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The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18, and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis. [ABSTRACT FROM AUTHOR]

To illustrate the anti-diabetic properties of Berberis orthobotrys seeds was the aim of the current study. After a series of experiments, two doses of aqueous methanolic extract of the seeds were selected i.e., 151 mg/kg and 301 mg/kg to assess the anti-diabetic potential in normoglycemic, alloxan-induced and glucose-loaded diabetic rats. The effect of the seeds extract on total cholesterol and triglycerides was also assessed. Histological examination of the pancreas and the GC-MS analysis of blood and urine samples of rats were also carried out. At 151 mg/kg and 301 mg/kg doses, the aqueous methanolic extracts of Berberis orthobotrys seeds showed promising results for their anti-diabetic potential comparable to Glibenclamide. Studies on the phytochemistry of AMEBO also exposed the existence of alkaloids, steroids, glycosides, flavonoids and resins. Serum lipid measurements showed a substantial reduction in triglycerides and total cholesterol on days 7 and 15. The pancreas's islets were protected by the extract, as shown by a histological analysis. The primary metabolite Berberine, which was qualitatively detected by GC-MS in blood and urine samples of rats, may be the alkaloid in command of insulin release or recovery of beta cells after alloxan destruction. More study is necessary to comprehend the underlying signaling process. [ABSTRACT FROM AUTHOR]

The pancreas suffers from lipotoxicity, which threatens the survival of pancreatic islets. Dual peroxisome proliferatoractivated receptor-alpha/gamma (PPAR-α/γ) agonism is a promising method for treating type 2 diabetes mellitus (T2DM). This study evaluated the effects of single PPAR-α and PPAR-γ or their combined activation on pancreatic islet remodelling, beta cell proliferation, identity and maintenance in an experimental obesity model. Fifty three-month-old mice, randomly divided to receive the control (C) or high-fat (HF) diet for ten weeks, were then redivided for a four-week treatment: C, HF, HF-a (received the PPAR-a agonist), HF-g (received the PPAR-γ agonist pioglitazone) and HF-d (received PPAR-α/γ agonists). The HF group was overweight, had oral glucose intolerance, showed a proinflammatory adipokine profile, exhibited increased alpha and beta cell masses and showed islet gene expression compatible with compromised beta cell proliferation and favoured dedifferentiation. All treatments reduced body weight, mitigated oral glucose intolerance and produced an anti-inflammatory adipokine profile, which rescued islet cytoarchitecture and beta cell function. Principal component analysis (PCA) revealed a shift in the antiapoptotic gene Bcl2 and beta cell proliferation genes (Pax4 and Neurog3) in HF-a. Conversely, HF-g and HF-d benefited from the upregulation of genes related to beta cell function (Fgf21, Glut2 and Glp1r), identity and maintenance (Pdx1, Neurod1, Mafa and Nkx6.1). The HF mice were glucose intolerant, showing islet hypertrophy and low beta cell identity-related genes. In contrast, PPAR activation rescued islet structure, and PCA showed that the PPAR-α/γ combination was the most effective treatment because it favoured beta cell function, identity and maintenance-related genes, halting the T2DM spectrum in diet-induced obese mice. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While glucokinase (GCK)-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY, such as hepatocyte nuclear factor-1-alpha (HNF1A)-MODY (formerly MODY-3) and HNF4A (formerly MODY-1), usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports. [ABSTRACT FROM AUTHOR]

A distinctive feature of both type 1 and type 2 diabetes is the waning of insulin-secreting beta cells in the pancreas. New methods for direct and specific targeting of the beta cells could provide platforms for delivery of pharmaceutical reagents. Imaging techniques such as Positron Emission Tomography (PET) rely on the efficient and specific delivery of imaging reagents, and could greatly improve our understanding of diabetes etiology as well as providing biomarkers for viable beta-cell mass in tissue, in both pancreas and in islet grafts. The DiGeorge Syndrome Critical Region Gene 2 (DGCR2) protein has been suggested as a beta-cell specific protein in the pancreas, but so far there has been a lack of available high-affinity binders suitable for targeted drug delivery or molecular imaging. Affibody molecules belong to a class of small affinity proteins with excellent properties for molecular imaging. Here, we further validate the presence of DGCR2 in pancreatic and stem cell (SC)-derived beta cells, and then describe the generation and selection of several Affibody molecules candidates that target human DGCR2. Using an in-house developed directed evolution method, new DGCR2-binding Affibody molecules were generated and evaluated for thermal stability and affinity. The Affibody molecules variants were further developed as targeting agents for delivering imaging reagents to beta cell. The Affibody molecule ZDGCR2:AM106 displayed nanomolar affinity, suitable stability and biodistribution, with negligible toxicity to islets, qualifying it as a suitable lead candidate for further development as a tool for specific delivery of drugs and imaging reagents to beta cells. [ABSTRACT FROM AUTHOR]

