Pancreatic Β-cell Dysfunction Research Articles

Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young.

MODY, or maturity-onset diabetes of the young, is a group of monogenic diseases characterized by autosomal dominant inheritance of a non-insulin-dependent form of diabetes that classically manifests in adolescence or in young adults under 25 years of age. MODY is a rare cause of diabetes, accounting for 1% of all cases, and is often misdiagnosed as type 1 or type 2 diabetes. It is of great importance to accurately diagnose MODY, as this allows for the most appropriate treatment of patients and facilitates early diagnosis for them and their families. This disease has a high degree of phenotypic and genetic polymorphism. The most prevalent forms of the disease are attributed to mutations in three genes: GCK (MODY 2) and (HNF)1A/4A (MODY 3 and MODY 1). The remaining MODY subtypes, which are less prevalent, have been identified by next generation sequencing (NGS) in the last decade. Mutations in the GCK gene result in asymptomatic, stable fasting hyperglycemia, which does not require specific treatment. Mutations in the HNF1A and HNF4A genes result in pancreatic β-cell dysfunction, which in turn causes hyperglycemia. This often leads to diabetic angiopathy. The most commonly prescribed drugs for the treatment of hyperglycemia are sulfonylurea derivatives. Nevertheless, with advancing age, some patients may require insulin therapy due to the development of resistance to sulfonylurea drugs. The strategy of gene therapy for monogenic forms of MODY is still an experimental approach, and it is unlikely to be widely used in the clinic due to the peculiarities of MODY structure and the high genetic polymorphism and clinical variability even within the same form of the disease. Furthermore, there is a lack of clear gene-phenotypic correlations, and there is quite satisfactory curability in the majority of patients. This review presents the main clinical and genetic characteristics and mutation spectrum of common and rarer forms of MODY, with a detailed analysis of the field of application of AVV vectors in the correction of hyperglycemia and insulin resistance.

The multifaceted function of FoxO1 in pancreatic β-cell dysfunction and insulin resistance: Therapeutic potential for type 2 diabetes.

The forkhead box O1 (FOXO1), the first discovered member of the FoxO family, is a critical transcription factor predominantly found in insulin-secreting and insulin-sensitive tissues. In the pancreas of adults, FoxO1 expression is restricted to islet β cells. We determined that in human islet microarray datasets, FoxO1 expression is higher than other FoxO transcription factors. Our analyses of three human islet datasets revealed that FoxO1 expression tends to shows a negative correlation with type 2 diabetes and no correlation with body mass index (BMI) between individuals with low levels of HbA1C (or ND, non-diabetic) and high levels of HbA1C (or T2D, type 2 diabetes). However, FoxO1 function is multifaceted and mainly regulated by post-translational modifications including phosphorylation and deacetylation that involved in pancreatic β cell function and insulin sensitivity. This study summarized the molecular mechanisms underlying the role of FoxO1 activity in pancreatic β-cell dysfunction and insulin resistance in T2D. In addition, we discussed the therapeutic potential of FoxO1 inhibitors in diabetes treatment.

Neuroimmune axis: Linking environmental factors to pancreatic β-cell dysfunction in Diabetes.

Pancreatic β-cells are specialized in secreting insulin in response to circulating nutrients, mainly glucose. Diabetes is one of the most prevalent endocrine-metabolic diseases characterized by an imbalance in glucose homeostasis, which result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and peripheral insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Pancreatic β-cell dysfunction and islet inflammation are common characteristics of both types of the disease. Pancreatic islets are a highly innervated tissue whose function can be influenced by the brain, either directly through the autonomic nervous system or indirectly via neuroendocrine mechanisms. In addition, it is well-established that there is a fine-tuned communication between the immune and neuroendocrine tissues in maintaining endocrine pancreas homeostasis. Various psycho-social, physico-chemical and lifestyle environmental factors have been associated with diabetes risk. In this review, I briefly comment on certain aspects of the psycho-neuro-immune interactions that link environmental factors and the endocrine pancreas, leading to metabolic health or diabetes. Interdisciplinary research, embracing new and broader perspectives, should be conducted to explore strategies for preventing or slowing down the constant increase in diabetes worldwide.

Autophagy modulators in type 2 diabetes: A new perspective.

