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Abstract The significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INS eGFP , INS eGFP /GCG mCHERRY ) as well as β-cell maturation (INS eGFP /MAFA mCHERRY ) and function (INS GCaMP6 ). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets.

The significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INSeGFP, INSeGFP/GCGmCHERRY) as well as β-cell maturation (INSeGFP/MAFAmCHERRY) and function (INSGCaMP6). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets. [ABSTRACT FROM AUTHOR]

The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP‐ or γ‐cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the Rosa26 locus, which is expressed upon Ppy‐promoter‐mediated Cre–loxP recombination. Whereas Insulin1‐CreERT‐mediated TAg expression in beta cells resulted in insulinoma, surprisingly, Ppy‐Cre‐mediated TAg expression resulted in the malignant transformation of Ppy‐lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct‐like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks of age, suggesting that PDAC can originate from the islet/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA‐sequencing analysis of Ppy‐lineage islet cells from 7‐day‐old TAg+ mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in Ppy‐lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy‐lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the most prevalent chronic diseases in the world and the incidence of diabetes has increased dramatically in developing countries such as India. Health-related quality of life (HRQOL) is an important factor for self-management behaviours of diabetic patients. These behaviours have special importance in preventing complications of diabetes. Health-related quality of life (HRQOL) has become an important measure for evaluating patient treatment with noncurable chronic disease. In the present paper demographic profile of 200 men and women in which 118 were suffering from diabetes in which 68 were men 50 were women from two districts of Uttar Pradesh. The demographic profile of respondents depicted age, gender, religion, educational status, marital status, occupation of respondents. These are the important contributing factors to access the quality of life of diabetic subjects. [ABSTRACT FROM AUTHOR]

The endocrine pancreas is composed of clusters of cell groups called pancreatic islets. These cells are responsible for the synthesis and secretion of hormones crucial for glycemic homeostasis, such as insulin and glucagon. Therefore, these cells were the targets of many studies. One method to study and/or understand endocrine pancreatic physiology is the isolation of these islets and stimulation of hormone production using different concentrations of glucose, agonists, and/or antagonists of specific secretagogues and mimicking the stimulation of hormonal synthesis and secretion. Many researchers studied pancreatic physiology in murine models due to their ease of maintenance and rapid development. However, the isolation of pancreatic islets involves meticulous processes that may vary between rodent species. The present study describes a simple and effective technical protocol for isolating intact islets from mice and rats for use as a practical guide for researchers. The method involves digestion of the acinar parenchyma by intraductal collagenase. Isolated islets are suitable for in vitro endocrine secretion analyses, microscopy techniques, and biochemical analyses. [ABSTRACT FROM AUTHOR]

AbstractThe "Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases" Workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report summarizes the workshop proceedings. The goal of the workshop was to forge connections and identify gaps in knowledge that could guide future research directions. Presentations were segregated into 6 major themes, including (a) Pancreas Anatomy and Physiology; (b) Diabetes in the Setting of Exocrine Disease; (c) Metabolic Influences on the Exocrine Pancreas; (d) Genetic Drivers of Pancreatic Diseases; (e) Tools for Integrated Pancreatic Analysis; and (f) Implications of Exocrine-Endocrine Crosstalk. For each theme, there were multiple presentations followed by panel discussions on specific topics relevant to each area of research; these are summarized herein. Significantly, the discussions resulted in the identification of research gaps and opportunities for the field to address. In general, it was concluded that as a pancreas research community, we must more thoughtfully integrate our current knowledge of the normal physiology as well as the disease mechanisms that underlie endocrine and exocrine disorders so that there is a better understanding of the interplay between these compartments.

Posttransplant diabetes mellitus (PTDM) is a common complication after kidney transplantation. Pathophysiologically, whether beta-cell dysfunction rather than insulin resistance may be the predominant defect in PTDM has been a matter of debate. The aim of the present analysis was to compare glucometabolism in kidney transplant recipients with and without PTDM. To this aim, we included 191 patients from a randomized controlled trial who underwent oral glucose tolerance tests (OGTTs) 6 months after transplantation. We derived several basic indices of beta-cell function and insulin resistance as well as variables from mathematical modeling for a more robust beta-cell function assessment. Mean ± standard deviation of the insulin sensitivity parameter PREDIM was 3.65 ± 1.68 in PTDM versus 5.46 ± 2.57 in NON-PTDM. Model-based glucose sensitivity (indicator of beta-cell function) was 68.44 ± 57.82 pmol∙min−1∙m−2∙mM−1 in PTDM versus 143.73 ± 112.91 pmol∙min−1∙m−2∙mM−1 in NON-PTDM, respectively. Both basic indices and model-based parameters of beta-cell function were more than 50% lower in patients with PTDM, indicating severe beta-cell impairment. Nonetheless, some defects in insulin sensitivity were also present, although less marked. We conclude that in PTDM, the prominent defect appears to be beta-cell dysfunction. From a pathophysiological point of view, patients at high risk for developing PTDM may benefit from intensive treatment of hyperglycemia over the insulin secretion axis. [ABSTRACT FROM AUTHOR]

