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This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm², from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM's protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy. [ABSTRACT FROM AUTHOR]

This opinion paper evaluates the potential of porcine islets as a promising alternative in beta cell replacement therapy for Type 1 Diabetes (T1D), juxtaposed with the current limitations of human donor islets. It analyzes the compatibility of pig islets with human glucose metabolism, their prospects as a limitless and high-quality source of beta cells, and the unique immunogenic challenges they present in xenotransplantation. Additionally, the paper discusses the regulatory and ethical considerations pertinent to the use of porcine islets. By synthesizing current research and expert perspectives, the paper highlights both the opportunities and significant barriers that need addressing to advance pig islets as a viable therapeutic option. The findings advocate for a balanced and forward-looking approach to the integration of pig islets in T1D treatment, underscoring the need for continued research and dialogue in this evolving field. [ABSTRACT FROM AUTHOR]

PDX1 is a crucial transcription factor in pancreas development and mature β-cell function. However, the regulation of PDX1 expression in larger animals mirroring human pancreas morphogenesis and endocrine maturation remains poorly understood. Therefore, we conducted a comparative analysis to characterize regulatory regions of goat PDX1 gene and assessed their transcriptional activity by transient transfection of several transgenic EGFP constructs in β- and non-β cell lines. We recognized several highly conserved regions encompassing the promoter and cis-regulatory elements (Area I-IV) at 5' flanking sequence of the genes. Within the promoter, we identified that a key E-box and nearby CAAT element synergistically drive transcription, constituting the basal promoter of goat PDX1 gene. Furthermore, each recognized regulatory area separately enhances this basal promoter activity in β-cells compared to non-β cells; however, cooperatively, they exhibit a bifunctional regulatory effect on transcription. Additionally, the intact ~ 3 kb upstream region (Area I-III) functions as the most efficient reporter transgene in vitro and shows islet-specific expression in native rat pancreas. Together, our findings suggest that the regulation of goat PDX1 gene is governed by conserved regions similar to other mammals, while both structurally and functionally, these regions exhibit a closer resemblance to those found in humans. [ABSTRACT FROM AUTHOR]

T cell receptor beta (TRB) sequences were recovered from the Cancer Genome Atlas Uveal Melanoma blood exome files. Intrinsic disorder scores for amino acid (AA) sequences of the entire TRB variable region were obtained and evaluated as potentially representative of overall survival (OS) distinctions, i.e., for cases representing the upper and lower 50th percentiles for intrinsic disorder scores. Analyses using four intrinsic disorder assessment tools indicated that a lower intrinsic disorder of the blood-sourced TRB variable regions, including continuous AA sequences of the V-gene segment, the complementarity-determining region-3, and the J-gene segment, was associated with a better OS probability (with log-rank p-values ranging from 0.002 to 0.014). We further determined that intrinsic disorder assessments could be used for OS stratification for a second, immunologically cold cancer: MYCN amplified neuroblastoma. Thus, intrinsic disorder assessments of blood-sourced, full TRB variable regions may provide a novel patient stratification approach for patients with immunologically cold cancers. [ABSTRACT FROM AUTHOR]

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism. [ABSTRACT FROM AUTHOR]

Attaining a true diabetes cure hinges on restoring functional β-cell mass, with regeneration offering advantages over transplantation, yet remaining elusive. The regenerative pathway is likely influenced by the severity of β-cell injury, involving replication or redifferentiation after mild-to-severe loss and neogenesis or reprogramming after extreme loss. Precision in understanding pathophysiological mechanisms and quantifying residual β-cell mass is essential for advancing personalized medicine and integrating regenerative therapies for diabetes. Safety in regenerative therapies demands targeted compound delivery, while efficacy and treatment personalization require a combination of therapies. The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes. [ABSTRACT FROM AUTHOR]

Background: A congenital portosystemic shunt (CPSS) is defined as abnormal vascular communications between the portal vein and the systemic vein. Encephalopathy, hepatopulmonary syndrome, and portopulmonary hypertension are manifestations in patients with CPSS. Hyperinsulinemic hypoglycemia is also one of the manifestations of CPSS. Hyperinsulinemic hypoglycemia secondary to CPSS is caused by a lack of hepatic first‐pass elimination of insulin, which is secreted from pancreatic beta cells. Case Presentation: A 7‐month‐old boy had hypergalactosemia detected by newborn mass screening. Enhanced abdominal computed tomography showed the absence of the portal vein trunk and extrahepatic portosystemic communication between the superior mesenteric vein and the inferior vena cava. He had suffered from uncontrollable hyperinsulinemic hypoglycemia under protein and lactose restriction. We performed living donor liver transplantation (LDLT) using a left lateral segment graft from his father. The postoperative course was uneventful and the hypoglycemic attacks disappeared. Conclusion: We believe that uncontrolled hyperinsulinemic hypoglycemia secondary to CPSS is an indication of LDLT. [ABSTRACT FROM AUTHOR]

Summary: Insulin resistance, defined as an impaired biological response to insulin stimulation in target tissues, arises most frequently in the presence of central obesity. Although obesity is generally associated with increased bone mass, recent data challenge this view and, if complicated by T2DM, obese patients are at high risk for fragility fractures. IR may play a key role in this increased fracture risk through effects on bone quality rather than bone quantity. Further understanding of the mechanisms and approaches to prevent osteoporotic fractures in IR-related diseases is needed. Clinical relevance: The dramatic increase in obesity and metabolic syndrome (MetS) over the last half-century has led to a worldwide epidemic of type 2 diabetes mellitus (T2DM) as well as in the incidence of insulin resistance (IR). IR is defined as an impaired biological response to insulin stimulation in target tissues and is primarily related to the liver, muscle, and adipose tissue. The most frequent underlying cause is central obesity, and it is known that excess abdominal adipose tissue secretes increased amounts of free fatty acids, which directly affects insulin signalling, reduces glucose uptake in muscle, and triggers excessive triglyceride synthesis and gluconeogenesis in the liver. When pancreatic β cells are unable to secrete the higher levels of insulin needed, T2DM, the main complication of IR, occurs. Observations: Although obesity is generally associated with increased bone mass, recent data challenge this view and highlight the multifaceted nature of the obesity-bone relationship. Patients with T2DM are at significant risk for well-known complications of diabetes, including retinopathy, nephropathy, macrovascular disease, and neuropathy, but it is clear that they are also at high risk for fragility fractures. Moreover, recent data provide strong evidence that IR may key role in the increased fracture risk observed in both obesity and T2DM. Conclusions: In this concise review article, the role of IR in increased risk of osteoporotic fractures in MetS, obesity, and T2DM is discussed and summarised, including consideration of the need for fracture risk assessment as a 'preventive measure', especially in patients with T2DM and chronic MetS with abdominal obesity. Personalised and targeted diagnostic and therapeutic approaches to prevent osteoporotic fractures in IR-related diseases are needed and could make significant contributions to health outcomes. [ABSTRACT FROM AUTHOR]

Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery. [ABSTRACT FROM AUTHOR]

The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia inmousemodels of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treatedwith BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM), a complex chronic disease with an intricate etiology and pathogenesis, involves the recognition of self-antigens by pancreatic islet autoantigen-specific T cells and plays crucial roles in both early- and late-stage destruction of beta cells, thus impacting disease progression. Antigen-specific T cells regulate and execute immune responses by recognizing particular antigens, playing broad roles in the treatment of various diseases. Immunotherapy targeting antigen-specific T cells holds promising potential as a targeted treatment approach. This review outlines the pathogenesis of diabetes, emphasizing the pivotal role of pancreatic islet autoantigen-specific T cells in the progression and treatment of T1DM. Exploring this avenue in research holds promise for identifying novel therapeutic targets for effectively managing diabetes. [ABSTRACT FROM AUTHOR]

Background: Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. However, the effects of TCF7L2 on β-cell function and ERK/MAPK signaling pathway are poorly understood. Objectives: This study aimed to elucidate the regulation of TCF7L2 in β-cell function and ERK/MAPK signaling pathway, which further participate in glucose metabolism and diabetes progression. Methods: After transfection of TCF7L2 siRNA and lenti-TCF7L2 plasmids, the activation of ERK/MAPK signaling and β-cell dedifferentiation were evaluated respectively. Six week-old male db / db mice were randomly grouped and fed a normal or high-fat diet, and then pancreatic level of TCF7L2 protein were measured respectively when the mice were fed to 8, 12, and 16 weeks of age. Furthermore, the contributions of TCF7L2 to ERK/MAPK signaling and glucose metabolism were investigated in a β-cell-specific TCF7L2 deletion mice model (TCF7L2β−/−). Results: The results demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, decreased pancreatic TCF7L2 protein in parallel with reduced functional β-cells were observed in db / db mice after weeks of normal or high-fat diet. However, the differences between were only significant when the mice were fed to 12 weeks of age. After weeks of high-fat diet feeding, impaired glucose tolerance and increased activation of ERK/MAPK signaling were simultaneously observed in TCF7L2β−/− mice. Conclusion: The study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes. Plain Language Summary: Inhibitory effect of TCF7L2 on pancreatic β-cell dedifferentiation via ERK/MAPK signaling pathway in diabetes Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. Nowadays, how TCF7L2 participates in β-cell dedifferentiation and how pancreatic TCF7L2 protein changes during diabetes progression are poorly understood. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. Here, we demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, declined pancreatic TCF7L2 protein in parallel with reduced mature β-cells were observed in db / db mice after weeks of normal or high-fat diet feeding. Furthermore, the role of TCF7L2 in dedifferentiation and glucose homeostasis were validated in mice with β cell-specific TCF7L2 deletion (TCF7L2β−/−). In conclusion, the study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes. [ABSTRACT FROM AUTHOR]

Background: To explore the association of long non-coding RNA (lncRNA) SNHG1/ miR-195 axis with type 2 diabetes mellitus (T2DM) and islet function. Methods: The expression of SNHG1 and miR-195 was measured in T2DM patients and in healthy subjects. Correlation between indciators was evaluated using Pearson correlation analysis. INS-1 cells were used to perform the cell function assays. Insulin secretion by INS-1 was detected using ELISA. Cell counting kit-8 (CCK-8) and flow cytometry was used to detect cell proliferation and apoptosis. Luciferase report assay was to used to verify the target of SNHG1. Results: The expression of SNHG1 was increased and miR-195 level was decreased in the serum of T2DM patients. Both SNHG1 and miR-195 could be biomarkers for T2DM diagnosis. The fasting plasma glucose (FPG) and HbA1c were positively related to SNHG1 and negatively related to miR-195. SNHG1 inhibited insulin secretion, and cell proliferation and promoted apoptosis of INS-1 cells via binding to miR-195. Conclusions: Detection of SNHG1 and miR-195 might predict T2DM. SNHG1 could suppress proliferation and insulin secretion, but promote apoptosis of INS-1 cells via sponging miR-195. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence from human and animal model studies indicates the significant role of microRNAs (miRNAs) in pancreatic beta cell function, insulin signaling, immune responses, and pathogenesis of type 1 diabetes (T1D). Methods: We aimed, using next-generation sequencing, to screen miRNAs from peripheral blood mononuclear cells of eight independent Kuwaiti-Arab families with T1D affected siblings, consisting of 18 T1D patients and 18 unaffected members, characterized by no parent-to-child inheritance pattern. Results: Our analysis revealed 20 miRNAs that are differentially expressed in T1D patients compared with healthy controls. Module-based weighted gene co-expression network analysis prioritized key consensus miRNAs in T1D pathogenesis. These included hsa-miR-320a-3p, hsa-miR-139-3p, hsa-miR-200-3p, hsa-miR-99b-5p and hsa-miR-6808-3p. Functional enrichment analysis of differentially expressed miRNAs indicated that PI3K-AKT is one of the key pathways perturbed in T1D. Gene ontology analysis of hub miRNAs also implicated PI3K-AKT, along with mTOR, MAPK, and interleukin signaling pathways, in T1D. Using quantitative RT-PCR, we validated one of the key predicted miRNA-target gene-transcription factor networks in an extended cohort of children with new-onset T1D positive for islet autoantibodies. Our analysis revealed that hsa-miR-320a-3p and its key targets, including PTEN, AKT1, BCL2, FOXO1 and MYC, are dysregulated in T1D, along with their interacting partners namely BLIMP3, GSK3B, CAV1, CXCL3, TGFB, and IL10. Receiver Operating Characteristic analysis highlighted the diagnostic potential of hsa-miR-320a-3p, CAV1, GSK3B and MYC for T1D. Discussion: Our study presents a novel link between hsa-miR-320a-3p and T1D, and highlights its key regulatory role in the network of mRNA markers and transcription factors involved in T1D pathogenesis. [ABSTRACT FROM AUTHOR]