Background: Pancreatic islet β‐cell mass expands during pregnancy, but underlying mechanisms are not fully understood. This study examines the impact of pregnancy and cafeteria diet on islet morphology, associated cellular proliferation/apoptosis rates as well as β‐cell lineage. Methods: Non‐pregnant and pregnant Ins1Cre/+;Rosa26‐eYFP transgenic mice were maintained on either normal or high‐fat cafeteria diet, with pancreatic tissue obtained at 18 days gestation. Immunohistochemical changes in islet morphology, β‐/α‐cell proliferation and apoptosis, as well as islet cell identity, neogenesis and ductal cell transdifferentiation were assessed. Results: Pregnant normal diet mice displayed an increase in body weight and glycaemia. Cafeteria feeding attenuated this weight gain while causing overt hyperglycaemia. Pregnant mice maintained on a normal diet exhibited typical expansion in islet and β‐cell area, owing to increased β‐cell proliferation and survival as well as ductal to β‐cell transdifferentiation and β‐cell neogenesis, alongside decreased β‐cell dedifferentiation. Such pregnancy‐induced islet adaptations were severely restricted by cafeteria diet. Accordingly, islets from these mice displayed high levels of β‐cell apoptosis and dedifferentiation, together with diminished β‐cell proliferation and lack of pregnancy‐induced β‐cell neogenesis and transdifferentiation, entirely opposing islet cell modifications observed in pregnant mice maintained on a normal diet. Conclusion: Augmentation of β‐cell mass during gestation arises through various mechanisms that include proliferation and survival of existing β‐cells, transdifferentiation of ductal cells as well as β‐cell neogenesis. Remarkably, cafeteria feeding almost entirely annuls pregnancy‐induced islet adaptations, which may contribute to the development of gestational diabetes in the setting of dietary provoked metabolic stress. [ABSTRACT FROM AUTHOR]

Background and Purpose: 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. Experimental Approach: 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. Key Results: 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. Conclusion and Implications: 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]

Context Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and nondiabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance. Objective To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects. Methods and participants In a crossover design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-hour hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant, overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, 2 hours into, and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques. Results We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. Although both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen. Conclusion Our findings suggest that beta2-agonist inhibits glycogenesis, whereas intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is characterized by a prolonged autoimmune attack resulting in the massive loss of insulin-producing beta cells. The initiation and progression of T1D depends on a complex interaction between genetic, immunological and environmental factors. Epidemiological, experimental and clinical evidence suggest a link between viral infections, particularly Coxsackievirus type B (CVB), and T1D development. Specifically, infections by the CVB serotype 1 (CVB1) contribute to the triggering of autoimmunity against beta cells in genetically predisposed individuals, and prolonged and probably non-lytic infections by CVB are associated with the development of T1D. However, the molecular mechanisms underlying CVB1 replication and establishing persistent infections in human pancreatic beta cells remain poorly understood. Here we show that the N6-methyladenosine (m6A) RNA epigenetic modification machinery regulates CVB1 amplification in the human beta cells. Using small interfering RNA (siRNA) targeting m6A writers and erasers, we observed that downregulation of m6A writers increases CVB1 amplification, while the downregulation of m6A erasers decreases it. Notably, the inhibition of Fat Mass and Obesity-associated protein (FTO), a key m6A eraser, reduced by 95% the production of infectious CVB1 in both human insulin-producing EndoC-βH1 cells and in induced pluripotent stem cell (iPSC)-derived islets. The FTO inhibitor reduced CVB1 expression within 6 h post-infection, suggesting a direct regulation of the CVB1 genome by m6A modification. Furthermore, in the absence of viral replication, FTO inhibition also decreased the translation of the incoming CVB1 genome, indicating that m6A plays a critical role in the initial stages of viral RNA translation. In addition, modulation of the m6A machinery affected the type I interferon response after poly-IC transfection, a mimic of RNA virus replication, but did not affect the cellular antiviral response in CVB1-infected cells. Altogether, these observations suggest that m6A directly affects CVB1 production. Our study provides the first evidence that the m6A epigenetic modification machinery controls CVB amplification in human pancreatic beta cells. This suggests that the m6A machinery is a potential target to control CVB infection in T1D and raises the possibility of an epigenetic control in the establishment of persistent CVB infections observed in the pancreas in individuals with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. Methods: The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. Results: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). Conclusion: HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine. [ABSTRACT FROM AUTHOR]

Clinical pancreatic islet xenotransplantation will most probably rely on genetically modified pigs as donors. Several lines of transgenic pigs carrying one and more often, multiple modifications already exist. The vast majority of these modifications aim to mitigate the host immune response by suppressing major xeno-antigens, or expressing immunomodulatory molecules that act locally at the graft site. While these modifications are essential and have proven beneficial in preclinical trials, ensuring good intrinsic islet secretory function is equally important to achieve normoglycemia in recipients. Neonatal and even adult porcine islets are known for their low secretory response to physiological stimulation, a shortcoming that is often overcome by implanting extremely large numbers of such islets to compensate for insulin requirement incompatibilities between donor pigs and rodent, non-human primate or human recipients. Recent studies have revealed the existence of secretory amplifying pathways in porcine beta-cells previously identified in murine and human cells. Building upon these findings, a new line of transgenic pigs where these pathways are activated specifically in beta-cells has been created. Compared to their wild-type counterparts, islets from these transgenic pigs have proven to be better insulin secretors in their native pancreas environment, in vitro after isolation and most importantly in vivo after transplantation to diabetic mice. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune chronic disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not stop disease progression. Thus, an effective therapy may require beta cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can reverse T1D. Within the National Clinical Trial (NCT) database, a majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on noninsulin pharmacological therapies, specifically immunomodulators. Many investigational new drugs fall under this category, such as the recently FDA‐approved CD3 monoclonal antibody teplizumab to delay the onset of T1D. In total, we identified 39 different immunomodulatory investigational drugs. FDA‐approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti‐CD3 monoclonal antibody), daclizumab (an anti‐CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG). Immunomodulators also play roles in islet transplantation and cellular therapies like FDA‐approved Lantidra. Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA‐approved for other uses. These include alemtuzumab, basiliximab, etanercept, and reparixin, some of which have been FDA‐approved for other uses. This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481, NCT01106157, NCT02215200, NCT00331162, NCT00679042, NCT01220856, NCT01817959 [ABSTRACT FROM AUTHOR]