Abstract The endocrine pancreas is composed of clusters of cell groups called pancreatic islets. These cells are responsible for the synthesis and secretion of hormones crucial for glycemic homeostasis, such as insulin and glucagon. Therefore, these cells were the targets of many studies. One method to study and/or understand endocrine pancreatic physiology is the isolation of these islets and stimulation of hormone production using different concentrations of glucose, agonists, and/or antagonists of specific secretagogues and mimicking the stimulation of hormonal synthesis and secretion. Many researchers studied pancreatic physiology in murine models due to their ease of maintenance and rapid development. However, the isolation of pancreatic islets involves meticulous processes that may vary between rodent species. The present study describes a simple and effective technical protocol for isolating intact islets from mice and rats for use as a practical guide for researchers. The method involves digestion of the acinar parenchyma by intraductal collagenase. Isolated islets are suitable for in vitro endocrine secretion analyses, microscopy techniques, and biochemical analyses.

Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research. [ABSTRACT FROM AUTHOR]

Peroxisomal dysfunction unhinges cellular metabolism by causing the accumulation of toxic metabolic intermediates (e.g. reactive oxygen species, very -chain fatty acids, phytanic acid or eicosanoids) and the depletion of important lipid products (e.g. plasmalogens, polyunsaturated fatty acids), leading to various proinflammatory and devastating pathophysiological conditions like metabolic syndrome and age-related diseases including diabetes. Because the peroxisomal antioxidative marker enzyme catalase is low abundant in Langerhans islet cells, peroxisomes were considered scarcely present in the endocrine pancreas. Recently, studies demonstrated that the peroxisomal metabolism is relevant for pancreatic cell functionality. During the postnatal period, significant changes occur in the cell structure and the metabolism to trigger the final maturation of the pancreas, including cell proliferation, regulation of energy metabolism, and activation of signalling pathways. Our aim in this study was to (i) morphometrically analyse the density of peroxisomes in mouse endocrine versus exocrine pancreas and (ii) investigate how the distribution and the abundance of peroxisomal proteins involved in biogenesis, antioxidative defence and fatty acid metabolism change during pancreatic maturation in the postnatal period. Our results prove that endocrine and exocrine pancreatic cells contain high amounts of peroxisomes with heterogeneous protein content indicating that distinct endocrine and exocrine cell types require a specific set of peroxisomal proteins depending on their individual physiological functions. We further show that significant postnatal changes occur in the peroxisomal compartment of different pancreatic cells that are most probably relevant for the metabolic maturation and differentiation of the pancreas during the development from birth to adulthood. [ABSTRACT FROM AUTHOR]

ObjectiveDiabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear.MethodsHere we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios.ResultsThe expression of Cyb5r3 is decreased in FoxO1-deficient β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability.ConclusionsThe findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.

Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown. Here, we aimed to capture the dysregulated miRNAs and to identify their pancreatic-specific gene targets in pancreatic progenitors (PPs) derived from wild-type induced pluripotent stem cells (WT-iPSCs) and from iPSCs lacking FOXA2 (FOXA2–/–iPSCs). To identify differentially expressed miRNAs (DEmiRs), and genes (DEGs), two different FOXA2–/–iPSC lines were differentiated into PPs. FOXA2–/– PPs showed a significant reduction in the expression of the main PP transcription factors (TFs) in comparison to WT-PPs. RNA sequencing analysis demonstrated significant reduction in the mRNA expression of genes involved in the development and function of exocrine and endocrine pancreas. Furthermore, miRNA profiling identified 107 downregulated and 111 upregulated DEmiRs in FOXA2–/– PPs compared to WT-PPs. Target prediction analysis between DEmiRs and DEGs identified 92 upregulated miRNAs, predicted to target 1498 downregulated genes in FOXA2–/– PPs. Several important pancreatic TFs essential for pancreatic development were targeted by multiple DEmiRs. Selected DEmiRs and DEGs were further validated using RT-qPCR. Our findings revealed that FOXA2 expression is crucial for pancreatic development through regulating the expression of pancreatic endocrine and exocrine genes targeted by a set of miRNAs at the pancreatic progenitor stage. These data provide novel insights of the effect of FOXA2 deficiency on miRNA-mRNA regulatory networks controlling pancreatic development and differentiation. [ABSTRACT FROM AUTHOR]

Successful pancreas or islet transplantation is currently the only cure for type 1 diabetes mellitus. Since the first pancreas transplant in 1966, there have been various refinements of surgical technique along with improved immunosuppressive regimens, resulting in significantly improved outcomes, with contemporary research into graft monitoring and newer biomarkers, potentially lengthening graft survival rates further. Patients with insulin-dependent diabetes mellitus who are eligible for pancreas or islet transplantation represent a select group, the tip of the iceberg for a significant global diabetes disease burden. In the last 50 years, there have been quantum advances in alternative technologies in diabetes therapy, both experimental and translational. Further development and improved access are required to treat the larger proportion of people suffering from diabetes. Emerging stem cell therapy is still experimental whereas alternatives including automated insulin delivery systems and islet cell transplantation are already used in some countries. Whilst automated insulin delivery systems have increased in efficacy, they still do not achieve the near physiological control of blood sugar, which can be achieved by successful pancreas or islet transplantation. This state-of-the-art review provides a summary of pancreas and islet transplantation to its current place in diabetes therapy, along with alternative and future therapies, including the obstacles associated with the dissemination of these new therapies. With the advent of these modern cellular and technological advances, this review addresses the question: are we entering an era where whole organ pancreas transplantation could be replaced entirely by modern technological advances in diabetes therapy? [ABSTRACT FROM AUTHOR]