Background:Moringa oleifera leaf is used for diabetes due to its pharmacologic effects. Patients with hyperglycemia experience beta cell destruction. However, no research on risk awareness has been done to ascertain its safety. The present study describes the antidiabetic effect of Moringa oleifera leaf, such as the protection of pancreatic beta cells and the induction of glycogen synthesis, before addressing the secondary effects of diabetes, such as hepatic and renal toxicity. Methods: Forty‐five Wistar rats weighed 160 ± 10 g were divided into nine groups. All animal operations complied with the National Institute of Health (NIH) guidelines for the care and use of laboratory animals as approved by the Animal Ethical Committee, University of Jos. Group I was normal control and Group II was diabetic animals induced with alloxan. Insulin and extract doses of 200, 400, and 800 mg/kg were given to diabetic Groups III‐VI. Normal animals in Groups VII–IX were given extract at doses of 200, 400, and 800 mg/kg for 28 days. Tissues were retrieved for biochemical and histological investigations using standard techniques. Results: There was decrease relative body weight of diabetic animals (95.50 ± 5.50) when compared to normal control (142.75 ± 20.08) with increased levels of urea (control 6.13 ± 0.523 and diabetes 29.23 ± 1.267) and creatinine (control 0.70 ± 0.057 and diabetes 2.13 ± 0.185). Histology of the liver and pancreas also points to organ damage due to hyperglycemia. However, oral administration of extract showed antidiabetic effect with protection of pancreatic beta cells and the induction of glycogen synthesis, no glycogen was deposited in the liver, addressing the secondary effects of diabetes, such as hepatic and renal toxicity. Further discovery revealed that extract elevated antioxidant enzyme expression. Conclusion: Leaf extract from Moringa oleifera reduces blood sugar and lessens the damage caused by hyperglycemia in the pancreas and liver. [ABSTRACT FROM AUTHOR]

Microorganisms have long been suspected to influence the outcome of immune-related syndromes, particularly autoimmune diseases. Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing beta cells of pancreatic islets, causing high glycemia levels. Genetics is part of its aetiology, but environmental factors, particularly infectious microorganisms, also play a role. Bacteria, viruses, and parasites influence the outcome of T1D in mice and humans. We used nonobese diabetic (NOD) mice, which spontaneously develop T1D, to investigate the influence of a parasitic infection, leishmaniasis. Leishmania amazonensis is an intracellular eukaryotic parasite that replicates predominantly in macrophages and is responsible for cutaneous leishmaniasis. The implication of Th1 immune responses in T1D and leishmaniasis led us to study this parasite in the NOD mouse model. We previously constructed osteopontin knockout mice with a NOD genetic background and demonstrated that this protein plays a role in the T1D phenotype. In addition, osteopontin (OPN) has been found to play a role in the immune response to various infectious microorganisms and to be implicated in other autoimmune conditions, such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in mice. We present herein data demonstrating the role of OPN in the response to Leishmania in NOD mice and the influence of this parasitic infection on T1D. This exploratory study aimed to investigate the environmental infectious component of the autoimmune response, including Th1 immunity, which is common to both T1D and leishmaniasis. [ABSTRACT FROM AUTHOR]

Primary cilia are sensory organelles present in many cell types, partaking in various signaling processes. Primary cilia of pancreatic beta cells play pivotal roles in paracrine signaling and their dysfunction is linked to diabetes. Yet, the structural basis for their functions is unclear. We present three-dimensional reconstructions of beta cell primary cilia by electron and expansion microscopy. These cilia are spatially confined within deep ciliary pockets or narrow spaces between cells, lack motility components and display an unstructured axoneme organization. Furthermore, we observe a plethora of beta cell cilia-cilia and cilia-cell interactions with other islet and non-islet cells. Most remarkably, we have identified and characterized axo-ciliary synapses between beta cell cilia and the cholinergic islet innervation. These findings highlight the beta cell cilia's role in islet connectivity, pointing at their function in integrating islet intrinsic and extrinsic signals and contribute to understanding their significance in health and diabetes. Müller, Klena et al. provide comprehensive insights into beta cell cilia structure, their interaction with islet cells and islet innervation. Their data imply that these cilia are elective compartments for contact with the cholinergic nervous system. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes. Caloric restriction (CR) can extend the organism life- and health-span. Here, the authors show that mild caloric restriction enhances insulin sensititivy to promote beta cell health and longevity, through an optimization of energy metabolism and homeostasis pathways. [ABSTRACT FROM AUTHOR]

This study aimed to identify the suitable induction protocol to produce highly qualified insulin producing cells (IPCs) from human adipose tissue derived stem cells (ADSCs) and evaluate the efficacy of the most functionally IPCs in management of diabetes mellitus (DM) in rats. The ADSCs were isolated and characterized according to the standard guidelines. ADSCs were further induced to be IPCs in vitro using three different protocols. The success of trans-differentiation was assessed in vitro through analysis of pancreatic endocrine genes expression, and insulin release in response to glucose stimulation. Then, the functionalization of the generated IPCs was evaluated in vivo. The in vitro findings revealed that the laminin-coated plates in combination with insulin-transferrin-selenium, B27, N2, and nicotinamide could efficiently up-regulate the expression of pancreatic endocrine genes. The in vivo study indicated effectual homing of the PKH-26-labelled IPCs in the pancreas of treated animals. Moreover, IPCs infusion in diabetic rats induced significant improvement in the metabolic parameters and prompted considerable up-regulation in the expression of the pancreatic related genes. The regenerative effect of infused IPCs was determined through histological examination of pancreatic tissue. Conclusively, the utilization of laminin–coated plates in concomitant with extrinsic factors promoting proliferation and differentiation of ADSCs could efficiently generate functional IPCs. [ABSTRACT FROM AUTHOR]