The meta-analysis study examines the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in children and adolescents with type 1 diabetes. The study included nine cross-sectional studies with 1007 participants, showing an overall MASLD prevalence of 16.69%. Variations in prevalence were observed based on world region and diagnostic method. The study highlights the importance of early detection and management of MASLD in this population, emphasizing the need for further research to validate these findings and explore screening recommendations. [Extracted from the article]

Green and Red LEDs increase insulin production, but their comparative effects on pancreatic and beta cell development are unclear. Zebrafish embryos were divided into three groups: Control (n = 60), Green (G) (n = 60), and Red (R) (n = 60), then irradiated for three days (14 hours/day) with 0.5 W/cm2 G (λpeak = 520 nm, 180 mA) and R (λpeak = 660 nm, 210 mA). At the end of 72 h, pancreatic and beta cells, circadian rhythm, and oxidative stress gene were analyzed using RT‐PCR. Malondialdehyde, nitric oxide, superoxide dismutase, and glutathione levels were also evaluated. In the Red group, pancreatic area increased by ~97.13% compared to the Control group and by approximately ~62.16% compared to the G group (both p < 0.0001), and no significant difference in beta cell area (p = 0.964). G group insulin expression increased 2.31‐fold compared to R group (p < 0.0001). Red LED treatment increased MDA levels (p < 0.001), oxidative stress (fth1b, nqo1) (p < 0.0001), and per1b during the photophase (p < 0.0001) compared to G group. R LED treatment increases oxidative stress and disrupts circadian rhythm, leading to reduced insulin secretion. The positive effects of G LED treatment have potential for metabolic syndrome, diabetes, and pancreatic diseases. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have linked mitochondrial dysfunction to the development of type 2 diabetes (T2D) by affecting glucose-stimulated insulin secretion in pancreatic beta cells and reducing oxidative phosphorylation in insulin-responsive tissues. Given the strong genetic underpinnings of T2D, research has explored the connection between mitochondrial DNA haplogroups, specific variants, and the risk and comorbidities of T2D. For example, haplogroups F, D, M9, and N9a have been linked to an elevated risk of T2D across various populations. Additionally, specific mitochondrial DNA variants, such as the rare mtDNA 3243 A>G and the more prevalent mtDNA 16189 T>C, have also been implicated in heightened T2D risk. Notably, these associations vary among different populations. Given the high incidence of T2D in the Gulf Cooperation Council countries, this study investigates the correlation between T2D and mitochondrial haplogroups and variants in Arab populations from the Gulf region. Methods: This analysis involved mitochondrial haplogroup and variant testing in a cohort of 1,112 native Kuwaiti and Qatari individuals, comprising 685 T2D patients and 427 controls. Complete mitochondrial genomes were derived from whole exome sequencing data to examine the associations between T2D and haplogroups and mitochondrial DNA variants. Results: The analysis revealed a significant protective effect of haplogroup H against T2D (odds ratio [OR] = 0.65; P = 0.022). This protective association persisted when adjusted for age, sex, body mass index (BMI) and population group, with an OR of 0.607 (P = 0.021). Furthermore, specific mitochondrial variants showed significant associations with T2D risk after adjustment for relevant covariates, and some variants were exclusively found in T2D patients. Conclusion: Our findings confirm that the maternal haplogroup H, previously identified as protective against obesity in Kuwaiti Arabs, also serves as a protective factor against T2D in Arabs from the Gulf region. The study also identifies mitochondrial DNA variants that either increase or decrease the risk of T2D, underscoring their role in cellular energy metabolism. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are related intestinal L-cell derived secretory products. GLP-1 has been extensively studied in terms of its influence on metabolism, but less attention has been devoted to GLP-2 in this regard. The current study compares the effects of these proglucagon-derived peptides on pancreatic beta-cell function, as well as on glucose tolerance and appetite. The insulin secretory effects of GLP-1 and GLP-2 (10−12–10−6 M) were investigated in BRIN-BD11 beta-cells as well as isolated mouse islets, with the impact of test peptides (10 nM) on real-time cytosolic cAMP levels further evaluated in mouse islets. The impact of both peptides (10−8–10−6 M) on beta-cell growth and survival was also studied in BRIN BD11 cells. Acute in vivo (peptides administered at 25 nmol/kg) glucose homeostatic and appetite suppressive actions were then examined in healthy mice. GLP-1, but not GLP-2, concentration dependently augmented insulin secretion from BRIN-BD11 cells, with similar observations made in isolated murine islets. In addition, GLP-1 substantially increased [cAMP]cyt in islet cells and was significantly more prominent than GLP-2 in this regard. Both GLP-1 and GLP-2 promoted beta-cell proliferation and protected against cytokine-induced apoptosis. In overnight fasted healthy mice, as well as mice trained to eat for 3 h per day, the administration of GLP-1 or GLP-2 suppressed appetite. When injected conjointly with glucose, both peptides improved glucose disposal, which was associated with enhanced glucose-stimulated insulin secretion by GLP-1, but not GLP-2. To conclude, the impact of GLP-1 and GLP-2 on insulin secretion is divergent, but the effects of beta-cell signaling and overall health are similar. Moreover, the peripheral administration of either hormone in rodents results in comparable positive effects on blood glucose levels and appetite. [ABSTRACT FROM AUTHOR]