Type 2 diabetes (T2D) is a chronic metabolic disorder caused by defective insulin signaling, insulin resistance, and impairment of insulin secretion. Autophagy is a conserved lysosomal-dependent catabolic cellular pathway involved in the pathogenesis of T2D and its complications. Basal autophagy regulates pancreatic β-cell function by enhancing insulin release and peripheral insulin sensitivity. Therefore, defective autophagy is associated with impairment of pancreatic β-cell function and the development of insulin rersistance (IR). However, over-activated autophagy increases apoptosis of pancreatic β-cells leading to pancreatic β-cell dysfunction. Hence, autophagy plays a double-edged sword role in T2D. Therefore, the use of autophagy modulators including inhibitors and activators may affect the pathogenesis of T2D. Hence, this review aims to clarify the potential role of autophagy inhibitors and activators in T2D.

Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells.

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca2+ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.

1-Deoxynojirimycin affects high glucose-induced pancreatic beta-cell dysfunction through regulating CEBPA expression and AMPK pathway.

This study aims to explore the role of 1-deoxynojirimycin (DNJ) in high glucose-induced β-cells and to further explore the molecular mechanism of DNJ effect on β-cells through network pharmacology. In the study, high glucose treatment of mouse INS-1 cells inhibited cell proliferation and insulin secretion, decreased the expression of Bcl-2 protein and Ins1 and Ins2 genes, promoted apoptosis, and increased cleaved caspase-3 and cleaved caspase-9 expression levels as well as intracellular reactive oxygen species production. DNJ treatment significantly restored the dysfunction of INS-1 cells induced by high glucose, and DNJ showed no toxicity to normal INS-1 cells. Silencing CEBPA promoted, while overexpression of CEBPA relieved the dysfunction of pancreatic β-cells induced by high glucose. DNJ treatment partially restored the pancreatic β-cell dysfunction caused by silencing CEBPA. In conclusion, DNJ can inhibit high glucose-induced pancreatic β-cell dysfunction by promoting the expression of CEBPA.

Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.

Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.

Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5

A rise in blood glucose is an early warning sign of underlying pancreatic cancer (PC) and may be an indicator of genetic events in PC progression. However, there is still a lack of mechanistic research on pancreatic cancer-associated new-onset diabetes (PCAND). In the present study, we identified a gene SRI, which possesses a SNP with the potential to distinguish PCAND and Type 2 diabetes mellitus (T2DM), by machine learning on the basis of the UK Biobank database. In vitro and in vivo, sorcin overexpression induced pancreatic β-cell dysfunction. Sorcin can form a positive feedback loop with STAT3 to increase the transcription of serpin E1 and CCL5, which may directly induce β-cell dysfunction. In 88 biopsies, the expression of sorcin was elevated in PC tissues, especially in PCAND samples. Furthermore, plasma serpin E1 levels are higher in peripheral blood samples from PCAND patients than in those from T2DM patients. In conclusion, sorcin may be the key driver in PCAND, and further study on the sorcin-STAT3-serpin E1/CCL5 signaling axis may help us better understand the pathogenesis of PCAND and identify potential biomarkers.

Revisiting the markers interleukin-6 and glucagon-like peptide-1 for targeting low-grade inflammation in type 2 diabetes: a meta-analysis and our lab experience.

Type 2 diabetes (T2DM) manifests as pancreatic disorder as a consequence of low-grade systemic inflammation, attributed to upregulated levels of interleukin-6 (IL-6). This in turn is associated with a reduced incretin effect with lower circulatory GLP-1 levels. Therefore, its important to monitor the circulating IL-6 and GLP-1 levels for better management and outcomes in T2DM patients. Limited studies being available in literature on circulating concentrations of GLP-1 and IL-6 in T2DM patients, a meta-analysis was conducted by identifying 1558 studies from 3 databases. As per inclusion and exclusion criteria, the studies were screened for the 2-markers.Forest plots were drawn for standardized mean differences and median values were deduced from the datasets. In parallel, analysis was conducted to ascertain the expression levels of the markers by ELISA (n = 52 T2DM patients) in real time. The meta-analysis showed a significant (p < 0.01) standardized mean difference of 3.82 and 1.04 for IL-6 and GLP-1 respectively. The median values obtained from analysis for IL-6 were 26.50 pg/ml which were higher than the controls downregulated levels of GLP-1(8.77 pg/ml) were noted. The above findings are corroborated by the results of our experimental analysis with IL-6 concentrations at 11.603pg/ml and GLP-1 at 13.05pg/ml. The study highlights that systemic concentrations of IL-6 and GLP-1 correspond to a persistent low-grade inflammation and decreased incretin effect in T2DM patients which manifest as pancreatic β-cell dysfunction. The expression of the markers is inversely correlated and monitoring their levels is clinically important for targeting them through their potential antagonists thus reducing the risk of complications, thereby improving the quality of life of the patients.