The canonical G406R mutation that increases Ca2+ influx through the CACNA1C-encoded CaV1.2 Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca2+ influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of CaV1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS. Gain of function mutant CaV1.2 channels drive life-threatening hypoglycemia in the multisystem disorder Timothy syndrome, but the underlying mechanisms are unknown. Here the authors show the mutant channels have adverse effects on counterregulatory hormones and CNS control of glucose homeostasis. [ABSTRACT FROM AUTHOR]

Following the near-total depletion of pancreatic beta-cells with streptozotocin (STZ), a partial recovery of beta-cell mass (BCM) can occur, in part due to the alpha- to beta-cell transdifferentiation with an intermediary insulin/glucagon bi-hormonal cell phenotype. However, human type 2 diabetes typically involves only a partial reduction in BCM and it is not known if recovery after therapeutic intervention involves islet cell transdifferentiation, or how this varies with age. Here, we used transgenic mouse models to examine if islet cell transdifferentiation contributes to BCM recovery following only a partial depletion of BCM. Cell lineage tracing was employed using Glucagon-Cre/yellow fluorescent protein (YFP) transgenic mice treated with STZ (25 mg/kg—neonates; 70 mg/kg—adults) or vehicle alone on 3 consecutive days. Mice were euthanized 2–30 days later with a prior glucose tolerance test on day 30, and immunofluorescence histology performed on the pancreata. Beta-cell abundance was reduced by 30–40% two days post STZ in both neonates and adults, and subsequently partially recovered in adult but not neonatal mice. Glucose tolerance recovered in adult females, but not in males or neonates. Bi-hormonal cell abundance increased 2–3-fold in STZ-treated mice vs. controls in both neonates and adults, as did transdifferentiated cells expressing insulin and the YFP lineage tag, but not glucagon. Transdifferentiated cell presence was an order of magnitude lower than that of bi-hormonal cells. We conclude that alpha- to beta-cell transdifferentiation occurs in mice following only a moderate depletion in BCM, and that this was accompanied by a partial recovery of BCM in adults. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic disease characterized by the immune-mediated destruction of the pancreatic beta cells responsible for insulin production. The secreted insulin and C-peptide are equimolar. Due to its longer half-life, C-peptide has become a safer means of assessing the pancreatic reserve. C-peptide levels were evaluated in a population of patients with T1D, focusing on the relationship between this variable and other factors. In addition, the influence of C-peptide on metabolic control and microvascular complications was investigated. This cross-sectional study included 95 patients who had been diagnosed with T1D at least five years earlier. These patients were evaluated using a clinical demographic survey, anthropometric data, laboratory tests, and fundoscopy. This study showed that 29.5% of patients had residual insulin secretion, which correlated directly with their age at diagnosis. No statistically significant differences in metabolic control or microvascular complications were observed between the C-peptide level groups. In addition, our results indicate that ancestry does not influence the persistence of residual C-peptide function in our highly mixed population. It is recommended that future research consider incorporating new variables, such as HLA and pancreatic autoimmunity, as factors that may influence residual β-cell function. [ABSTRACT FROM AUTHOR]

Background: Estimation of beta cell mass is currently restricted to evaluating pancreatic tissue samples, which provides limited information. A non-invasive imaging technique that reliably quantifies beta cell mass enables monitoring of changes of beta cell mass during the progression of diabetes mellitus and may contribute to monitoring of therapy effectiveness. We assessed the specificity of radiolabelled exendin for beta cell mass quantification in humans. Fourteen adults with pancreas tumours were injected with 111In-labeled exendin-4 prior to pancreatic resection. In resected pancreas tissue, endocrine-exocrine ratios of tracer uptake were determined by digital autoradiography and accumulation of 111In-labeled exendin-4 was compared to insulin and GLP-1 receptor staining. Of four participants, abdominal single photon emission computed tomography/computed tomography (SPECT/CT) images were acquired to quantify pancreatic uptake in vivo Results: Tracer uptake was predominantly present in the endocrine pancreas (endocrine-exocrine ratio: 3.6 [2.8–10.8]. Tracer accumulation showed overlap with insulin-positive regions, which overlapped with GLP-1 receptor positive areas. SPECT imaging showed pancreatic uptake of radiolabelled exendin in three participants. Conclusion: Radiolabelled exendin specifically accumulates in the islets of Langerhans in human pancreas tissue. The clear overlap between regions positive for insulin and the GLP-1 receptor substantiate the beta cell specificity of the tracer. Radiolabelled exendin is therefore a valuable imaging agent for human beta cell mass quantification and has the potential to be used for a range of applications, including improvement of diabetes treatment by assessment of the effects of current and novel diabetes therapies on the beta cell mass. Trial registration: ClinicalTrials.gov NCT03889496, registered 26,032,019, URL https://clinicaltrials.gov/study/NCT03889496?term=NCT03889496. ClinicalTrials.gov NCT04733508, registered 02022021, URL https://clinicaltrials.gov/study/NCT04733508. [ABSTRACT FROM AUTHOR]

Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin (CaN) as a new potential modulator of beta cell regeneration. We showed that CaN overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, CaN inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. CaN appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal CaN as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration. [ABSTRACT FROM AUTHOR]

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges. A study combined experiments, image analysis and mathematical modeling to understand the coupling between bioenergetics and mitochondrial dynamics and investigates how excess nutrients and starvation affect mitochondrial morphology. [ABSTRACT FROM AUTHOR]