Background: The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross‐talk between the immune system and insulin‐producing beta cells, has hindered the development of effective disease‐modifying therapies. The discovery that the pharmacological activation of LRH‐1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH‐1/NR5A2 activation and improve islet survival. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH‐1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T‐cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001‐target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co‐cultures of PBMCs and iPSCs‐derived islet organoids were performed to assess the impact of BL001 on beta cell viability. Results: LRH‐1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro‐inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro‐inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro‐inflammatory to an anti‐inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T‐cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T‐cells and Th2 cells within PBMCs while decreasing CD8+ T‐cell proliferation. Additionally, BL001 alleviated PBMC‐induced apoptosis and maintained insulin expression in human iPSC‐derived islet organoids. Conclusion: These findings demonstrate the potential of LRH‐1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach. Key Points: LRH‐1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro‐inflammatory cell surface markers and cytokine release.LRH‐1/NR5A2 promotes a mitohormesis‐induced immuno‐resistant phenotype to pro‐inflammatory macrophages.Mature dendritic cells acquire a tolerogenic phenotype via LRH‐1/NR5A2‐stimulated mitochondria turnover.LRH‐1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T‐cell subpopulation.Pharmacological activation of LRH‐1/NR5A2 improves the survival iPSC‐islets‐like organoids co‐cultured with PBMCs from individuals with T1D. [ABSTRACT FROM AUTHOR]

Obesity is one of the leading causes of the development of insulin resistance, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. With the progression of insulin resistance, both glucose and free fatty acid (FFA) plasma levels are elevated, leading to cardiometabolic complications such as impaired glucose tolerance (IGT), type 2 diabetes, and liver fat accumulation. In this study, oral minimal models were used to estimate insulin sensitivity indexes (SI and SIFFA) in 375 adolescents with obesity. Differences between normal glucose tolerance (NGT) and IGT were assessed by using Mann–Whitney U test, while the relationship between insulin sensitivities and plasma alanine transaminase (ALT) was assessed using Spearman correlation and linear regression model of the log-transformed variables. Also, 48 youths repeated the oral glucose tolerance test and the measurement of liver function test after ∼1.3 yr of follow-up. SI was statistically different between NGT and IGT (P < 10−6) and correlated with each other (ρ = 0.7, P < 10−6). Lipolysis was completely suppressed after 30 min in NGT, compared with 120 min in IGT. SI and SIFFA were both statistically correlated with ALT (ρ = −0.19, P < 10−3). Also, the percentages of variation of SIFFA and ALT between the first and second visits correlated significantly (ρ = −0.47, P = 0.002). FFA minimal model can be used to estimate adipose tissue lipolysis in youths with obesity. The relationship of SI and SIFFA with ALT, along with the progression of the impairment of adipose tissue insulin sensitivity, shows that systemic insulin resistance underlies the relationship of glucose and FFA metabolism with hepatic damage. NEW & NOTEWORTHY: In this study, we applied glucose, Cpeptide, and FFA minimal models to assess insulin sensitivities, insulin secretion, and lipolytic flux in NGT and IGT in adolescents with obesity. The results show that glucose and adipose tissue insulin sensitivities are strongly correlated with each other and with ALT plasma level. The longitudinal results show that changes in FFA insulin sensitivity are inversely associated with changes of beta cell secretion and with biomarkers of metabolic dysfunction-associated steatohepatitis. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterised by an autoimmune response specifically mounted against the insulin-producing beta cells. Within the islet, high cellular connectivity and extensive vascularisation facilitate intra-islet communication and direct crosstalk with the surrounding tissues and the immune system. During the development of T1D, cytokines and extracellular vesicles released by beta cells can contribute to the recruitment of immune cells, further amplifying autoimmunity and aggravating beta cell damage and dysfunction. In this review, we will evaluate the role of beta-cell-derived extracellular vesicles as mediators of the autoimmune response and discuss their potential for early diagnosis and new therapeutic strategies in T1D. [ABSTRACT FROM AUTHOR]

Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Adipsin, an adipokine, is known to play an important role in maintaining the function of pancreatic beta cells in mice. This study aimed to investigate whether adipsin could be a circulating biomarker for evaluating the function of beta cells in patients with type 2 diabetes (T2D). Methods: Plasma adipsin concentrations were measured using immunoassay in three distinct subject groups: normoglycemia, T2D without insulin treatment (T2D-w/o-insulin), and T2D treated with insulin (T2D-with-insulin). Adipsin expressions were evaluated in three distinct mouse groups: normal diet (ND), high-fat diet (HFD), and HFD with streptozotocin (STZ) and nicotinamide (NA). Results: The T2D-with-insulin group exhibited a significant decrease in plasma adipsin concentration (3.91 ± 1.51 μg/mL) compared to the T2D-w/o-insulin group (5.11 ± 1.53 μg/mL; p < 0.001), whereas the T2D-w/o-insulin group showed a significantly increased plasma adipsin concentration compared to the normoglycemia group (4.53 ± 1.15 μg/mL). Plasma adipsin concentration was positively correlated with fasting C-peptide level (p < 0.001), 2-h C-peptide level (p < 0.001), and 2-h C-peptidogenic index (p < 0.001) in the diabetic groups. HFD mice showed a significant increase in pancreatic islet size, plasma insulin and adipsin levels, as well as adipsin expression in white adipose tissue (WAT) compared to ND mice. In contrast, the insulin-deficient T2D model (HFD-STZ-NA) demonstrated a marked reduction in pancreatic islet size, plasma insulin and adipsin concentrations, and adipsin expression in WAT compared to the HFD mice. Conclusions: plasma adipsin may be useful for evaluating pancreatic beta cell function in patients with T2D. [ABSTRACT FROM AUTHOR]