The datasets of this article present the experimental parameters resulting from the assessment of δ-cells in the islet organs of the endocrine pancreas as a potential biomarker of endocrine disruption (ED) mediated by graphene oxide (GO), using Japanese medaka fish as the model. These datasets support the article “Evaluation of pancreatic δ-cells as a potential target site of graphene oxide toxicity in Japanese medaka (Oryzias latipes) fish”. GO used in the experiments was either obtained from a commercial source or synthesized in the laboratory by us. GO was sonicated for 5 min in ice temperature before application. The experiments were conducted on reproductively active adult fish maintained as a breeding pair (one male and one female) in 500 ml balanced salt solution (BSS) either by immersion (IMR) in GO (20 mg/L) continuously for 96 h with the refreshing of media once in every 24 h, or by a single intraperitoneal (IP) administration of GO (100 µg/g) to both male and female partners. Control fish were maintained in BSS only (IMR experiment), or nanopure water (vehicle) was injected into the peritoneal cavity (IP experiment). The IP experimental fish were anesthetized in MS-222 (100 mg/L in BSS); the injected volume (0.5 µL/10 mg fish) never exceeds 50 µl/fish. After injection, the injected fish were allowed for recovery in clean BSS and after recovery both partners were transferred to 1 L glass jars with 500 mL BSS. During depuration, the media of the breeders refreshed once every 24 h and the eggs were collected. After 21 days, the survived fish were anaesthetized, and the trunk region was preserved in 4% paraformaldehyde in PBS (20 mM) containing 0.05% Tween 20. The phenotypic sex of adult fish was assessed externally by secondary sex characters (fin features) and internally by gonad (testis and ovary) histology. Once the location of pancreas was determined after HE stains, immunohistochemical technique was applied on next few slides using rabbit derived polyclonal antisomatostatin antibody as primary antibody and a commercial kit for colorimetric determination of δ-cells in the islet organs was used. Images were captured using an Olympus CKX53 inverted microscope with DP22 camera and CellSens software. Using imagej software, a minimum 3 images of principal islets and one image of secondary islets were assessed. The immunoreactivity of δ-cells, due to neuron-like appearance and filopodia like processes, enabled us to separate them from other cell types found in the pancreatic islets of medaka. Based on immunoreactivity, we have classified islet cells into three categories; noncommunicating delta cells (NCDC), communicating cells (CC), and non-delta cells (NDC), and expressed as number of cells (NCDC/CC/NDC)/mm2 of islet organs. The nuclear area (µm2) and the linear length of filopodia of NCDCs were also considered for evaluation. Numerical data were analysed by Kruskal-Wallis test followed by Mann-Whitney's test as post hoc test and presented as means ± SEM. Statistically significant differences were considered for p ≤ 0.05.

Obesogenic endocrine-disrupting chemicals (EDCs) belong to the group of environmental contaminants, which can adversely affect human health. A growing body of evidence supports that chronic exposure to EDCs can contribute to a rapid increase in obesity among adults and children, especially in wealthy industrialized countries with a high production of widely used industrial chemicals such as plasticizers (bisphenols and phthalates), parabens, flame retardants, and pesticides. The main source of human exposure to obesogenic EDCs is through diet, particularly with the consumption of contaminated food such as meat, fish, fruit, vegetables, milk, and dairy products. EDCs can promote obesity by stimulating adipo- and lipogenesis of target cells such as adipocytes and hepatocytes, disrupting glucose metabolism and insulin secretion, and impacting hormonal appetite/satiety regulation. In vitro models still play an essential role in investigating potential environmental obesogens. The review aimed to provide information on currently available two-dimensional (2D) in vitro animal and human cell models applied for studying the mechanisms of obesogenic action of various industrial chemicals such as food contaminants. The advantages and limitations of in vitro models representing the crucial endocrine tissue (adipose tissue) and organs (liver and pancreas) involved in the etiology of obesity and metabolic diseases, which are applied to evaluate the effects of obesogenic EDCs and their disruption activity, were thoroughly and critically discussed. [ABSTRACT FROM AUTHOR]

Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM). TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes ('brittle diabetes'). We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Lipoxygenases are a family of enzymes that catalyze the enzymatic peroxidation of polyunsaturated fatty acids (PUFA). Products of this process are lipid peroxides, mediators of many pathological conditions, including inflammation, cancer and neurodegenerative diseases. 5-lipoxygenase is found in vasculature, in endothelial cells, as well as throughout the central nervous system, in both neurons and glia. Arachidonic acid, one of the most important PUFA in mammalian cells, is a substrate for 5- lipoxygenase. Boswellic acids are distinguished as 5-lipoxygenase inhibitors and are present in the resin of Boswellia serrata. From the 45 designed and by molecular docking tested boswellic acid derivatives, five chlorine substituted derivatives with the lowest binding energy values toward 5-lipoxygenase were chosen for further investigation. The designed derivatives were obtained by introducing chlorine atoms at different positions of the basic structure of acetyl-11-keto-β-boswellic acid (AKBA). Using the online platform Ochem.eu. additional druglikeness characteristics (log P, PSA, ...) were calculated for these derivates as well. Values of the binding energy for tested compounds obtained by YASARA 23.9.29 software ranged from -9.76 to -9.37 kcal/mol. Besides these values, dissociation constants were also predicted, and the results ranged from 0.070 to 0.137 mM. Druglikeness values for lipohilicity ranged from 5.5 to 6.1, which exceeded recommended log P for druglikeness parameters, partially because of the chlorine introduction. Another reason for high log P values was the original steroidal structure of boswellic acids, however, since boswellic acids are distinguished as 5-lipoxygenase inhibitors, the high logP values were not limiting factor. Introduction of chlorine substituents at different positions enhanced the binding affinity of boswellic acid derivatives towards 5-lipoxygenase compared to that of the basic structure of acetyl-11-keto-β-boswellic acid, making these derivatives interesting alternatives for inhibiting 5-lipoxygenase. [ABSTRACT FROM AUTHOR]

Sulforaphane (SFN) is a natural sulphur-containing compound with various beneficial biological effects that is found in cruciferous vegetables. Among others, these effects include the activation of Nrf2, a transcription factor that plays an important role in the prevention of ferroptosis, a cell death characterized by the accumulation of labile iron, glutathione (GSH) depletion and lipid peroxidation. Recently, we have demonstrated the antiferroptotic hepatoprotective effect of SFN in diabetic mice. Since ferroptosis has also been confirmed by us and others as one of the causes of β-cell destruction in diabetes, we aimed to investigate the potential of SFN treatment in preventing/eliminating injury of pancreatic islets during diabetes development in vivo. For this purpose, male C57BL/6 mice were divided into four groups (n=8): Control (Crtl), SFN-treated (SFN, 2.5 mg/kg), diabetic (DM, treated with 40 mg/kg streptozotocin from day 1-5) and diabetic SFN-treated (DM+SFN) group. All animals received an intraperitoneal injection of SFN or vehicle for 42 days and were sacrificed on day 43. Pancreata were isolated and prepared for histologic analysis and determination of GSH content. Glycemia was measured once a week during the experiment. Consistent with the improved glycemia, we observed histologic evidence of improvement in the endocrine pancreas of the DM+SFN animals: pancreatic GSH content was restored, average islet size and insulin immunopositivity returned to control values, and there was less insulitis than in the DM group. Lipid peroxidation, which was greatly increased in the DM islets as shown by 4-HNE immunopositivity, also decreased in the DM+SFN animals, while Nrf2 increased. As a sign of improved islet regeneration, PDX-1 immunoexpression strongly increased in this group. To investigate whether SFN as a natural H2S donor affects the endogenous production of this gasotransmitter in islet cells, immunoexpression of cystathionine-βsynthase (CBS) and cystathionine gamma-lyase (CSE) was also analyzed. The results showed that SFN increased CBS expression in islets under diabetogenic insults. In summary, we have shown that SFN prevents diabetogenic islet damage by activating antiferroptotic signaling pathways. Moreover, our results indicate the importance of the H2S/CBS signaling pathway in protecting islet cells from DM insult, indicating this pathway as a potential antidiabetic target. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The dopamine receptor 2 (DRD2) binds dopamine in both central tissues (e.g., basal ganglia, pituitary gland) and peripheral tissues (e.g., adrenal gland, kidneys, intestine) and mediates dopamine actions in cognition, emotional processing, and prolactin- secretion inhibition and stimulation, and in DRD2-/- knockout mice insulin secretion is impaired. Variants in or around the DRD2 gene have been implicated in major depressive disorder (MDD), schizophrenia, obesity, and type 2 diabetes (T2D) but not in comorbid MDD-T2D patients; DRD2 agonists (e.g., bromocriptine) are approved treatments in T2D. This study aimed to detect whether the DRD2 gene plays a role in T2D, MDD, and T2D-MDD comorbidity in Italian families. SUBJECTS AND METHODS: In 212 Italian families with T2D and MDD, we investigated the presence of linkage and linkage disequilibrium of variants in the DRD2 gene with T2D and/or MDD. A test was considered statistically significant if p was <0.05. RESULTS: We found 3 novel variants (rs6276, rs35608204, and rs1800499) significantly linked to and/or associated with the risk of T2D and 1 novel variant (rs112646785) significantly linked and associated to the comorbidity of T2D and MDD. CONCLUSIONS: This is the first study to link and associate DRD2 variants with the comorbidity of T2D and MDD. [ABSTRACT FROM AUTHOR]

One major goal of regenerative medicine is the production of pancreatic endocrine islets to treat insulin-dependent diabetic patients. Among the different methods developed to achieve this goal, a particularly promising approach is direct lineage reprogramming, in which non-β-cells are directly converted to glucose-responsive, insulin-secreting β-like cells. Efforts by different research groups have led to critical insights in the inducing factors necessary and types of somatic tissues suitable for direct conversion to β-like cells. Nevertheless, there is limited understanding of the molecular mechanisms underlying direct cell fate conversion. Significant challenges also remain in translating discoveries into therapeutics that will eventually benefit diabetic patients. This review aims to cover the advances made in the direct reprogramming of somatic cells into β-like cells and discuss the remaining challenges. [ABSTRACT FROM AUTHOR]