Introduction: According to WHO, in 2019, diabetes was the ninth leading cause of death with an estimated 1.5 million deaths directly caused by diabetes. In 2014, 8.5% of adults aged18 years and older had diabetes. The crude prevalence of diabetes in adults aged 20years or older in India increased by 39·4% . Key for prevention of the complication among the diabetic patients is prompt and aggressive treatment aimed at maintaining normal blood sugar levels. C-peptide is commonly used in preference to insulin measurement when assessing b-cell function in clinical practice. Age is a factor which is a determinant of functionality of the human body. Hence it needed to assess the effect of aging on the c-peptide levels i.e., the insulin production in the body. Early initiation of the insulin treatment for the patients of diabetes is depended on the c-peptide levels. This necessitates the need to understand the c-peptide levels as a proxy of insulin levels amongst the diabetics and the correlation between theage of the diabetes and the c-peptide levels. Objectives: To estimate the level of C-peptide in patients with newly diagnosed type 2 Diabetes Mellitus and to correlate C-peptide levels in different age groups of newly diagnosed type 2 Diabetics Mellitus. Materials And Methods: The present study is a cross-sectional study conducted in KR Hospital, Mysuru. Patients who were newly diagnosed with Diabetes Mellitus, who satisfy the inclusion criteria and consented to participants in the study was included inthe study. Detailed history, Examination and investigations were done to the selected study participants. C-peptide levels was estimated in all the patients. Data was analysed using SPSS software. Results: Around 50% of the patients belonged to the age group of 30-40 years. While21.9% belong to 51-60 years. Mean age was 49.45 years. 5.71% of them fall under 71-80 years of age category. 52.38% of the study participants were males while 47.61%were females. Mean Fasting blood sugars and Post Prandial blood sugars of the newly diagnosed diabetes mellitus study participants are 217.85 mg/dl and 342.42 mg/dlrespectively. The mean glycosylated hemoglobin is 10.71% among the patients.68.57% of the newly detected diabetes mellitus in our study had high c-peptide levelswhile 31.42% of them had low c-peptide levels. Mean c-peptide levels among the study participants is 6.51 ng/ml with standard deviation of 1.14 ng/ml. There was a negative correlation between the age and c-peptide. The decrease in the c-peptide levels indicates low insulin production by the beta cells of pancreases. Conclusion: The present study concludes that there is a strong negative correlation between the c-peptide levels and age among the study participants Thisindicates the true deficiency in the insulin production in our participants which bring the need for the early initiation of the insulin therapy, at the time of diagnosis in a newlydetected type 2 diabetes mellitus. Hence, c-peptide levels measured at diagnosis orearlier after the diagnosis of diabetes mellitus at any age helps in understanding theinsulin reserve of the patients. Thus, better treatment can be given by seeing the c-peptidelevels to have good control of blood sugar levels and in preventing thecomplication of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Introduction: Health systems are confronted with not only the growing worldwide childhood obesity epidemic but also associated comorbidities. These subsequently cause variations in distinct metabolic pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this evidence map is to systematically evaluate the evidence and to identify research gaps on glucagon-induced amino acid (AA) turnover and its metabolic interaction with MASLD. Methodology: A systematic literature search was conducted up to April 2023 in three electronic databases. Studies were required to include at least two of the main research areas, glucagon, AA metabolism and MASLD. Two independent reviewers screened titles and abstracts according to prespecified eligibility criteria, as well as full-text articles. Results are summarized in tables stratified by human and animal studies and study population age. Results: Thirty-four references were ultimately included. The publication years dated back to 1965 showed a great increase from 2012 to 2023. In total, there were 19 animal studies and 15 human studies. Among the human studies, except for two studies in adolescents, all the studies were conducted in adults. In human studies, the methods used to evaluate metabolic changes differed among hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests. Thirteen studies focused on the metabolic effects of MASLD, while only two studies explored the interaction between MASLD, glucagon and AA metabolism in humans. The other 19 studies focused on metabolomics, beta cell function or just one topic of a research area and not on interactions between one another. Conclusion: Research on the interaction between MASLD, glucagon and AA metabolism in humans is sparse and complete lacking in pediatrics. Furthermore, longitudinal studies with a focus on hyperglucagonemia independent of diabetes but related to MASLD present an unambiguous research gap. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic metabolic disease resulting from an autoimmune destruction of pancreatic beta cells. Beta cells activate various stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling, and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D; therefore, we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2-like protein 1 (BCL2L1). Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses. NEW & NOTEWORTHY: Beta cell senescence is an emerging contributor to the pathogenesis of type 1 diabetes, but candidate therapeutic targets have not been identified in human beta cells. In this study, we examined the role of a secreted factor, GDF15, and found that although it is not required to maintain viability during senescence, it is required to fine-tune gene expression programs involved in the senescence response during DNA damage in human beta cells. [ABSTRACT FROM AUTHOR]

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines play a role in the failure of β cells in type 1 and type 2 diabetes. While existing data from 'omics' experiments allow for some understanding of the molecular mechanisms behind cytokine-induced dysfunction in β cells, no report thus far has provided information on the direct imaging of the β cell landscape with nanoscale resolution following cytokine exposure. In this study, we use Airyscan-based optical super-resolution microscopy of Insulinoma 1E (INS-1E) cells to investigate the structural properties of two subcellular membranous compartments involved in the production, maturation and secretion of insulin-containing granules, the endoplasmic reticulum (ER) and the Golgi apparatus (GA). Our findings reveal that exposure of INS-1E cells to IL-1β and IFN-γ for 24 h leads to significant structural alterations of both compartments. In more detail, both the ER and the GA fragment and give rise to vesicle-like structures with markedly reduced characteristic area and perimeter and increased circularity with respect to the original structures. These findings complement the molecular data collected thus far on these compartments and their role in β cell dysfunction and lay the groundwork for future optical microscopy-based ex vivo and in vivo investigations. [ABSTRACT FROM AUTHOR]

Introduction: Glucose homeostasis is a physiological process mediated by a variety of hormones. Fibroblast growth factor (FGF) 21 is a protein expressed in the liver, adipose tissue, muscle and pancreas and exerts actions in multiple targets including adipose, liver, pancreas and hypothalamus. The aim of this study was to examine the possible involvement of FGF21 in pancreatic and central control of glucose by measuring reflective changes in the release of insulin and glucagon. Methods: Thirty adult male Wistar Albino rats were divided; Control, PD + aCSF, PD + FGF21 groups (n = 10). Effects of intracerebroventricular (icv) FGF21 administration to pancreatic denervated (PD) rats. Agouti-related protein (AgRP), Pro-opiomelanocortin (POMC) levels and blood glucose homeostasis were investigated. Results: Administration of FGF21 to 3rd ventricle increased food consumption but body weight didn't change significantly. AgRP level increased, pancreatic insulin levels increased, and glucagon level decreased. Conclusion: Central FGF21 administration is effective in regulating blood glucose homeostasis by increasing the amount and efficiency of insulin and changing glucose use. [ABSTRACT FROM AUTHOR]