Pentachlorophenol increases diabetes risk by damaging β-cell secretion and disrupting gut microbial-related amino acids and fatty acids biosynthesis

Pentachlorophenol (PCP), a ubiquitous environmental pollutant, has been reported as a possible contributor to diabetes. However, evidence for general population is scarce while related mechanisms are largely unknown. Using a representative population-based case-control study in Beijing (n = 1796), we found a positive association between PCP exposure and diabetes risk with the odds ratio reaching 1.68 (95 % confidence interval: 1.30 to 2.18). A further rat experiment revealed that low-dose PCP mimicking real-world human exposure can significantly impair glycemic homeostasis by inducing pancreatic β-cell dysfunction, with non-linear dose-response relationships. Subsequent multi-omics analysis suggested that low-dose PCP led to notable gut microbiota dysbiosis (especially the species from genus Prevotella, such as intermedia, dentalis, ruminicola, denticola, melaninogenica, and oris), decreased serum amino acids (L-phenylalanine, L-tyrosine, and L-tryptophan) and increased serum fatty acids (oleic and palmitic acid) in rats, while strong correlations were observed among alterations of gut microbes, serum metabolites and glycemic-related biomarkers (e.g., fasting blood glucose and insulin). Collectively, these results imply PCP may increase diabetes risk by disrupting gut microbial-related amino acids and fatty acids biosynthesis. This will help guide future in-depth studies on the roles of PCP in the development of human diabetes.

8433 Elucidation of the Molecular Basis of Human and Mouse Pancreatic β-Cell Senescence Induced by Hyperglycemia

Abstract Disclosure: K. Iwasaki: None. P. Carapeto: None. C. Aguayo-Mazzucato: None. Background and AIM: Senescent cells accumulate with age and contribute to the development of chronic diseases, including Type 2 Diabetes (T2D). Whereas senescence is an important pathogenic mechanism in diabetes, the role of hyperglycemia as a metabolic driver of pancreatic β-cells has not been clarified. The aim of this study is to elucidate the molecular basis of hyperglycemia-induced pancreatic β-cell senescence using human and rodent islets. Methods: 1) Human islets were cultured for 2 weeks in 20.2 mM high (HG) or 2.8mM low glucose (LG), and analyzed by qPCR and glucose-responsive insulin secretion (GSIS) to explore the molecular basis of senescence in ex vivo. To test the effects of senescent cell removal, senolytics Dasatinib (1μM) and Quercetin (20μM) (DQ) were used. 2) To evaluate the effects of hyperglycemia in vivo, we transplanted mouse and human islets under the kidney capsule of normoglycemic (NG) or streptozocin-induced hyperglycemic (Stz-Db) immunodeficient mice for two weeks. Graft function was evaluated by intraperitoneal glucose tolerance test and cellular identity using qPCR or immunohistochemistry. DQ (5mg/kg/day + 50mg/kg/day) was used to evaluate the effects of removing senescent cells in transplantation (Tx). To investigate the effect of specific removal of p16-positive senescent β-cells in transplanted islets, INK-ATTAC mice islets (p16Ink4a-mediated apoptosis by targeted activation of caspases) were transplanted into Stz-Db and treated with BB homodimer (BB) to remove p16+ cells or vehicle. Results: (1) Human islets from 5 healthy donors cultured in HG had an increased senescence index (mean of senescence markers p16, p21 and HMGB1 mRNA) when compared to LG islets (p&amp;lt;0.05) and lost glucose responsiveness as evaluated by ex vivo GSIS compared to LG (p&amp;lt;0.05). 2) Human islets (1000IEQ) were transplanted to Stz-Db or NG mice. In Stz-Db graft, P21 mRNA significantly increased with decreased expression of β-cell genes when compared to NG. Stz-Db mice treated with DQ (Db-DQ) for 5 days after Tx, significantly decreased expression of senescence index (p&amp;lt;0.05) and increased in β-cell index (mean of β-cell hallmark genes) (p&amp;lt;0.05) at mRNA levels. Stz-Db mice transplanted with INK-ATTAC mice islets had lower fed glucose levels, decreased p16 mRNA, increased expression β-cell hallmark genes and improved insulin secretion ex vivo after removal of p16+ cells. Conclusion: Sustained exposure of human islets to hyperglycemia induced cellular senescence, leading to pancreatic β-cell dysfunction and loss of cellular identity. Furthermore, elimination of senescent cells may protect pancreatic β-cells from hyperglycemia-induced functional decline, which may have potential clinical application in both Type 1 Diabetes and T2D. Presentation: 6/2/2024

Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications.