Abstract Background Children with transfusion-dependent thalassemia (TDT) suffer from secondary hemosiderosis and the delirious effects this iron overload has on their different body organs, including the pancreas. They are also more prone to develop zinc deficiency than the general pediatric population. This study aimed to determine the effect of zinc deficiency and iron overload on the endocrine and exocrine pancreas in TDT children. Methods Eighty children, already diagnosed with TDT, were included in this study. We assessed the following in the participant children: serum ferritin, serum zinc, endocrine pancreatic function (oral glucose tolerance test (OGTT), fasting insulin level and from them, HOMA-IR was calculated), and exocrine pancreatic function (serum lipase and serum amylase). Results Forty-four TDT children had a subnormal zinc level, while 36 of them had a normal serum zinc level. TDT children with low serum zinc had significantly more impaired endocrine pancreatic function and an abnormally high serum lipase than children with normal serum zinc, p

Background: Diabetes is an endocrinopathy and rare in the case of SARS-CoV-2, the virus primarily involves the lungs by its affinity to Angiotensin Converting enzyme(ACE-2) receptors, associated symptoms include Nausea, Vomiting, and Breathlessness. Case Presentation: We present the case of a 41-year-old male with pneumonia-like symptoms and a positive nasal swab RT-PCR test with Imaging studies highly suggestive of CO RADS-5 Progressive stage, the patient was immediately admitted to the Intensive care unit (ICU), and the treatment was started with Medical Oxygen, Intravenous Normal Saline Tablet Doxycycline, and Tablet Ivermectin as per the guidelines, he was admitted for 21 days. After 3 weeks the patient comes for a routine checkup and was found to have an elevated Fasting glucose level of 121 mg/dl (normal reference range 80-100mg/dl) further workup for diabetes revealed that he was a non-diabetic on the previous visit 2 months ago, he also had an increase in weight during this time. With the Body Mass Index(BMI) now being 30.2 from the previous 28.4 (Reference range >30 is obese), the pro-inflammatory cytokines like C-reactive protein were 111.6 (normal 0-6), and elevation in D-Dimer which is a fibrin degradation product was elevated to 1048ng/dl ( normal range 0-500 ng/dl) other measures for the increase in blood sugar also showed elevation as seen in table 1. Discussion: There have been many hypotheses to find a causal relationship between both Diabetes and Covid-19 like the use of Dexamethasone or that the virus produces proinflammatory cytokines like Interleukin-6(IL-6) that lead to impaired signaling and decreased lipolysis or that there is a direct action on the ACE 2 found in the pancreas by the virus and maybe the least looked upon factor being lockdown leading to sedentary life, no exercises and increase in consumption of fatty foods, whichever may be the case it could very well be a multifactorial cause with many of these ideas involved. Conclusion: In this case, the association may be with decreased physical activity and an increase in Lipolysis or the proinflammatory states as seen by the increase in the C-reactive protein and Interleukin-6 levels. Table: Parameter Values before COVID Values after Covid Reference range Total WBC 4900 11,400 4000-10000/cu.mm Platelet count 200000 450000 140000-440000/cu.mm C-reactive protein 1.55 111.6 0-6 D-Dimer 0.4 1048 0-500 ng/dl Interleukin (IL-6) - 97.42

Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic b-cell mediated insulin release opposed by increments in a-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic b-cells resulting in pronounced aberrations in glucose control. Yet beyond the beta-cell perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise. [ABSTRACT FROM AUTHOR]

Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic β-cell mediated insulin release opposed by increments in α-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic β-cells resulting in pronounced aberrations in glucose control. Yet beyond the beta-cell perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise.

Background. Leptin is a hormone synthetized and secreted by the adipose tissue, with a regulating role in the neuro-endocrine-metabolic functions in humans during fasting. Obesity associates metabolic syndrome which combines a leptin resistance status with an insulin resistance status, a disorder that increases the risk of occurrence of type 2 diabetes mellitus. After the bariatric treatment, the decrease of leptin levels in obese patients improves the endocrine function of the pancreas and decreases the risk of developing type 2 diabetes mellitus over time. Aim. In the present study, we have monitored the dynamics of the serum values of leptin, insulin and glucose in correlation with the decrease of BMI (body mass index) after the bariatric surgery. Material and methods. Glucose, insulin and leptin serum levels were assessed in 48 obese individuals before and at 6 months after the bariatric surgery. Results. Leptin and insulin serum levels are decreasing significantly along with the decrease of BMI and pancreatic beta cells optimize their endocrine functionality. Conclusion. Pancreatic endocrine function in obese individuals who undergo bariatric treatment improves significantly at 6 months after the surgery procedure.

