a secreter de l'insuline, par l'intermediaire de la regulation du miR-181a-5p, ce qui laisse entendre qu'il s'agirait d'un biomarqueur prometteur dans le diagnostic et le traitement du DS. Mots-cles : diabete sucre, ARN non codants longs de plasmocytome, cellule pancreatique [beta], apoptose, stress oxydatif, secretion d'insuline., Introduction Diabetes mellitus (DM) is a global chronic disease with metabolic disorders that require both continuous medical care and self-management (Wen et al. 2018). It is characterized by persistent hyperglycemia [...]

[beta] Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying [beta] cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying [beta] cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for [beta] cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of [beta] cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with [beta] cell loss, but rather loss of [beta] cell identity. Sel1L-Hrd1 ERAD controlled [beta] cell identity via TGF-[beta] signaling, in part by mediating the degradation of TGF-[beta] receptor 1. Inhibition of TGF-[beta] signaling in Sel1L-deficient [beta] cells augmented the expression of [beta] cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in [beta] cells, providing a framework for therapies targeting distinct mechanisms of protein quality control., Introduction Type 2 diabetes (T2D) is a heterogeneous multicomponent disease, in which disease initiation and progression are triggered and propelled by pancreatic [beta] cell dysfunction and death. Recent studies have [...]

BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between [beta] cell function and pathology and clinical characteristics. METHODS. Individuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and [beta] cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/ arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort. RESULTS. Of the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with [HLA.sup.-]/[AAb.sup.-] and [HLA.sup.+]/[AAb.sup.-] Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as 'likely pathogenic' (rare exome variant ensemble learner [REVEL] >0.75). CONCLUSION. All Medalists retained insulin-positive [beta] cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to [beta] cell function, and many with [HLA.sup.+] diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D. FUNDING. Funding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA)., Introduction Pancreatic [beta] cell depletion attributed to autoimmunity is the hallmark of type 1 diabetes (T1D). However, recent studies have shown that residual [beta] cells may exist despite very long-duration [...]

Pancreatic β cells have one of the highest protein secretion burdens in the body, as these cells must synthesize and secrete insulin in proportion to postprandial rises in blood glucose. Remarkably, it is now becoming clear that adult β cells retain plasticity and can dedifferentiate into embryonic fates or adopt alternate islet endocrine cell identities. This property is especially important, because changes in cell fate alter β cell function and could form the basis for defects in insulin secretion that occur early in the pathogenesis of the most prevalent form of β cell dysfunction, type 2 diabetes. In this issue, three different studies provide complementary perspectives on how the transcription factors NK2 homeobox 2 (NKX2.2), paired box 6 (PAX6), and LIM domain-binding protein 1 (LDB1) serve to maintain mature adult β cell identity, revealing clues as to how adult p cells can partially dedifferentiate or become reprogrammed into other islet endocrine cells., β Cell plasticity A growing body of evidence from studies in mice and humans indicates that dedifferentiation or partial transdifferentiation/reprogramming of β cells into alternate endocrine cell fates can alter [...]

Loss of β cell identity, the presence of polyhormonal cells, and reprogramming are emerging as important features of β cell dysfunction in patients with type 1 and type 2 diabetes. In this study, we have demonstrated that the transcription factor NKX2.2 is essential for the active maintenance of adult β cell identity as well as function. Deletion of Nkx2.2 in β cells caused rapid onset of a diabetic phenotype in mice that was attributed to loss of insulin and downregulation of many β cell functional genes. Concomitantly, NKX2.2-deficient murine β cells acquired non-β cell endocrine features, resulting in populations of completely reprogrammed cells and bihormonal cells that displayed hybrid endocrine cell morphological characteristics. Molecular analysis in mouse and human islets revealed that NKX2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of a functional, monohormonal β cell identity by directly activating critical β cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. This study demonstrates the highly volatile nature of the β cell, indicating that acquiring and sustaining β cell identity and function requires not only active maintaining of the expression of genes involved in β cell function, but also continual repression of closely related endocrine gene programs., Introduction Type 1 and type 2 diabetes mellitus (T1D and T2D) are chronic conditions in which glycemic control becomes severely dysregulated. Although there are many causes of diabetes, one of [...]

The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2)--factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets., Introduction All forms of diabetes are characterized by reduced numbers and/ or dysfunction of insulin-producing pancreatic islet β cells (1, 2). The β cell is unique in its ability to [...]

Type 2 diabetes is thought to involve a compromised β cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult β cell identity and function. PAX6 was downregulated in β cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in β cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of β cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of β cell genes, thus maintaining mature β cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human β cells. We conclude that reduced expression of PAX6 in metabolically stressed β cells may contribute to β cell failure and α cell dysfunction in diabetes., Introduction Mature pancreatic β cells are highly specialized for sensing blood glucose levels and secreting insulin. Extensive efforts have resulted in a detailed understanding of the transcriptional cascades leading to [...]