Beta-cell Dysfunction Research Articles

Covid-19 Pneumonia Presenting as a ‘Typical Radiological Bronchopneumonia’ Pattern in Clinical-Radiological-Pathological Phenotype with Transient Hyperglycemia

Radiological phenotypes are radiological patterns or observable characteristics of COVID19 pneumonia. Various phenotypic classifications have been reported in literature. CT severity radiological phenotypes are widely used and universally accepted radiological phenotypic methods. Radiological CT severity phenotypic differentiation has documented very crucial role in initial assessment and during triaging of these cases in indoor and outdoor setting. Typical COVID-19 lung parenchymal involvement described as predominant ground glass opacities (GGOs) and consolidations in peripheral and subpleural portion of any lobe, predominantly involving lower lobes. Atypical Radiological patterns in COVID-19 has been documented as bronchopneumonia, multifocal consolidations, necrotizing pneumonia, cavitations with GGOs with or without consolidations. In present case report, 43-year male, presented with acute febrile respiratory illness with acute hypoxic respiratory failure documented as oxygen saturation of 80% at room air with tachypnea and respiratory distress. HRCT thorax was showing Pleural based, peripheral, central, multifocal patchy, confluent & ill-defined GGOs and consolidations in bilateral lung fields in upper, middle and lower lobes. These typical radiological features suggestive of bronchopneumonia like radiological pattern which was very unusual for typical COVID-19 radiology. His laboratory parameters have shown abnormally raised inflammatory markers like CRP, Ferritin, LDH, D-Dimer and IL-6. Importantly, his random blood sugars were raised with abnormally raised HbA1c levels to label as diabetes mellitus. He was diagnosed with diabetes mellitus this time with COVID-19 illness without use of steroids. He was treated with standardized COVID-19 management institutional protocol with combination of low molecular weight heparin, methylprednisolone, remdesivir, meropenem and teicoplanin. Patient required BIPAP support with higher oxygen requirement with nasals canula for one week due to advanced radiological disease with more anatomical involvement. We have documented successful treatment outcome with use of rational treatment in timely by predicting disease severity with use of composite analysis of clinical, laboratory and radiological markers of illness. Transient hyperglycemia is known to occur and reported after COVID-19 illness due to virus induced inflammatory response and pancreatopathy with beta cell dysfunction. Transient hyperglycemia can be easily managed with insulin during hospitalization and oral anti-diabetic agents after discharge for few weeks. Dietary and lifestyle modification will help in majority with complete reversal of abnormally high sugar levels with restoration of normal HbA1c levels to non-diabetic range.

Association between a polygenic lipodystrophy genetic risk score and diabetes risk in the high prevalence Maltese population.

Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI. In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes. 814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored. A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution. This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.

DNA Methylation-Based Assessment of Cell Composition in Human Pancreas and Islets.

Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example insulin as a marker of beta-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here we demonstrate the use of cell type-specific DNA methylation markers for determining the fraction of specific cell types in human islet and pancreas specimens. We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition. In islet preparations, normalization of insulin secretion to beta-cell DNA revealed similar beta-cell function in pre-T1D, T1D and T2D , which was significantly lower than in non-diabetic donors. In histological pancreas specimens from recent-onset T1D this assay showed beta-cell fraction within the normal range, suggesting a significant contribution of beta-cell dysfunction. In T2D pancreata we observed increased alpha-cell fraction and normal beta-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease.

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations

BackgroundType 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations.MethodsWe applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger’s Z-test and further validated in a pediatric cohort without diabetes (aged 9–12 years old, n = 3866).ResultsWe identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta − 0.08 SD, 95% CI [− 0.10–0.07], p = 6.50 × 10−32) and beta-cell dysfunction (Beta − 0.10 SD, 95% CI [− 0.12, − 0.08], p = 1.46 × 10−47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06–0.10, p = 8.0 × 10−33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02–1.62, p = 0.03).ConclusionsWe successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.

Placenta-derived exosomes exacerbate beta cell dysfunction in gestational diabetes mellitus through delivery of miR-320b.