Three-dimensional bioprinting of an endocrine pancreas is a promising future curative treatment for patients with insulin secretion deficiency. In this study, we present an end-to-end concept from the molecular to the macroscopic level. Building-blocks for a hybrid scaffold device of hydrogel and functionalized polycaprolactone were manufactured by 3D-(bio)printing. Pseudoislet formation from INS-1 cells after bioprinting resulted in a viable and proliferative experimental model. Transcriptomics showed an upregulation of proliferative and ß-cell-specific signaling cascades, downregulation of apoptotic pathways, overexpression of extracellular matrix proteins, and VEGF induced by pseudoislet formation and 3D-culture. Co-culture with endothelial cells created a natural cellular niche with enhanced insulin secretion after glucose stimulation. Survival and function of pseudoislets after explantation and extensive scaffold vascularization of both hydrogel and heparinized polycaprolactone were demonstrated in vivo. Computer simulations of oxygen, glucose and insulin flows were used to evaluate scaffold architectures and Langerhans islets at a future perivascular transplantation site. [ABSTRACT FROM AUTHOR]

Objectives: Until recently, communication between neighboring cells in islets of Langerhans was overlooked by genomic technologies, which require rigorous tissue dissociation into single cells. Methods: We utilize sorting of physically interacting cells (PICs) with single-cell RNA-sequencing to systematically map cellular interactions in the endocrine pancreas after pancreatectomy. Results: The pancreas cellular landscape features pancreatectomy associated heterogeneity of beta-cells, including an interaction-specific program between paired beta and delta-cells. Conclusions: Our analysis suggests that the particular cluster of beta-cells that pairs with delta-cells benefits from stress protection, implying that the interaction between beta- and delta-cells might safeguard against pancreatectomy associated challenges. The work encourages testing the potential relevance of physically-interacting beta-delta-cells also in diabetes mellitus.

From among a great number of digestive system diseases in domestic animals there is pancreatitis which is caused by an early zymogenesis in the acinar cells. The problem of studying the structural organization of a pancreata in sick cats is topical because of a progressive spreading of pancreatitis in domestic animals. Thus, the purpose of the research was to study out the morphological changes of cats pancreata under acute pancreatitis. Working with vertebrate animals we were guided by “European Convention for the Protection of Vertebtate Animals used for Experimental and other Scientific Purposes” (Strasbourg, 1986). The results of the histological examination of cats pancreata under acute pancreatitis show some pathological changes both in endocrine and exocrine pancreas. Such changes were manifested in necrosis of exocrine pancreatitis as well as in spreading and swelling of acinar space, that testified to the infancy of an inflammatory process. Some dystrophic changes, followed by karyolysis, were found in the focus of tissue nicrosis. Pancreatocyte cytoplasm was cloudy, its basal and apical zones were obscure, clearly defined interstitial tissue swelling was found between the particles and unequal swelling was found inside the particles. Intercellular space was exaggerated. Morphometrically in a group of sick animals was detected an increase in specific weihgt of stromal component (р

Contrasting evidence is present regarding the contribution of stem/progenitor cell populations to pancreatic regeneration in diabetes. Interestingly, a cell compartment with stem/progenitor cell features has been identified in the pancreatic duct glands (PDGs). The aims of the present study were to evaluate pancreatic islet injury and regeneration, and the participation of the PDG compartment in type 2 diabetic mellitus (T2DM) and in an experimental model of diabetes. Human pancreata were obtained from normal (N = 5) or T2DM (N = 10) cadaveric organ donors. Experimental diabetes was generated in mice by intraperitoneal injection of 150 mg/kg of streptozotocin (STZ, N = 10); N = 10 STZ mice also received daily intraperitoneal injections of 100 µg of human recombinant PDX1 peptide (STZ + PDX1). Samples were examined by immunohistochemistry/immunofluorescence or RT-qPCR. Serum glucose and c-peptide levels were measured in mice. Islets in T2DM patients showed β-cell loss, signs of injury and proliferation, and a higher proportion of central islets. PDGs in T2DM patients had a higher percentage of proliferating and insulin+ or glucagon+ cells compared to controls; pancreatic islets could be observed within pancreatic duct walls of T2DM patients. STZ mice were characterized by reduced islet area compared to controls. PDX1 treatment increased islet area and the percentage of central islets compared to untreated STZ mice but did not revert diabetes. In conclusion, T2DM patients show signs of pancreatic islet regeneration and involvement of the PDG niche. PDX1 administration could support increased endocrine pancreatic regeneration in STZ. These findings contribute to defining the role and participation of stem/progenitor cell compartments within the pancreas.

Background: Children with transfusion-dependent thalassemia (TDT) suffer from secondary hemosiderosis and the delirious effects this iron overload has on their different body organs, including the pancreas. They are also more prone to develop zinc deficiency than the general pediatric population. This study aimed to determine the effect of zinc deficiency and iron overload on the endocrine and exocrine pancreas in TDT children.Methods: Eighty children, already diagnosed with TDT, were included in this study. We assessed the following in the participant children: serum ferritin, serum zinc, endocrine pancreatic function (oral glucose tolerance test (OGTT), fasting insulin level and from them, HOMA-IR was calculated), and exocrine pancreatic function (serum lipase and serum amylase).Results: Forty-four TDT children had a subnormal zinc level, while 36 of them had a normal serum zinc level. TDT children with low serum zinc had significantly more impaired endocrine pancreatic function and an abnormally high serum lipase than children with normal serum zinc, p < 0.05 in all. Serum zinc was significantly lower in TDT children with serum ferritin above the ferritin threshold (≥2500 ng/ml) than those below (59.1 ± 20.2 vs. 77.5 ± 28.13), p = 0.02. TDT children, having a serum ferritin ≥2500 ng/ml, had significantly more frequently impaired endocrine pancreatic function and abnormally high serum lipase than TDT children below the ferritin threshold, p < 0.05 in all.Conclusion: In children with transfusion-dependent thalassemia, zinc deficiency aggravates iron-induced pancreatic exocrine and endocrine dysfunction. [ABSTRACT FROM AUTHOR]