Sedentary behavior (SB) has been linked to risk factors of cardiometabolic disease, with inconsistent findings reported in the literature. We aimed to assess the associations of SB with multiple biomarkers of inflammation and insulin resistance in adults. Domain-specific SB, sitting time and moderate-to-vigorous physical activity (MVPA) were measured in 78 adults (mean ± SD 52.0 ± 10.8 y). Body fat percentage (BF%) was assessed using multi-frequency bioelectrical impedance. A blood draw assessed glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin. Adiponectin-leptin ratio (ALR), homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were calculated. Multivariable linear regression analyses, controlling for age, sex, MVPA, and BF%, were used to assess associations. After adjustment for age, sex and MVPA, total SB (7.5 ± 2.5 h/day) was positively associated with leptin, insulin, HOMA-IR, HOMA-β (Standardized Beta (β) range 0.21–0.32) and negatively associated with ALR (β = -0.24, p < 0.05 for all). Similarly, total sitting time (7.2 ± 2.9 h/day) was associated with TNF-α (β = 0.22) and ALR (β = -0.26). These associations were attenuated to non-significance after adjustment for BF%. Leisure screen time was detrimentally associated with IL-6 (β = 0.24), leptin (β = 0.21), insulin (β = 0.37), HOMA-IR (β = 0.37), and HOMA-β (β = 0.34), independent of age, sex and MVPA (p < 0.05 for all). Only the associations with insulin (β = 0.26), HOMA-IR (β = 0.26), and HOMA-β (β = 0.23) remained significant after further controlling BF% (p < 0.05). Self-reported SB is associated with biomarkers of inflammation and insulin resistance, independent of MVPA, and in some cases BF%. [ABSTRACT FROM AUTHOR]

Macrophages are suspected to be involved in the pathogenesis of type 1 diabetes. The role of macrophages in the transmission of coxsackievirus B4 (CVB4) to pancreatic cells and in the alteration of these cells was investigated. Human monocytes isolated from peripheral blood were differentiated into macrophages with M‐CSF (M‐CSF macrophages) or GM‐CSF (GM‐CSF macrophages). M‐CSF macrophages were inoculated with CVB4. M‐CSF and GM‐CSF macrophages were activated with lipopolysaccharide and interferon (IFN)‐γ. Human pancreatic beta cells 1.1B4 were inoculated with CVB4 derived from M‐CSF macrophages or were cocultured with CVB4‐infected M‐CSF macrophages. The antiviral activity of synthetic molecules in macrophage cultures was evaluated. Activated macrophages were cocultured with CVB4‐persistently infected 1.1B4 cells, and the specific lysis of these cells was determined. Our study shows that CVB4 can infect M‐CSF macrophages, leading to the release of interleukin‐6 and tumor necrosis factor‐α and later IFN‐α. M‐CSF macrophage‐derived CVB4 can infect 1.1B4 cells, which were then altered; however, when these cells were cultured in medium containing agarose, cell layers were not altered. Fluoxetine and CUR‐N373 can inhibit CVB4 replication in macrophage cultures. Supernatants of activated M‐CSF and GM‐CSF macrophage cultures induced lysis of CVB4‐persistently infected 1.1B4 cells. The cytolytic activity of activated GM‐CSF macrophages was higher towards CVB4‐persistently infected 1.1B4 cells than mock‐infected 1.1B4 cells. In conclusion, macrophages may play a role in CVB4 infection of pancreatic cells, and are capable of inducing lysis of infected pancreatic cells. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, β-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine's protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine's immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved β-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 1010 plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 1010 pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies. [ABSTRACT FROM AUTHOR]

Mulberry (family Moraceae) has been historically used in traditional and modern medicine. This review explores the bioactive compounds in mulberry roots, their chemical composition, biological activities, traditional uses and modern applications. Mulberry roots contain phytochemicals with significant therapeutic potential, including antioxidant, antiinflammatory, antidiabetic and antitumor effects. Mulberry root extracts, rich in compounds like morusin, kuwanon C and sanggenons, exhibit potent anti-inflammatory properties by inhibiting inflammatory mediators and modulating immune responses. These extracts also possess strong antioxidative effects due to compounds such as morusin and oxyresveratrol, which neutralize reactive oxygen species and protect cells from oxidative stress. The antidiabetic properties are attributed to bioactive compounds that regulate blood glucose levels and enhance insulin sensitivity. Studies indicate that these extracts lower blood glucose, improve insulin production and protect pancreatic b cells. Additionally, mulberry root extracts demonstrate antitumor activities by inducing apoptosis and inhibiting cell proliferation in various cancer cell lines. Compounds like sanggenol M and mulberrofurans have shown cytotoxic effects against leukemia, melanoma and colorectal cancer cells. The anti-dopaminergic effects of these extracts make them potential candidates for managing psychotic disorders, as they reduce aggression, enhance catalepsy and decrease stereotyped behavior in animal models. Recent research highlights the potential of mulberry root extracts in developing pharmaceuticals and nutraceuticals for metabolic health and chronic disease prevention. Future research should focus on clinical trials to validate their efficacy and safety in humans, bioavailability studies for optimizing therapeutic use, and mechanistic studies to elucidate molecular pathways. Standardization and quality control measures are essential for ensuring consistency and regulatory approval. In conclusion, mulberry roots are a valuable source of bioactive phytochemicals with diverse health benefits. Integrating traditional knowledge with contemporary scientific research can enhance the therapeutic applications of mulberry roots in modern medicine. [ABSTRACT FROM AUTHOR]