This review explores the pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of diabetes and its complications, highlighting the therapeutic potential of various oral hypoglycemic drugs targeting this pathway. NLRP3 inflammasome activation, triggered by metabolic stressors like hyperglycemia, hyperlipidemia, and free fatty acids (FFAs), leads to the release of pro-inflammatory cytokines interleukin-1β and interleukin-18, driving insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. These processes contribute to diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases (CVD). Here we discuss the various transcriptional, epigenetic, and gut microbiome mediated regulation of NLRP3 activation in diabetes. Different classes of oral hypoglycemic drugs modulate NLRP3 inflammasome activity through various mechanisms: sulfonylureas inhibit NLRP3 activation and reduce inflammatory cytokine levels; sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress inflammasome activity by reducing oxidative stress and modulating intracellular signaling pathways; dipeptidyl peptidase-4 inhibitors mitigate inflammasome activation, protecting against renal and vascular complications; glucagon-like peptide-1 receptor agonists attenuate NLRP3 activity, reducing inflammation and improving metabolic outcomes; alpha-glucosidase inhibitors and thiazolidinediones exhibit anti-inflammatory properties by directly inhibiting NLRP3 activation. Agents that specifically target NLRP3 and inhibit their activation have been identified recently such as MCC950, Anakinra, CY-09, and many more. Targeting the NLRP3 inflammasome, thus, presents a promising strategy for managing diabetes and its complications, with oral hypoglycemic drugs offering dual benefits of glycemic control and inflammation reduction. Further research into the specific mechanisms and long-term effects of these drugs on NLRP3 inflammasome activity is warranted.

Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NAD+/AMPK/SIRT1/HIF-1α Pathway.

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

Metformin and vitamin D combination therapy ameliorates type 2 diabetes mellitus-induced renal injury in male Wistar rats.

Diabetic kidney disease is a major microvascular diabetes mellitus (DM) complication clinically associated with a gradual renal function decline. Although metformin is a common drug for managing DM, however, monotherapy treatment with any antidiabetic drug will necessitate dosage increment since type 2 DM (T2DM) deteriorates over time due to the increasing pancreatic β-cell dysfunction and will eventually require a combination therapy approach with another antidiabetic medication. Vitamin D is a food supplement that has been proven to have antidiabetic and reno-protective activities. Hence, we explore the combination of vitamin D and metformin on T2DM-induced renal dysfunction. Thirty male Wistar rats were randomized into five (5) groups: control, diabetes untreated, diabetics treated with metformin, vitamin D, and vitamin D + metformin. Vitamin D and metformin significantly reversed DM-induced hyperglycemia, electrolyte imbalance, and dyslipidemia. Also, vitamin D and metformin reversed T2DM-induced increase in serum creatinine and urea and renal lactate, LDH, and oxido-inflammatory response. These observed alterations were accompanied by an increase in proton pump activities and modulation of Nrf2/Nf-κB and XO/UA signaling. This study revealed that vitamin D and/or metformin ameliorated T2DM-induced renal injury.

PERIAPICAL INFLAMMATORY LESIONS AND DIABETES MELLITUS TYPE II– A REVIEW

Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a “metabolically-triggered” low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. Diabetes mellitus (DM) is a group of complex multisystem metabolic disorders due to a deficiency in insulin secretion caused by pancreatic β-cell dysfunction and/or insulin resistance in liver and muscle. Objective: In this paper, the current status of knowledge regarding the relationship between periapical inflammation and diabetes mellitus type II is reviewed. Material and method: Research was conducted on scientific papers published on Medline - Pub med in the past 10 years (from 2012-2022). The search was performed using the Mesh (Medical Subject Headings) key words: periapical inflammatory lesions, periapical periodontitis and diabetes mellitus type II. Results: Several studies have analyzed the possible association between periapical inflammatory lesions and diabetes mellitus type II. The results of studies carried mainly in animal models, less in humans suggested association between endodontic variables such as apical periodontitis, root canal treatment and diabetes mellitus type 2.The demonstration of association does not prove by itself the existence of a cause-effect relationship. Conclusion: A review of the literature showed connection between periapical inflammatory lesions and diabetes mellitus type II, but prospective case control clinical studies are needed for further clarifying this relation.

Biomimetic nanoplatform with microbiome modulation and antioxidant functions ameliorating insulin resistance and pancreatic β-cell dysfunction for T2DM management

Insulin resistance and pancreatic β-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet β-cell and enhanced pancreatic β-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.