Purpose: Type 1 Diabetes (T1D) pathogenesis involves immune cells infiltrating pancreatic Islets of Langerhans, leading to T cell activation, beta cell destruction, and impaired insulin production. However, infiltration has a heterogenic nature that isn't described in detail, as not all islets are infiltrated. The aim of this study was to investigate if the observed heterogeneity is coupled to differences in immune and/or dysfunctional status of islets or exocrine cells, and if specific markers could elucidate mechanistic details of T1D pathogenesis. Procedures: The GeoMx platform was used to spatially quantify protein levels in pancreatic islets and exocrine tissue in Non-Obese Diabetic (NOD) mice. The protein panel included 17 immune activity markers and nine dysfunction markers. Immunohistochemical (IHC) staining and digital image analysis was used to analyze select marker proteins. Results: Use of the GeoMx platform to investigate T1D was shown to be possible, as Granzyme B protein levels were found to be lower in distal islet areas when compared to proximal areas. Smooth Muscle Actin protein levels were higher in exocrine areas proximal to immune-infiltrated islets, when compared to distally located exocrine areas. Findings from GeoMx were however not observed in IHC-stained sections. Conclusions: This study demonstrates that investigating T1D is possible with spatial proteomics, as the assays revealed presence of heterogenic islet areas in NOD mice, which may play a role in T1D progression and escape from immune recognition. This study highlights the potential of spatial technologies for elucidating T1D pathogenesis and future treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion (I/R) injury is inevitable during the perioperative period. The pancreas is susceptible to I/R injury. Autophagy, a self-digestion process, is upregulated during I/R injury and strongly induced by hypoxia. This study aims to determine whether dexmedetomidine can decrease pancreatic ß-cell damage by regulating autophagy under hypoxia. Methods: INS-1 rat insulinoma cells were cultured in dexmedetomidine before being exposed to cobalt chloride (CoCl2)-induced hypoxia. Cell viability and the expression of autophagy-related proteins (light chain 3B [LC3B]-II, p62, and ATGs) were assessed. The expression of apoptosis-related proteins (BCL-2 and P-BAD) were also evaluated. Co-Cl2-treated INS-1 cells were pretreated with the autophagosome formation inhibitor, 3-methyladenine (3-MA), to compare its effects with those of dexmedetomidine. Bafilomycin-A1 (Baf-A1) that inhibits autophagosome degradation was used to confirm the changes in autophagosome formation induced by dexmedetomidine. Results: Dexmedetomidine attenuated the increased expression of autophagic proteins (LC3B-II, p62, and ATGs) and reversed the CoCl2-induced reduction in the proliferation of INS-1 cells after hypoxia. Dexmedetomidine also alleviated the decreased expression of the anti-apoptotic protein (BCL-2) and the increased expression of apoptotic protein (BAX). Dexmedetomidine reduces the activation of autophagy through inhibiting autophagosome formation, as confirmed by a decrease in LC3B-II/I ratio, a marker of autophagosome formation, in LC3B turnover assay combined with Baf-A1. Conclusions: Dexmedetomidine alleviates the degree of cellular damage in INS-1 cells against CoCl2-induced hypoxia by regulating autophagosome formation. These results provide a basis for further studies to confirm these effects in clinical practice. [ABSTRACT FROM AUTHOR]

Insulin and thyroid hormones play important roles in our body. Insulin helps regulate the glucose level while the thyroid hormones affect various cells and tissues, metabolizing protein, lipids, and glucose. Hyperthyroidism and thyrotoxicosis are potential hazards for type 2 diabetes mellitus. There is a high prevalence of hypothyroidism being more common compared to hyperthyroidism coexisting with diabetes mellitus. Thyroid hormones affect glucose metabolism through its action on peripheral tissues (gastrointestinal tract, liver, skeletal muscles, adipose tissue, and pancreas). High-level thyroid hormone causes hyperglycemia, upregulation of glucose transport, and reduction in glycogen storage. The reverse is observed during low levels of thyroid hormone along with insulin clearance. The net result of thyroid disorder is insulin resistance. Type 2 diabetes mellitus can downsize the regulation of thyroid stimulating hormones and impair the conversion of thyroxine to triiodothyronine in peripheral tissues. Furthermore, poorly managed type 2 diabetes mellitus may result in insulin resistance and hyperinsulinemia, contributing to the proliferation of thyroid tissue and an increase in nodule formation and goiter size. Although metformin proves advantageous for both type 2 diabetes mellitus and thyroid disorder patients, other antidiabetics like sulfonylureas, pioglitazone, and thiazolidinediones may have adverse effects on thyroid disorders. Moreover, antithyroid drugs such as methimazole can weaken glycemic control in individuals with diabetes. Thus, an interplay between both endocrinopathies is observed and individualized care and management of the disorder needs to be facilitated. [ABSTRACT FROM AUTHOR]