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses, significantly affects cellular function and viability. It plays a pivotal role in modulating membrane potentials, particularly action potentials (APs), essential for properly functioning excitable cells such as neurons, smooth muscles, pancreatic beta cells, and myocytes. The interaction between oxidative stress and AP dynamics is crucial for understanding the pathophysiology of various conditions, including neurodegenerative diseases, cardiac arrhythmias, and ischemia-reperfusion injuries. This review explores how oxidative stress influences APs, focusing on alterations in ion channel biophysics, gap junction, calcium dynamics, mitochondria, and Interstitial Cells of Cajal functions. By integrating current research, we aim to elucidate how oxidative stress contributes to disease progression and discuss potential therapeutic interventions targeting this interaction. [ABSTRACT FROM AUTHOR]

Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D. [ABSTRACT FROM AUTHOR]

Background: The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes. Methods: The glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice. Key findings: First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis. Conclusions: Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications The pharmacology of flavonoids on β‐cell function is largely undefined especially in the context of defective secretion of insulin. We sought to identify flavonoids that increased the insulin‐secreting function of β‐cells and to explore the underlying mechanisms.INS‐1 β‐cells in culture and islets of Langerhans isolated from control and diabetic male rats were used for insulin secretion experiments. Pharmacological and electrophysiological approaches were used for mechanistic studies.Among a set of flavonoids, exposure of INS‐1 β‐cells to resokaempferol (ResoK) enhanced glucose‐stimulated insulin secretion and therefore we further characterised its activity and its pharmacological mechanism. ResoK glucose‐dependently enhanced insulin secretion in INS‐1 β‐cells and pancreatic islets isolated from rats. Mechanistically, whole cell patch clamp recordings in INS‐1 cells showed that ResoK rapidly and dose‐dependently enhanced the L‐type Ca2+ current whereas it was inactive towards T‐type Ca2+ current. Accordingly, pharmacological inhibition of L‐type Ca2+ current but not T‐type Ca2+ current blocked the effects of ResoK on glucose‐stimulated insulin secretion. ResoK was still active on dysfunctional β‐cells as it ameliorated glucose‐stimulated insulin secretion in glucotoxicity‐induced dysfunctional INS‐1 cells and in pancreatic islets isolated from diabetic rats.ResoK is a glucose‐dependent activator of insulin secretion. Our results indicated that the effects of ResoK on insulin secretion involved its capacity to stimulate L‐type Ca2+ currents in cultured β‐cells. As ResoK was also effective on dysfunctional β‐cells, our work provides a new approach to stimulating insulin secretion, using compounds based on the structure of ResoK. [ABSTRACT FROM AUTHOR]

We previously demonstrated that boundary cap neural crest stem cells (BCs) induce the proliferation of beta-cells in vitro, increase survival of pancreatic islets (PIs) in vivo after transplantation, and themselves strongly increase their proliferation capacity after exposure to space conditions. Therefore, we asked if space conditions can induce the proliferation of beta-cells when PIs are alone or together with BCs in free-floating or 3D-printed form. During the MASER 15 sounding rocket experiment, half of the cells were exposed to 6 min of microgravity (µg), whereas another group of cells were kept in 1 g conditions in a centrifuge onboard. The proliferation marker EdU was added to the cells just before the rocket reached µg conditions. The morphological assessment revealed that PIs successfully survived and strongly proliferated, particularly in the free-floating condition, though the fusion of PIs hampered statistical analysis. Proliferation of beta-cells was displayed in 3D-printed islets two weeks after µg exposure, suggesting that the effects of µg may be delayed. Thus, PIs in 3D-printed scaffolds did not fuse, and this preparation is more suitable than free-floating specimens for morphological analysis in µg studies. PIs maintained their increased proliferation capacity for weeks after µg exposure, an effect that may not appear directly, but can emerge after a delay. [ABSTRACT FROM AUTHOR]

AbstractThe study aimed to assess the toxic effect of cadmium (Cd) on the exocrine and endocrine functions of pancreas, the changes in pancreatic tissue after Cd withdrawal, and the protective effects of vitamin C (VC) and Nigella sativa (NS) against Cd-induced damage. Rats were assigned to: control, Cd-treated (0.5 mg/kg/d intraperitoneal [IP] injection), VC and Cd-treated (receiving 100 mg/kg/d VC orally and Cd concomitantly), NS and Cd-treated (receiving 20 mg/kg/d NS and Cd, simultaneously), and Cd withdrawal (receiving Cd for 30 d then living free for recovery for other 30 d). Blood samples were collected and post-sacrifice pancreatic specimens were processed for light and electron microscope study. Quantitative analyses of pancreatic collagen area%, pancreatic islet parameters, β cell density, and insulin immunoexpression were done. Fasting blood glucose was significantly increased in Cd-treated and Cd-withdrawal groups, while co-treatment with VC and NS caused significant reductions (p < 0.05). Cd-induced extensive degenerative changes in pancreatic acini and islets at light and ultrastructure levels. Obvious fibrosis and congestion of blood vessels were noticed. Significant reductions in pancreatic islet number, volume, and surface area and diminished beta cell count and insulin immunoexpression were observed. After withdrawal of Cd, the whole pancreatic tissue still showed a serious impact. Concomitant treatment with VC or NS obviously reduced these degenerative changes and significantly improved pancreatic islet parameters and insulin immunoexpression. VC showed a better amendment than NS, but this difference was statistically insignificant. Therefore, VC and NS could be used as prophylactic agents that lessen Cd consequences on the pancreas. [ABSTRACT FROM AUTHOR]

This review article provides an in-depth examination of various aspects related to tirzepatide, a synthetic peptide given the positive signal by the "United States Food and Drug Administration" for managing type 2 diabetes. Beginning with an overview of diabetes introduction, epidemiology, and issues related to β-cell dysfunction, is explored in the narrative. It further delves into the significance of incretins in the context of diabetes and introduces tirzepatide as a novel "twincretin" owing to its dual agonistic activity on the glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. The document delves into the chemistry and structure of tirzepatide, providing insights into its unique composition of 39 amino acids derived from native GLP-1, GIP, and semaglutide sequences. Tirzepatide's pharmacology, with a focus on its pharmacokinetic characteristics, and its mechanism of action (MOA) are extensively discussed. Notably, tirzepatide exhibits a preference for GIP receptors, leading to effective reduction of hyperglycemia and positive effects on pancreatic β-cells. Clinical trials examining tirzepatide's impact on glycemic and obesity control are detailed, demonstrating its efficacy in reducing body weight and appetite. Furthermore, the review article explores tirzepatide's effects on cardiovascular and kidney function, highlighting potential renal benefits for diabetic and elevated cardiovascular risk individuals. The narrative also addresses the association between tirzepatide and NAFLD, emphasizing potential benefits in mitigating NAFLD outcomes. Additionally, a comprehensive overview of tirzepatide's side effects, supported by scientific trials, is presented in this article. In conclusion, this review article provides a thorough examination of tirzepatide's multifaceted impact on diabetes management, shedding light on its pharmacological properties, clinical implications, and potential side effects. The information presented contributes to a comprehensive understanding of tirzepatide's role in the evolving landscape of T2D therapeutics. [ABSTRACT FROM AUTHOR]