Background: Diabetes is now a global problem and millions of people are suffering all over the world. Reports exist for the allopathic use of turmeric, black pepper, and date palm as an antidiabetic and antioxidant agent. Aim: The current study was designed to assess the antihyperglycemic, antioxidants and antihyperlipidemic consequences of black pepper (BP), turmeric (T), ajwa pulp (AP), and ajwa seeds (AS) in alloxan-induced diabetic rats. Methodology: Diabetes was induced by a single intraperitoneal injection of alloxan (150 mg/kg b.w) in rats. They were randomly divided into 11 groups of 18 male and 18 female rats each. Group-1 normal control, group-2 diabetic control, group-3 was administered with glibenclamide (10 mg/kg), group-4 was administered with aqueous extract of BP (50 mg/kg), group-5, 6, 7 were administered with T, AP and AS (500 mg/kg) and group-8, 9, 10, 11 were administered with different combinations of aqueous extract (500 mg/kg) once in a day for eight weeks. The antihyperglycemic potential was determined through biochemical and histological investigations of the experimental animals at the end of the experiment. Results: The results of the study revealed that treatments improved glucose (229.53 mg/dL), Ghb (7.68%), insulin (13.63 U/L), Tg (95.92 mg/dL), Tc (152.86 mg/dL), HDL (23.22 mg/dL), LDL (110.30 mg/dL), TAC (1.89 mmol/L) and TOS (20.05 μmol/L) in comparison to diabetic control rats after 8 weeks of study period. Histological and immunohistochemical investigation of tissues exhibited severe changes in the pancreas of diabetic rats and treatments modulate these changes; this improvement in cells may explain the antidiabetic effects. Conclusion: It is concluded that aqueous extract of BP+AS; and BP+T+AP+AS could be promising nutraceutical therapy for diabetes management and its associated complications.

Aquaglyceroporins are a group of the aquaporin (AQP) family of transmembrane water channels. While AQPs facilitate the passage of water, small solutes, and gases across biological membranes, aquaglyceroporins allow passage of water, glycerol, urea and some other solutes. Thanks to their glycerol permeability, aquaglyceroporins are involved in energy homeostasis. This review provides an overview of what is currently known concerning the functional implication and control of aquaglyceroporins in tissues involved in energy metabolism, i.e. liver, adipose tissue and endocrine pancreas. The expression, role and (dys)regulation of aquaglyceroporins in disorders affecting energy metabolism, and the potential relevance of aquaglyceroporins as drug targets to treat the alterations of the energy balance is also addressed. • Aquaglyceroporins facilitate permeation of glycerol, urea, small solutes and water. • Liver and adipocyte aquaglyceroporins participate to triacylglycerols metabolism. • Pancreatic aquaglyceroporin AQP7 plays a role in insulin secretion. • Aquaglyceroporins are involved in metabolic diseases. • Aquaglyceroporins as drug targets. [ABSTRACT FROM AUTHOR]

Background. Leptin is a hormone synthetized and secreted by the adipose tissue, with a regulating role in the neuro-endocrine-metabolic functions in humans during fasting. Obesity associates metabolic syndrome which combines a leptin resistance status with an insulin resistance status, a disorder that increases the risk of occurrence of type 2 diabetes mellitus. After the bariatric treatment, the decrease of leptin levels in obese patients improves the endocrine function of the pancreas and decreases the risk of developing type 2 diabetes mellitus over time. Aim. In the present study, we have monitored the dynamics of the serum values of leptin, insulin and glucose in correlation with the decrease of BMI (body mass index) after the bariatric surgery. Material and methods. Glucose, insulin and leptin serum levels were assessed in 48 obese individuals before and at 6 months after the bariatric surgery. Results. Leptin and insulin serum levels are decreasing significantly along with the decrease of BMI and pancreatic beta cells optimize their endocrine functionality. Conclusion. Pancreatic endocrine function in obese individuals who undergo bariatric treatment improves significantly at 6 months after the surgery procedure. [ABSTRACT FROM AUTHOR]

Pancreas of 24 buffalo foetii collected from abattoir and veterinary clinics, GADVASU, Ludhiana were studied. The buffalo foetii were divided into three groups after measuring their CVRL, viz. Group I (CVRL between 0–20 cm), Group II (CVRL above 20 cm and up to 40 cm) and Group III (CVRL above 40 cm) and their approximate age was calculated. The tissues were processed and paraffin sections were cut and stained with different histological stains. In Group I, at 7.5 cm CVRL (62 days), the endocrine cells were scattered either in between the developing acinar cells and primitive tubules or were localized within primitive tubules. The alpha cells were large, round or oval in shape having eosinophilic cytoplasm and large nucleus whereas beta cells were small basophilic cells. At 12.8 cm CVRL (86 days), small groups of cells were present containing purely alpha cells or purely beta cells. Well developed islets of Langerhans with ill-defined capsule were observed at 19 cm CVRL (114 days). At 10.7 cm CVRL (77 days), certain cells which were morphologically different from cells of islets of Langerhans and acinar cells started to assemble and many capillaries were invading these cells. At 12.8 cm CVRL (86 days), these assembled cells formed well developed islets called perilobular islets. These large sized islets were developing at the periphery of lobules. The perilobular islets underwent regressive changes whereas islet of Langerhans increased in number simultaneously.