Background: Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity. Purpose: Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells. Results: Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1β, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression. Conclusion: The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: This study investigates the therapeutic mechanisms of Cai's Herbal Tea in Type 1 Diabetes Mellitus (T1DM) mice, focusing on its effects on mitochondrial change and autophagy via the AMP-activated protein kinase (AMPK)—mammalian target of rapamycin (mTOR) pathway. Methods: The composition of Cai's Herbal Tea was analyzed by Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-Q/TOF-MS). C57BL/6 mice and Min6 pancreatic beta cells were divided into control, diabetic mellitus (DM)/high glucose (HG), and treatment groups (low, medium, and high doses of Cai's Tea, and Metformin). Key physiological parameters, pancreatic islet health, Min6 cell morphology, viability, and insulin (INS) secretion were assessed. Small Interfering RNA-AMPK (si-AMPK) was utilized to confirm the pathway involvement. Results: Cai's Herbal Tea improved body weight, pancreatic islet pathological injury, and INS secretion whereas reduced total triglycerides, fasting blood sugar, and Interferon gamma (INF-γ) in T1DM mice, particularly at higher doses. In Min6 cells, Cai's Tea mitigated HG-induced damage and proinflammatory response, enhancing cell viability and INS secretion. Notably, it reduced swelling and improved cristae structure in treated groups of mitochondria and promoted autophagy via the AMPK-mTOR pathway, evidenced by increased LC3II/LC3I and P-AMPK/AMPK ratios, and decreased P-mTOR/mTOR and P62 expressions in pancreatic islet β-cells. Furthermore, these effects were converted by si-AMPK interference. Conclusion: Cai's Herbal Tea exhibits significant therapeutic efficacy in T1DM mice by improving mitochondrial health and inducing autophagy through the AMPK-mTOR pathway in pancreatic islet β-cells. These findings highlight its potential as a therapeutic approach for T1DM management. [ABSTRACT FROM AUTHOR]

Introduction: Insulin secretion is a highly regulated process critical for maintaining glucose homeostasis. This abstract explores the intricate interplay between three essential pathways: The Triggering Pathway, The Metabolic Amplifying Pathway, and Cellular Transduction, in orchestrating glucose-dependent biphasic insulin secretion. Mechanism: During the triggering pathway, glucose metabolism in pancreatic beta-cells leads to ATP production, closing ATP-sensitive potassium channels and initiating insulin exocytosis. The metabolic amplifying pathway enhances insulin secretion via key metabolites like NADH and glutamate, enhancing calcium influx and insulin granule exocytosis. Additionally, the cellular transduction pathway involves G-protein coupled receptors and cyclic AMP, modulating insulin secretion. Result and Conclusion: These interconnected pathways ensure a dynamic insulin response to fluctuating glucose levels, with the initial rapid phase and the subsequent sustained phase. Understanding these pathways' complexities provides crucial insights into insulin dysregulation in diabetes and highlights potential therapeutic targets to restore glucose-dependent insulin secretion. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions. [ABSTRACT FROM AUTHOR]

For many autoimmune diseases, including type 1 diabetes mellitus (T1DM), efforts have been made to modify the disease process through pharmacotherapy. The ultimate goal must be to develop therapies with curative potential by achieving an organ without signs of parenchymal cell destruction and without signs of immune cell infiltration. In the case of the pancreas, this means regenerated and well-preserved beta cells in the islets without activated infiltrating immune cells. Recent research has opened up the prospect of successful antibody combination therapy for autoimmune diabetes with curative potential. This goal cannot be achieved with monotherapies. The requirements for the implementation of such a therapy with curative potential for the benefit of patients with T1DM and LADA (latent autoimmune diabetes in adults) are considered. [ABSTRACT FROM AUTHOR]

Objective: Serum 1, 5-AG is a glycaemic marker reflecting control and fluctuations of short-term glucose. To reveal the relationship between 1, 5-AG with β-cell function, we investigated a certain number of Chinese adults with different glucose metabolisms. Methods: In clinical cross-sectional study, 2184 subjects with no prior diabetes history are included and underwent an OGTT. HOMA-IR and HOMA-β were calculated. Correlations between 1, 5-AG and HOMA-IR or HOMA-β were observed, correcting for interference factors, and independent factors for HOMA-β and HOMA-IR were analysed. Subjects were divided into three groups according to OGTT results, and 1, 5-AG levels differed significantly between them. Results: A significant positive correlation existed between 1, 5-AG and HOMA-β only in the diabetes mellitus group (r = 0.265, p < 0.001). Above phenomenon remained after adjusting for indicators, however, disappeared after considering serum uric acid. Both 1, 5-AG and HbA1c were independent factors for HOMA-β (1, 5-AG: β = 0.772, p = 0.023; HbA1c: β = -7.52, p = 0.003). Conclusion: 1, 5-AG remained a factor for HOMA-β only for those with NUA. 1, 5-AG reflects different glucose metabolism statuses and is an auxiliary observation reflecting the secretory function of β cells in NUA patients. [ABSTRACT FROM AUTHOR]