Background: Our previous genome‑wide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. Methods: We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. Results: We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45β, respectively. Conclusions: This study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis. [ABSTRACT FROM AUTHOR]

This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to "treatment failure," and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024 diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care. The second concerns advances in diabetes research that have not yet found their way into guidelines, though they are endorsed by strong evidence and are ready for real-world use in appropriate patients. The final theme addresses lingering misconceptions about the underpinnings of type 2 diabetes—fundamental fallacies that continue to be asserted in the textbooks and continuing medical education upon which physicians build their approaches. A corrected and up-to-date understanding of the disease state is essential for practitioners to both conceptually and translationally manage initial onset through late-stage type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed β-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported. Case presentation: We present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally. Conclusions: This rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis. [ABSTRACT FROM AUTHOR]

Background/Aims: There are evidences that a decrease in the functional activity of pancreatic β-cells under type 2 diabetes conditions may be associated with their senescence, therefore, senotherapy may be a prospective strategy for the diabetes treatment. Methods: The senotherapeutic potential of peroxiredoxin 6 (PRDX6) was studied in RIN-m5F pancreatic β-cells with streptozotocin-induced senescence by measuring markers, associated with senescence. Results: Exposure to streptozotocin (STZ) resulted in the senescence of the β-cells. The addition of PRDX6 to the culture medium of RIN-m5F β-cells before treatment with STZ decreased the levels of the following senescence markers: the percentage of SA-β-Gal-positive cells, the phosphorylation of histone H2AX and p21 proteins, and the secretion of the proinflammatory cytokine IL-6 but not the anti-inflammatory cytokine IL-10. These effects were accompanied by a decrease in the production of reactive oxygen species (ROS) and the restoration of impaired NF-κB activation. In addition, PRDX6 altered the production of the heat shock protein HSP90: the production of the constitutive form of HSP90-beta decreased, while the level of inducible HSP90-alpha increased. Conclusion: PRDX6 prevented the senescence of RIN-m5F cells in response to the DNA damage-inducing agent streptozotocin, indicating a potential protective role of PRDX6 in type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Introduction: A significant global public health issue is diabetes. By repairing, maintaining, or increasing the original tissue function, regenerative medicine aims to lessen the patients' suffering. Due to their ability to multitask, herbal medicines are gaining attractiveness in traditional medicine. Aim to the Work: To study the possible regenerative capacity of Harmine on diabetic pancreas experimentally induced by streptozotocin in adult male rats. Material and Methods: Thirty adult albino rats divided equally into three groups. Control group (group I). Diabetic group (group II): rats were nurtured a fat excessive diet pro three weeks prior to a single intraperitoneal dose of freshly supplied STZ (40 mg/kg). Diabetic+ harmine group (group III): rats treated as group II and on day eight after the onset of diabetes, harmine was given in a dose 6.5 mg/kg over the course 28 daylights in a gavage approach. Paraffin sections were practiced for H&E and Immunohistochemical study. Results: The pancreatic islets histology of the diabetic group concealed marked distortion alongside cellular vacoulations and nuclear pyknosis. Consequently confirmed immunohistochemically by significant increase (p>0.01) in caspase-3 and significant decrease (p>0.01) in insulin, Ki67 and HSP70 immunoexpression. The pancreatic islets of diabetic rats given harmine for four weeks displayed reduced degenerative structure, greater islets mass, and fewer vacuolated cells. Immunohistochemical beta cell indicators, such as a statistically significant decrease (p>0.01) in caspase-3 immunoexpression and a significant increase (p>0.01) in insulin, Ki67, and HSP70 immunoexpression compared to group II, served as proof of this. Conclusion: Harmine is proficient pro beta cell projiferation, expansion of islet build and recover glycemic check. These findings implying harmine analogs possibly will partake unique therapeutic potential for the medication of human diabetes. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B∗39:06, B∗39:01, and B∗38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B∗39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B∗39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B∗39:06 by only two amino acids. HLA-B∗38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B∗39:06 and B∗39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B∗39:06 and B∗39:01 provided an explanation for the distinct peptide C terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B∗38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B∗39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding. [ABSTRACT FROM AUTHOR]

Characterizing changes in beta cell function during prolonged hyperinsulinemia and dietary stress is important to study to prevent diseases like metabolic dysfunction-associated steatotic liver disease and insulin resistance. This research investigates how a moderate sucrose (MS) diet affects insulin resistance and β-cell mass in two rat strains: LEW.1WR1 and Wistar Furth (WF). LEW.1WR1 rats seem to be sensitive to beta cell disruptions as weanlings. Twenty-one male LEW.1WR1 rats and sixteen male WF rats were studied over 18 weeks. The rats were divided into groups and given either the control or MS diet. Their body weight was monitored twice a week. Insulin tolerance tests (ITTs) and fasting blood glucose measurements were taken at intervals. Urine samples were analyzed to assess metabolic shifts, and pancreas tissue was examined to evaluate changes in β-cell mass. The LEW.1WR1 rats became overweight and showed higher insulin resistance than the WF rats. Both strains of rats on the MS diet displayed changes in urine metabolite profiles in terms of levels of lactic acid and alanine. This study highlights the impact or lack thereof of a moderate sucrose diet on body mass, insulin resistance, and β-cell mass, with notable effects observed specifically in LEW.1WR1 rats. These findings contribute to our understanding of how dietary sugar intake can affect metabolism when observed in models sensitive to metabolic defects. [ABSTRACT FROM AUTHOR]