Abstract Introduction Obesity has become a pandaemic even in children. We aimed to investigate the impact of obesity in youth on later pancreatic intrinsic nervous system (PINS) phenotype and control of insulin secretion. Methods Young mice (5‐week‐old, T0 group) were fed either a normal diet (ND group) or a Western diet (WD group) for 12 weeks. Pancreas nervous system density, PINS phenotype and pancreas anatomy were analysed by immunohistochemistry at T0 and in adulthood (ND and WD groups). Insulin secretion was also studied in these 3 groups using a new model of ex vivo pancreatic culture, where PINS was stimulated by nicotinic and nitrergic agonists with and without antagonists. Insulin was assayed in supernatants by ELISA. Results Pancreas nervous system density decreased with age in ND (P

Maternal high-fat diet (HFD) is related to an increased risk of glucose metabolism disorders throughout the whole life of offspring. The pancreas is a glucose homeostasis regulator. Accumulating evidence has revealed that maternal HFD affects offspring pancreas structure and function. However, the potential mechanism remains unclear. In this study, the mouse dam was fed with HFD or control diet (CD) during prepregnancy, pregnancy and lactation. The pancreatic insulin secretion function and islet genome methylome of offspring were analyzed. Pancreatic islet specific gene methylation was detected by using MeDIP qPCR. The results showed that body weight, blood glucose after oral glucose loads, fasting serum insulin, and HOMA-IR index values were significantly higher in male 12-week-old offspring from HFD dams than in the offspring from CD dams. Maternal HFD induced insulin secretion defects in male offspring. Compared with that in maternal CD group, methylation of the Abcc8 and Kcnj11 genes was increased in maternal HFD group in male offspring pancreatic islets. Furthermore, the expression levels of Abcc8 and Kcnj11 were downregulated by intrauterine exposure to a maternal HFD. In summary, maternal HFD results in a long-term functional disorder of the pancreas that is involved in insulin secretion-related gene DNA hypermethylation. [ABSTRACT FROM AUTHOR]

The mechanisms by which fetal programming predisposes offspring to reduced β-cell function later in life are poorly understood. We hypothesized that maternal under- and over-nutrition during gestation would negatively affect offspring pancreas development and alter DNA methylation patterns. Pregnant ewes (n = 78) were fed 100, 60, or 140% of NRC requirements beginning at d 30.2 ± 0.2 of gestation. The fetuses are referred to as CON, RES, and OVER, respectively. Fetal pancreas tissue was collected at d 90 or 135 of gestation or within 24 h of birth. Tissue was preserved for histological (n = 8 to 9 offspring per treatment per time point) and DNA methylation analyses (n = 3 to 4 fetuses per treatment per sex). At d 135, OVER exhibited an increased islet size, reduced islet number, and greater insulin positive area compared with CON (p ≤ 0.03). An increased islet size was also observed at d 135 in RES (p ≤ 0.03) compared with CON. Cellular proliferation was reduced at birth in OVER vs. CON (p = 0.01). In the RES vs. CON females, 62% of the differentially methylated regions (DMRs) were hypomethylated (p ≤ 0.001). In the RES vs. CON males, 93% of the DMRs were hypermethylated (p ≤ 0.001). In OVER, 66 and 80% of the DMRs were hypermethylated in the female and male offspring compared with CON (p ≤ 0.001). In conclusion, changes to maternal diet during pregnancy affects the islet hypertrophy and cellular proliferation of the offspring at early post-natal time points. Additionally, changes in DNA methylation patterns appear to be in a diet-specific and sex-dependent manner.

Background: Epigenetics, in the broadest sense, governs all aspects of the life of any multicellular organism, as it controls how differentiated cells arrive at their unique phenotype during development and differentiation, despite having a uniform (with some exceptions such as T-cells and germ cells) genetic make-up. The endocrine pancreas is no exception. Transcriptional regulators and epigenetic modifiers shape the differentiation of the five major endocrine cell types from their common precursor in the fetal pancreatic bud. Beyond their role in cell differentiation, interactions of the organism with the environment are also often encoded into permanent or semi-permanent epigenetic marks and affect cellular behavior and organismal health. Epigenetics is defined as any heritable – at least through one mitotic cell division – change in phenotype or trait that is not the result of a change in genomic DNA sequence, and it forms the basis that mediates the environmental impact on diabetes susceptibility and islet function. Scope of review: We will summarize the impact of epigenetic regulation on islet cell development, maturation, function, and pathophysiology. We will briefly recapitulate the major epigenetic marks and their relationship to gene activity, and outline novel strategies to employ targeted epigenetic modifications as a tool to improve islet cell function. Major conclusions: The improved understanding of the epigenetic underpinnings of islet cell differentiation, function and breakdown, as well as the development of innovative tools for their manipulation, is key to islet cell biology and the discovery of novel approaches to therapies for islet cell failure.

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.