The current work attempted to examine the histological and immunohistochemical features of the pancreas in the southern white-breasted hedgehog (Erinaceus concolor). Five adult male individuals were used in this study. Utilizing hematoxylin and eosin as well as Masson's trichrome, staining was performed on paraffin sections of the pancreas. Immunofluorescent staining investigated the expression pattern of glucagon, insulin, somatostatin, neuropeptide Y (NY), and pancreatic polypeptide (PP). The exocrine pancreas comprised pyramidal and oval-shaped acini, exhibiting the clustering of zymogen droplets in the apical cytoplasm of acinar cells. The endocrine pancreas was distinguished as a large α islet of Langerhans and small β islets. Alpha cells were localized on the periphery of islets with an intensity of 20.6% ± 12.56. In comparison, Beta cells with 25.14% ± 5.89 intensity were gathered in the middle of the pancreatic islets. Delta cells exhibited 25.69% ± 5.13 intensity and were distributed through the islets. NY and PP cells were detected with 22.74% ± 3.25 and 16.80% ± 4.77 intensity, respectively. These cells showed prevalent distribution in the islets. In conclusion, it appears that although the pancreas of the southern white-breasted hedgehog is generally like other mammalian species, there are some species-specific features in density and dispersal of endocrine cells which can be attributed to the physiological purpose of the pancreas in this species. Future histophysiological investigations are still needed to explore the exact relationship between the histological organization of the pancreas and its function in that animal. [ABSTRACT FROM AUTHOR]

Exendin-4 (ex-4) is a peptide molecule that regulates blood glucose levels without causing hypoglycemia by providing insulin secretion from beta cells in the pancreas. Self-nanoemulsifying drug delivery systems (SNEDDS) attract attention for oral administration of therapeutic peptide/proteins because they protect therapeutic peptide/proteins from the gastric environment, reduce changes due to food effects, are easy to prepare and scale-up. Ex-4 has no commercial form that can be administered orally. In this study, the cytotoxicity, cellular uptake, and insulin secretion of ex-4 and ex-4/chymostatin (chym) SNEDDS were investigated on INS-1E rat pancreatic beta cells. The effect of ex-4 and ex-4/chym SNEDDS on cell viability in INS-1E cells increased when the dilution ratio higher. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 2.8 mM (low-dose) glucose-induced INS-1E cells 2.21-fold and 2.17-fold compared to control, respectively. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 16.7 mM (high dose) glucose-induced INS-1E cells compared to control, respectively. In cellular uptake studies, coumarin-6 solution penetrated the apical membrane of INS-1E cells and remained in the cytoplasm, while coumarin-6 loaded SNEDDS were visualized in the nuclei of the cell. These findings will likely be useful in the development of new formulations for the oral administration of peptides/proteins. [ABSTRACT FROM AUTHOR]

Aims In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function. Methods Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. Results Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P <.05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI:.4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P <.01 and R = 0.19, P <.01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P <.01, R = 0.18, P <.01, respectively). Conclusion The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes. [ABSTRACT FROM AUTHOR]

Glucolipotoxicity (GLT) has emerged as established mechanism in the progression of diabetes. Identifying compounds that mitigate GLT‐induced deleterious effect on β‐cells are considered important strategy to overcome diabetes. Hence, in the present study, astaxanthin‐s‐allyl cysteine (AST‐SAC) diester was studied against GLT in β‐cells. Mus musculus pancreatic β‐cell line (βTC‐tet) was treated with high glucose (25 mM; HG) and 95 μM palmitate (PA) for 24 h to induce GLT. AST‐SAC at various concentrations (5, 10, and 15 μg/ml) were treated to understand the protective effect against HG + PA exposure in β‐cells. Under HG + PA exposure conditions oxidative stress, deregulation of mTOR pathway and endoplasmic reticulum (ER) stress are witnessed. AST‐SAC treatment eased oxidative stress, mitochondrial depolarization, DNA damage, calcium overload and accumulation of autophagosome against HG + PA exposure conditions thereby protected the cell viability of β‐cells. AST‐SAC maintained the level of proteins involved in mTOR pathway under HG + PA exposure conditions. Also, AST‐SAC treatment has mitigated the increased expression of genes and proteins such as IRE1 and PERK involved in ER stress‐mediated unfolded protein response (UPR) signaling pathways. In correspondence to it, the expression of genes involved in insulin secretion was preserved by AST‐SAC. Due to these protective effects of AST‐SAC the insulin secretion was well‐maintained in β‐cells under HG + PA exposure conditions. AST‐SAC through normalizing antioxidant status and mTOR axis as well as preventing the harmful effect of ER‐stress mediated UPR pathway has promoted the β‐cell survival and insulin secretion against GLT. Simultaneously targeting oxidative stress/mTOR axis/ER stress is required to efficiently overcome GLT in β‐cells. [ABSTRACT FROM AUTHOR]