Recent studies have shown placenta-derived exosome (pdE) acts as an important mediator of organ-to-organ interplay regulating maternal metabolic alterations, however, the function and mechanisms of placental exosomes on pancreatic β-cell maladaptation in gestational diabetes mellitus (GDM) remain unclear. The purpose of this investigation was to ascertain how placental exosomes affected the β-cell dysfunction associated with the onset of GDM. Exosomes were isolated from chorionic villi explants of pregnant mice and humans with normal glucose tolerance (NGT) and GDM. The effects of pdE from GDM on glucose tolerance in vivo and islets function in vitro were determined. Isolated islets from mice fed on the chow diet displayed an increase in apoptosis and observed their glucose-stimulated insulin secretion (GSIS) greatly diminished by PdE from GDM mice. Mice that accepted PdE from mice with GDM possessed glucose intolerance.Based on miRNA microarray assay and bioinformatics analysis from human placental exosomes, we identified miR-320b selectively enriched in PdE secreted in GDM compared with NGT. Importantly, the level of placental miR-320b was positively correlated with the 1h-glucose and 2-h glucose of a 75g oral glucose tolerance test (OGTT) during human pregnancies. Furthermore, miR-320 overexpression attributed to impaired insulin secretion and increased apoptosis in MIN6 cells and islets obtained from mice with normal insulin sensitivity. This study firstly proposed that altered miRNAs in pdE contribute to defective adaptation of β cells during pregnancy, which expands the knowledge of GDM pathogenesis. Exosomes from the placenta may be an emerging therapeutic target for GDM.

Gliptins and acute pancreatitis in patients with type 2 diabetes: a review

Diabetes mellitus is a chronic, metabolic, and complex disease that requires continuous treatment and medical care. Type 2 diabetes (T2DM) is disinfected by dysfunction of beta cells and insulin resistance. Gliptins are oral anti-hyperglycemic agents that control hyperglycemia. Acute pancreatitis (AP) is an acute inflammation that occurs in the pancreas. The correlation between acute pancreatitis and diabetes is complex, and there are many incorporated factors, such as anti-hyperglycemic drugs. The oresnt review aimed at providing an overview of acute pancreatitis and its association with T2DM, gliptins as a treatment for T2DM, and the correlation between AP and gliptins among T2DM patients. Scientific databases were used for searching for articles related to our subject. A variety of keywords were used for the search purpose, including "T2DM, AP, Association, Correlation, Incidence, Prevalence, Gliptin, dipeptidyl-peptidase-4 inhibitors." Articles of relevance included those written in the English language, of any type, and conducted on the current subject. To cover as much of the current topic as possible, the discussion of the review contained three major sections. The first section covered acute pancreatitis and its connection to T2DM. In the second section, gliptin agents, safety, and negative effects were discussed. The third section discussed the correlation between acute pancreatitis and gliptin in T2DM patients. Acute pancreatitis was highly developed among type 2 diabetic patients; however, the correlation between acute pancreatitis and gliptins is controversial.

Double whammy: Coexistence of Mature onset diabetes of the young and autoimmune diabetes: A case report

Maturity-Onset Diabetes of the Young (MODY)encompasses genetic disorders caused by mutations in single genes associated with beta cell dysfunction, constituting 1-6% of all diabetes cases. Mutations in ATP binding cassette transporter subfamily C member 8 (ABCC8) causes MODY 12 which accounts for 1% among MODY cases. It can present in childhood, adolescence or adulthood. Despite growing awareness, accurate MODY diagnosis remains challenging, often leading to misclassification as type 1 or type 2 diabetes. Correct identification is crucial for tailored treatment and implications for family members. The coexistence of MODY and autoimmune related diabetes is a very rare phenomenon with only a handful of cases reported. We describe a unique case where the index patient was initially diagnosed with type 1 diabetes at age 8 due to antibody positivity, leading to insulin treatment. After 15 years, he presented with evidence of all microvascular complications. Interestingly, his brother also developed diabetes at age of 14 years but with out antibody positivity. Due to a strong family history, both siblings underwent genetic testing, revealing a heterozygous mutation in the ABCC8 gene (C.4799630 G>A; P-Arg 1600His).

Obesity: A Major Factor in Diabetes

Obesity is currently recognized as a significant risk factor contributing to the onset of diabetes, presenting a substantial challenge to public health worldwide. This abstract provides a concise overview of the intricate relationship between obesity and diabetes, with a specific focus on the impact of excess body weight on insulin resistance and beta-cell dysfunction. These two mechanisms serve as the primary contributors to the development of diabetes. The abstract delves into the complex interplay between adipose tissue, insulin signaling, and inflammation, elucidating the underlying mechanisms by which obesity exacerbates insulin resistance. Additionally, the role of visceral adiposity, genetic factors, and lifestyle modifications are explored within the context of obesity-related diabetes. The abstract also highlights the adverse health consequences associated with obesity-related diabetes, particularly the heightened risk of cardiovascular disease and other comorbidities. Acknowledging these detrimental effects strengthens the urgency in addressing this widespread issue. Consequently, the abstract briefly outlines the various effective management strategies available to combat obesity-related diabetes, including weight loss interventions, pharmacotherapy, and bariatric surgery. In conclusion, the abstract underscores the necessity of adopting a comprehensive and multidisciplinary approach in tackling both obesity and diabetes. Prevention measures are emphasized as a crucial component in alleviating the burden posed by these two interrelated health conditions. By implementing proactive strategies, it is possible to mitigate the escalating prevalence of obesity-related diabetes and enhance public health outcomes.