Reduced insulin clearance in paediatric metabolic (dysfunction)-associated fatty liver disease and its dual role in beta-cell offload and diabetes risk.

Diminished hepatic insulin clearance (HIC) is observed in obese adults and is presumed to be mediated by fatty liver. However, few reports have examined HIC in Chinese children with metabolic (dysfunction)-associated fatty liver disease (MAFLD). This study aimed to investigate the correlation between HIC, insulin sensitivity and β-cell function in obese Chinese children with MAFLD. In total, 204 obese children (74 MAFLD) aged 4-17 years were enrolled into this study. HIC, insulin sensitivity and β-cell function were calculated using the oral glucose tolerance test (1.75 g/kg body weight). Correlation analyses between the HIC and clinical variables were performed using Pearson's product-moment correlation coefficients. HIC and glucose homeostasis were assessed in a high-fat diet mouse model, and liver samples were collected for molecular analysis. Obese children with MAFLD exhibited significantly lower HIC (AUCC-peptide/insulin ratio, p = 0.0019), higher insulin resistance (homeostatic model assessment of insulin resistance, p = 0.002), and increased compensatory β-cell function (homeostatic model assessment-β, p = 0.046) than obese children without liver involvement. Notably, HIC was negatively correlated with insulin sensitivity (r = -0.5035, p < 0.0001) and β-cell function (r = -0.4576, p < 0.0001). However, pancreatic β-cell dysfunction (p = 0.046) was accompanied by future reduced HIC (p = 0.034) in children with MAFLD in prediabetes. In a high-fat diet mouse model, MAFLD mice showed a 50% reduction in insulin-degrading enzyme expression, consistent with the observed decrease in HIC. A lower HIC may offload pancreatic β-cells at an early stage. However, obese children with MAFLD are at risk of developing diabetes, and preventive efforts should be prioritized.

The Regulatory Effect of Vitamin D on Pancreatic Beta Cell Secretion in Patients with Type 2 Diabetes.

Increasing evidence suggests that vitamin D is one of the causes of accelerated development of Insulin Resistance (IR) and islet cell secret dysfunction. Numerous studies have shown that vitamin D can reduce inflammation, activate the transcription of the insulin receptors and related genes, and increase insulin-mediated glucose transport, thereby reducing IR. This article reviews the molecular mechanisms related to vitamin D deficiency and pancreatic β-cell dysfunction in patients with Type 2 Diabetes (T2D).

Puerarin ameliorates high glucose-induced MIN6 cell injury by activating PINK1/Parkin-mediated mitochondrial autophagy

The dysfunction of pancreatic β-cells plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite numerous studies demonstrating the anti-inflammatory and antioxidant properties of puerarin, the protective effects of puerarin on β-cells remain poorly understood. Hence, this study aimed to explore the effects of puerarin on β-cell dysfunction in a hyperglycemic environment via the PINK/Parkin-mediated mitochondrial autophagy pathway. The alterations in cell viability of MIN6 cells exposed to glucose concentrations of 5 mM, 10 mM, 20 mM, and 30 mM for 24 h, 48 h, and 72 h, respectively, were assessed using the CCK-8 assay to optimize the modeling conditions. Subsequently, cellular insulin secretion was measured using enzyme-linked immunosorbent assay (ELISA), apoptosis rate by flow cytometry, mitochondrial membrane potential alteration by JC-1, cellular ROS production by the DCFH-DA fluorescent probe, and fusion of cellular autophagosomes and lysosomes through adenoviral infection analysis. Furthermore, gene and protein expression levels of the PINK/Parkin-mediated mitochondrial autophagy pathway and mitochondrial apoptosis pathway were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. Results indicated a significant decrease in MIN6 cell viability following 48 h of exposure to 30 mM glucose concentration. Puerarin intervention markedly attenuated ROS production, restored mitochondrial membrane potential, induced PINK/Parkin-mediated mitochondrial autophagy, suppressed activation of the mitochondrial apoptotic pathway, mitigated apoptosis, and enhanced insulin secretion in a high glucose (HG) environment. The findings of this investigation contribute to a deeper understanding of the precise mechanism underlying the protective effects of puerarin on β-cells and offer a theoretical foundation for advancing puerarin-based therapeutics aimed at ameliorating T2DM.

Innate Immunity in Type 1 Diabetes.

Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance and promotion of inflammation either directly using innate effector mechanisms or by providing activation signals to anti-islet adaptive autoimmunity. We provide an overview of various deleterious and protective roles of innate immunity in T1D inside pancreatic islets, regional lymph nodes, and distant locations such as the gut.