Type 1 diabetes results from the destruction of pancreatic beta cells by autoreactive T cells. As an autoantigen with extremely high expression in beta cells, insulin triggers and sustains the autoimmune CD4+ and CD8+ T cell responses and islet inflammation. We have previously shown that deficiency for insulin-degrading enzyme (IDE), a ubiquitous cytosolic protease with very high affinity for insulin, induces endoplasmic reticulum (ER) stress and proliferation in islet cells and protects non-obese diabetic mice (NOD) from diabetes. Here we wondered whether IDE deficiency affects autoreactive CD8+ T cell responses to insulin and thereby immune pathogenesis in NOD mice. We find that Ide-/- NOD harbor fewer diabetogenic T cells and reduced numbers of CD8+ T cells recognizing the dominant autoantigen insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Using in vitro digestions and cellular antigen presentation assays, we show that generation of the dominant insulin epitope B15-23 involves both the proteasome and IDE. IDE deficiency attenuates MHC-I presentation of the immunodominant insulin epitope by beta cells to cognate CD8+ T cells. Consequently, Ide-/- islets display reduced susceptibility to autoimmune destruction upon grafting, and to killing by insulin-specific CD8+ T cells. Moreover, Ide-/- mice are partly resistant to disease transfer by CD8+ T cells specific for insulin but not for IGRP. Thus, IDE has a dual role in beta cells, regulating ER stress and proliferation while at the same time promoting insulin-directed autoreactive CD8+ T cell responses. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is considered the most common metabolic disorder of the pregnancy period. It is characterized by pancreatic beta-cell dysfunction in the setting of chronic insulin resistance. Zinc is a nutrient involved in numerous metabolic processes and shows a relationship with glycometabolic disorders and GDM. The latest data have demonstrated the association of zinc with insulin sensitivity and resistance. The exact role of zinc in the connection with indexes of insulin resistance and insulin sensitivity is still not fully clarified. The aim of the study is to analyze the newly calculated indexes Glu/Zn, Ins/Zn, and HOMA-IR/Zn as surrogate markers to explore the correlation between serum zinc status and some indexes of insulin sensitivity and insulin resistance. The possible role of these indexes as markers of insulin resistance in pregnant women was analyzed too. An ROC analysis demonstrated that HOMA-IR/Zn with AUC 0.989, p < 0.001 (95% CI 0.967–1.000) and Ins/Zn with AUC 0.947, p < 0.001 (95% CI 0.889–1.000) in the GDM group, and only HOMA-IR/Zn index with AUC 0.953, p < 0.001 (95% CI 0.877–1.000) in healthy pregnant women, have good power as markers of insulin resistance in both groups. We speculate that these new ratios could be suitable for the assessment of pregnant women at high risk of insulin resistance development and, probably, for the evaluation of the specific pathophysiologic characteristics of women with GDM. [ABSTRACT FROM AUTHOR]

Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research. [ABSTRACT FROM AUTHOR]

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is an important regulatory protein responsible for maintaining calcium homeostasis within cells. Impairment of SERCA associated with activity/expression decrease has been implicated in multiple chronic conditions, including cardiovascular diseases, diabetes, cancer, neurodegenerative diseases, and skeletal muscle pathologies. Natural polyphenols have been recognized to interact with several target proteins involving SERCA. To date, only a limited number of polyphenolic compounds or their derivatives have been described either to increase SERCA activity/expression directly or to affect Ca2+ signaling pathways. In this study, we tested polyphenols for their ability to activate SERCA1a in the absence or presence of methylglyoxal or palmitate and to impact insulin release in pancreatic beta cells. The protective effects of these compounds against methylglyoxal- or palmitate-induced injury were evaluated. Results indicate that 6-gingerol, resveratrol, and ellagic acid activate SERCA1a and protect against activity decrease induced by methylglyoxal and palmitate. Molecular docking analysis revealed the binding of these polyphenols to Glu439 in the SERCA1a P-domain, suggesting a critical role in the stimulation of enzyme activity. Ellagic acid was found to directly stimulate the activity of SERCA1a, marking the first instance of such an observation. [ABSTRACT FROM AUTHOR]

To be clinically efficient, beta cell replacement therapies such as pig islet xenotransplantation must ensure sufficient insulin secretion from grafted islets. While protection from host immune reaction is essential for islet engraftment and their subsequent functioning, intrinsic physiological properties of used cells are also a key factor. We have previously shown that islets with adenoviral-mediated expression of a dipeptidyl peptidase-resistant form of glucagon-like- peptide- 1 (GLP-1) and a constitutively activated form of type 3 muscarinic receptor (M3R) in their beta cells have greatly improved insulin secretory response to glucose stimulation that is otherwise 4 to 10 times lower than human islets. Here, we describe in vitro characterization of the secretory function of pancreatic islets, derived from transgenic pigs expressing the GLP-1M3R cassette under the porcine insulin promoter (InsGLP-1M3R), and their usage to treat insulin-dependent diabetes in an immunodeficient mouse model. Our results show that InsGLP-1M3R islets isolated from neonatal and adult pigs secrete up to 15-fold more insulin in response to glucose stimulation compared to wild-type (WT) islets. They also proved to be more efficient in treating diabetes in a preclinical model as shown by a significantly higher percentage of normoglycemic recipients and higher porcine C-peptide levels up to 9 mo post implantation. [ABSTRACT FROM AUTHOR]

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]

Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase‐4 (DPP‐4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N‐Pal]PP, and [N‐Pal,P3]PP, and their impact on pancreatic beta‐cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP‐4 degradation. In addition, all peptides inhibited alanine‐induced insulin secretion from BRIN‐BD11 beta cells. Native PP and related analogs (10−8 and 10−6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine‐induced beta‐cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N‐Pal,P3]PP. In mice, all peptides, except [N‐Pal]PP and [N‐Pal,P3]PP, evoked a dose‐dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon‐like peptide‐1 (GLP‐1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose‐regulatory actions of GLP‐1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid‐chain acylation, creates PP analogs with benefits on beta‐cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity. [ABSTRACT FROM AUTHOR]

Background: Individuals with maturity‐onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real‐world setting. Methods: Individuals with MODY from the diabetes prospective follow‐up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. Results: A total of 1640 individuals were identified with GCK‐MODY (n = 941) and HNF1A‐MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow‐up: 4.2 years [2.6–6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK‐MODY (Q1–Q3: 6.2–13.1 years) and INS‐MODY (2.7–13.7 years) to 14.3 years (5.0–17.1) in KCNJ11‐MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A‐MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A‐MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8‐MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and "insulin only" treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. Conclusions: Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY. [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]