Comparative Analysis of Metformin and Imeglimin: Exploring Therapeutic Implications

The landscape of type 2 diabetes mellitus (T2DM) management is evolving with the emergence of imeglimin alongside the longstanding use of metformin. While both drugs share structural similarities and target mitochondrial complex I, they exhibit distinct mechanisms of action and therapeutic effects. Imeglimin, with its mitochondrial modulation and competitive inhibition of complex I, holds promise in mitigating beta-cell dysfunction, improving insulin sensitivity, and offering potential cardiovascular benefits. Efficacy studies suggest comparable outcomes with metformin, underscoring the utility of imeglimin as a valuable addition to the T2DM armamentarium. There is mixed evidence on the cardio-renal benefits of metformin while imeglimin’s tissue-protective effects in preclinical studies offer a glimpse into potential cardiovascular advantages. Studies suggest imeglimin’s superior gastrointestinal tolerability. Imeglimin’s potential as an anti-diabetic agent is further underscored by its diverse combination options. In clinical practice, metformin remains a cornerstone in the management of T2DM. Imeglimin, with its lesser gastrointestinal side effects and theoretically lower risk of lactic acidosis, offers a compelling alternative, particularly in patients intolerant to metformin. With preliminary signs pointing toward potential cardiovascular and renal benefits of imeglimin, exploring its application in patients with atherosclerotic cardiovascular disease presents an enticing prospect. As the field advances, adopting a nuanced and personalized approach to T2DM management could lead to imeglimin carving out a significant niche in the dynamic landscape of diabetes therapeutics.

Insulin Resistance, Obesity, and Lipotoxicity.

Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.

The Revolutionary Role of GLP-1 Agonists and SGLT-2 Inhibitors in Managing Diabetes and Chronic Kidney Disease in Liver Transplant Recipients

Successful liver transplant is the only life-saving intervention for patients with end-stage liver disease, but post-transplant complications, particularly diabetes mellitus and chronic kidney disease, significantly compromise both patient and graft survival. These complications not only heighten clinical and economic burdens but also worsen long-term outcomes due to the rising prevalence of metabolic syndrome, which predisposes many liver transplant recipients to metabolic dysfunctions like diabetes and chronic kidney disease. Additionally, metabolic syndrome is a key driver of Metabolic Associated Steatotic Liver Disease, a leading cause of liver failure and a growing indication for liver transplantation worldwide. While liver transplantation resolves end stage liver disease, it fails to address the underlying metabolic challenges, such as pre-existing or post-transplant diabetes and chronic kidney disease. The use of calcineurin inhibitors ,a cornerstone of immunosuppression, exacerbates these issues by disrupting glucose metabolism, increasing insulin resistance, and causing pancreatic beta-cell dysfunction, which further contributes to post-transplant diabetes mellitus. Post-transplant diabetes mellitus is associated with increased morbidity, mortality, and graft rejection, underscoring the need for improved management strategies. Emerging therapies, such as GLP-1 receptor agonists and SGLT-2 inhibitors, have shown promise in mitigating the effects of diabetes and chronic kidney disease in non-transplant populations. These agents offer potential benefits for liver transplant recipients by improving glycemic control, promoting weight loss, and offering renal protection. However, their application in liver transplantation remains underexplored, with limited clinical data available. This review explores the pathogenesis of diabetes and chronic kidney disease in liver transplant recipients, the challenges posed by current immunosuppressive regimens, and the potential role of GLP-1 agonists and SGLT-2 inhibitors in improving patient and graft outcomes. Future research is essential to optimize post-transplant care and reduce the burden of metabolic complications in liver transplant recipients.

METABOLIC SYNDROME – A COMMON CONDITION IN MODERN SOCIETIES

The presence of multiple unknowns and uncertainty factors in medical research has made it extremely challenging to distinguish the preclinical phase of a chronic disease, such as the metabolic syndrome (MS), from the initial condition of health. MS is a complex and multifactorial medical condition characterized by the presence of at least three of the following conditions: high insulin levels (normal HOMA qualitative index 2), elevated serum glucose level > 126 mg/dl, patients with abdominal obesity, a body mass index (BMI) ≥ 30 kg/m2 , a lipid panel showing a triglyceride level ≥ 150 mg/dl, and HDL-CO 35 mg/dl in men and 45 mg/dl in women. In all developed countries, the number of obese people diagnosed with insulin resistance (IR) has rapidly increased to > 40% in recent years. This condition precedes the development of MS. The likelihood of having MS rises with advancing age. Additionally, new research has identified other influential hormones produced by adipose tissue that significantly impact metabolism, such as lipid cytokines, leptin, adiponectin, and rezistin. Researchers believe that central obesity and the chronic inflammatory process play a key role in the development of metabolic syndrome and focus on mitochondrial dysfunction, changes in the gut microbiome, and pancreatic beta cell dysfunction. The primary determinant in averting the development of MS is humanity's struggle against its own bioenergetic entropy, which may induce catabolic processes that abbreviate life expectancy while promoting negentropy until the fulfillment of the life program predetermined in the genetic code.

Tangeretin enhances pancreatic beta-TC-6 function by ameliorating tunicamycin-induced cellular perturbations.

Pancreatic beta cell health and its insulin-secreting potential are severely compromised under the diabetic condition. One of the key mediators of beta cell dysfunction is endoplasmic reticulum (ER) stress. Pharmacological intervention of ER stress and associated complications in pancreatic beta cells may be an effective strategy for the management of diabetes. In the present study, we evaluated the efficacy of tangeretin, a citrus pentamethoxyflavone, in the alleviation of ER stress and associated perturbations in pancreatic Beta-TC-6 cell lines. Tunicamycin (pharmacological ER stress inducer) at subtoxic levels was observed to induce beta cell dysfunction by upregulation of intracellular ROS levels, lowering mitochondrial number/biogenesis and membrane potential, elevation of UPR markers, XBP-1, GADD153, and ER resident chaperones. Treatment with tangeretin was successful in improving the beta cell function by lowering the ROS levels and improving the mitochondrial biogenesis and mitochondrial membrane potential. Tangeretin also downregulated the expression levels of XBP-1, GADD153, and ER resident chaperones. GLUT2 expression, however, did not undergo any significant change under ER stress. We also observed altered expression of Pdx-1, TRB3, and p-Akt under the ER stress condition. Tangeretin augmented the expression levels of Pdx-1, and p-Akt while curtailing the expression of TRB3 in beta cells. Tunicamycin treatment suppressed the insulin levels, however, co-treatment with tangeretin could only marginally improve the levels. Targeting ER stress and associated pathways in pancreatic Beta-TC-6 cell lines by tangeretin can be an effective strategy for improving beta cell function.

An extended minimal model of OGTT: estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect.

Loss of insulin sensitivity, α- and β-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, β- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and β-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.

Systemic lupus erythematosus and diabetic mellitus is it single or two entity(es)

Introduction: Systemic lupus erythematosus (SLE) is a complex and chronic autoimmune disease with varied clinical manifestations and multi-organ involvement. The disease may present with acute, severe, and life-threatening symptoms or present as a fluctuating and chronic process that impacts several systems and increases the risk of malignancy. Systemic lupus erythematosus (SLE) often coexists with other diseases. Diabetes mellitus (DM) is an example and patients with SLE-DM can present with clinical features common to both disorders. Type 2 diabetes (T2D) is characterized by insulin resistance the inability of tissues to respond to insulin, and a progressive pancreatic beta cell dysfunction in response to glucose levels. The disease is thought to be caused by environmental and inherited factors in about equal proportions. Many environmental risk factors are known, including obesity, sedentary lifestyle, stress, nutritional factors and toxins. The report aims to describe Systemic Lupus Erythematosus and Diabetes mellitus as single or two entity(es). Case presentation: A 14-year-old female patient who was admitted to the hospital with complaints of weakness and drowsiness was getting worse 3 days before admitted from hospital. There have been complaints of fatigue for last 3 years accompanied by a lot of eating and drinking and urinating. Complaints of pain in both joints of the hands and both knees appeared in the last 3 months and had been getting worse. Hair loss existed in the past 4 months before being admitted to the hospital. Blurred vision in the right eye in the last 6 months has worsened in the last 1 month. Vision loss in the last 3 months. Body weight was reduced 4 kilograms within 3 months without any loss of appetite. Initial laboratory results revealed hyperglycemia, antinuclear antibodies (ANA) IF 1:100 and ANA Profile Sm (+), dyslipidemia, increase of creatinine serum with glomerular filtration rate 72.41 m2/BSA (decreased 38%). Other examinations showed that C-peptide is normal and beta islet antibody is negative. Echocardiography resulted tricuspid regurgitation with normal ventricle function. Conclusion: Systemic Lupus Erythematosus and Diabetes mellitus is a rare condition that warrants a thorough evaluation to both determine the diagnosis and predict the clinical course of disease.

Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently.

Insulin-positive (+) cells (IPCs), detected in multiple organs, are of great interest as a probable alternative to ameliorate pancreatic beta-cells dysfunction and insulin deficiency in diabetes. Liver is a potential source of IPCs due to it common embryological origin with pancreas. We previously demonstrated the presence of IPCs in the liver of healthy and diabetic rats, but detailed description and analysis of the factors, which potentially can induced ectopic hepatic expression of insulin in type 1 (T1D) and type 2 diabetes (T2D), were not performed. In present study we evaluate mass of hepatic IPCs in the rat models of T1D and T2D and discuss factors, which may stimulate it generation: glycaemia, organ injury, involving of hepatic stem/progenitor cell compartment, expression of transcription factors and inflammation. Quantity of IPCs in the liver was up by 1.7-fold in rats with T1D and 10-fold in T2D compared to non-diabetic (ND) rats. We concluded that ectopic hepatic expression of insulin gene is activated by combined action of a number of factors, with inflammation playing a decision role.

Butyrate functions as a histone deacetylase inhibitor to protect pancreatic beta cells from IL-1β-induced dysfunction.

Butyrate, a gut microbial metabolite, has beneficial effects on glucose homeostasis and has become an attractive drug candidate for type 2 diabetes (T2D). Recently, we showed that butyrate protects pancreatic beta cells against cytokine-induced dysfunction. In this study, we explored the underlying mechanisms of butyrate action. Pancreatic mouse islets were exposed to a non-cytotoxic concentration of interleukin-1β (IL-1β) for 10 days to mimic low-grade inflammation in T2D. Similar to the effect of butyrate, an isoform-selective histone deacetylase 3 (HDAC3) inhibitor normalized IL-1β-reduced glucose-stimulated insulin secretion and insulin content. In contrast, free fatty acid receptor 2 and 3 (FFAR2/3) agonists failed to normalize IL-1β-induced beta cell dysfunction. Furthermore, butyrate inhibited HDAC activity and increased the acetylation of histone H3 and H4 by 3- and 10-fold, respectively. Genome-wide analysis of histone H3 lysine 27 acetylation (H3K27ac) revealed that butyrate mainly increased H3K27ac at promoter regions (74%), while H3K27ac peaks regulated by IL-1β were more equally distributed at promoters (38%), introns (23%) and intergenic regions (23%). Gene ontology analysis showed that butyrate increased IL-1β-reduced H3K27ac levels near several genes related to hormone secretion and reduced IL-1β-increased H3K27ac levels near genes associated with inflammatory responses. Butyrate alone increased H3K27ac near many genes related to MAPK signaling, hormone secretion, and differentiation, and decreased H3K27ac at genes involved in cell replication. Together, these results suggest that butyrate prevents IL-1β-induced pancreatic islet dysfunction by inhibition of HDACs resulting in changes in H3K27ac levels at genes relevant for beta cell function and inflammatory responses.

PTPN2 Regulates Metabolic Flux to Affect β-Cell Susceptibility to Inflammatory Stress.

Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation and models of T1D, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, low and high dose streptozotocin (STZ) treated Ptpn2 βKO mice displayed hyperglycemia and accelerated death, respectively. Furthermore, cytokine treated Ptpn2 KO islets resulted in impaired glucose-stimulated insulin secretion, mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to maladaptive metabolic fitness. Consistent with the phenotype, proteomic analysis identified an important metabolic enzyme ATP-citrate lyase (ACLY) as a novel PTPN2 substrate.

The selective NOX4 inhibitor GLX7013159 decreases blood glucose concentrations and human beta-cell apoptotic rates in diabetic NMRI nu/nu mice transplanted with human islets

NADPH oxidase 4 (NOX4) inhibition has been reported to mitigate diabetes-induced beta-cell dysfunction and improve survival in vitro, as well as counteract high-fat diet-induced glucose intolerance in mice. We investigated the antidiabetic effects of the selective NOX4 inhibitor GLX7013159 in vivo in athymic diabetic mice transplanted with human islets over a period of 4 weeks. The GLX7013159-treated mice achieved lower blood glucose and water consumption throughout the treatment period. Furthermore, GLX7013159 treatment resulted in improved insulin and c-peptide levels, better insulin secretion capacity, as well as in greatly reduced apoptotic rates of the insulin-positive human cells, measured as colocalization of insulin and cleaved caspase-3. We conclude that the antidiabetic effects of NOX4 inhibition by GLX7013159 are observed also during a prolonged study period in vivo and are likely to be due to an improved survival and function of the human beta-cells.