Type 2 Diabetes Research Articles

Neurodevelopmental Pathways to Obesity and Type 2 Diabetes: Insights From Prenatal Exposure to Maternal Obesity and Gestational Diabetes Mellitus: A Report on Research Supported by Pathway to Stop Diabetes.

Incidences of childhood obesity and type 2 diabetes (T2D) are climbing at alarming rates. Evidence points to prenatal exposures to maternal obesity and gestational diabetes mellitus (GDM) as key contributors to these upward trends. Children born to mothers with these conditions face higher risks of obesity and T2D, beyond genetic or shared environmental factors. The underpinnings of this maternal-fetal programming are complex. However, animal studies have shown that such prenatal exposures can lead to changes in brain pathways, particularly in the hypothalamus, leading to obesity and T2D later in life. This article highlights significant findings stemming from research funded by my American Diabetes Association Pathway Accelerator Award and is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. This critical support, received more than a decade ago, paved the way for groundbreaking discoveries, translating the neural programming findings from animal models into human studies and exploring new avenues in maternal-fetal programming. Our BrainChild cohort includes >225 children, one-half of whom were exposed in utero to maternal GDM and one-half born to mothers without GDM. Detailed studies in this cohort, including neuroimaging and metabolic profiling, reveal that early fetal exposure to maternal GDM is linked to alterations in brain regions, including the hypothalamus. These neural changes correlate with increased energy intake and predict greater increases in BMI, indicating that early neural changes may underlie and predict later obesity and T2D, as observed in animal models. Ongoing longitudinal studies in this cohort will provide critical insights toward breaking the vicious cycle of maternal-child obesity and T2D.

High expression of CNOT6L contributes to the negative development of type 2 diabetes.

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by reduced responsiveness of body cells to insulin, leading to elevated blood sugar levels. CNOT6L is involved in glucose metabolism, insulin secretion regulation, pancreatic beta-cell proliferation, and apoptosis. These functions may be closely related to the pathogenesis of T2D. However, the exact molecular mechanisms linking CNOT6L to T2D remain unclear. Therefore, this study aims to elucidate the role of CNOT6L in T2D. The T2D datasets GSE163980 and GSE26168 profiles were downloaded from the Gene Expression Omnibusdatabase generated by GPL20115 and GPL6883.The R package limma was used to screen differentially expressed genes (DEGs). A weighted gene co-expression network analysis was performed. Construction and analysis of the protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis, and comparative toxicogenomics database (CTD) analysis were performed. Target Scan was used to screen miRNAs that regulate central DEGs. The results were verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and blood glucose measurements in mice. A total of 1951 DEGs were identified. GO and KEGG enrichment analysis revealed that differentially expressed genes were mainly enriched in the insulin signaling pathway, ECM-receptor interaction, and PPAR signaling pathway. Metascape analysis indicated enrichment primarily in the cAMP signaling pathway and enzyme-linked receptor protein signaling pathway. WGCNA analysis yielded 50 intersecting genes. PPI network construction and algorithm identification identified two core genes (CNOT6L and GRIN2B), among which CNOT6L gene was associated with multiple miRNAs. CTD analysis revealed associations of core genes with type 2 diabetes, diabetic complications, dyslipidemia, hyperglycemia, and inflammation. WB and RT-qPCR results showed that in different pathways, CNOT6L protein and mRNA levels were upregulated in type 2 diabetes. CNOT6L is highly expressed in type 2 diabetes mellitus, and can cause diabetes complications, inflammation and other physiological processes by regulating miRNA, PPAR and other related signaling pathways, with poor prognosis. CNOT6L can be used as a potential therapeutic target for type 2 diabetes.

Trends in anti-diabetic medication use, severe hyperglycaemia and severe hypoglycaemia among American Indian and Alaska Native Peoples, 2009-2013.

Type 2 diabetes (T2D) and its complications disproportionally affect American Indian and Alaska Native (AI/AN) peoples. Prescribing decisions for anti-diabetic medications are complicated and require balancing medication benefits, costs and side effects. Little is known about trends in anti-diabetic medication use as well as acute diabetes complications among AI/AN adults. Here, we examined patterns and trends in anti-diabetic medication use and rates of hospital admissions or emergency department (ED) visits due to severe hypoglycaemia and hyperglycaemia among AI/AN adults with T2D. We conducted a retrospective analysis of Indian Health Service (IHS) Improving Health Care Delivery Data Project. A total of 39 183 AI/AN adults aged ≥18 years with T2D who used IHS or Tribal health services during any of the fiscal years (FYs) 2009-2013 were included. Utilization rates of each class of anti-diabetic medications and rates of severe hypoglycaemia and severe hyperglycaemia in emergency room and/or inpatient discharge diagnoses were calculated for each year. Longitudinal statistical models were fitted to examine time trends of anti-diabetic medication use and complications. During 2009-2013, use of metformin (56.0%-60.5%), insulin (31.4%-35.9%) and dipeptidyl peptidase-4 inhibitors (1.4%-9.0%) increased, whereas the use of sulfonylureas (40.3%-32.9%) and thiazolidinediones (TZDs, 31.6%-8.8%) decreased significantly. Trends in severe hypoglycaemia (1.6%-0.8%) and severe hyperglycaemia (2.0%-1.6%) declined gradually. There were significant changes in the utilization of different anti-diabetic medication classes during 2009-2013 among AI/AN adults with T2D. Concurrently, there were significant reductions in severe hypoglycaemia and severe hyperglycaemia.

Efficacy and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors for the Primary Prevention of Cardiovascular, Renal Events and Safety Outcomes in Patients with Systemic Lupus Erythematosus and Comorbid Type 2 Diabetes: A Population-based Target Trial Emulation.

Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose co-transporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D). We performed an emulated clinical trial in an insurance-based cohort in the U.S., evaluating SGLT2i versus dipeptidyl peptidase 4 inhibitors (DPP4i) for primary prevention of cardiovascular, renal, and other clinical outcomes among patients with both SLE patients and comorbid T2D. SGLT2i initiators were matched to DPP4i initiators using propensity scores (PS) based on clinical and demographic factors. Hazard ratios (HR with 95% confidence intervals) were calculated using Cox models. Outcomes among 2,165 patients starting SGLT2i and 2,165 PS-matched patients starting DPP4i were compared. Over 753.1 (±479.2) mean days, SGLT2i recipients had significantly lower risks of incident acute kidney injury (HR 0.49, 95% CI 0.39-0.63), chronic kidney disease (HR 0.61, 0.50-0.76), end-stage renal disease (HR 0.40, 0.20-0.80), heart failure (HR 0.72, 0.56-0.92), and emergency department visits (HR 0.90, 0.82-0.99). Risks of all-cause mortality (HR 0.89, 0.65-1.21), lupus nephritis (HR 0.67, 0.38-1.15), myocardial infarction (HR 0.81, 0.54-1.23), stroke (HR 1.03, 0.74-1.44), and hospitalizations (HR 0.76, 0.51-1.12) did not differ. Genital infection risk (HR 1.31, 1.07-1.61) was increased, but urinary tract infection risk (HR 0.90, 0.79-1.03) did not differ. No significant difference was observed for diabetic ketoacidosis risk (HR 1.065, 0.53-2.14) and fractures (HR 0.95, 0.66-1.36). In this emulated clinical trial, SGLT2i vs. DPP4i use was associated with significantly reduced risks of several cardiorenal complications among patients with both SLE and T2D.

Sexual Dimorphism in Impairment of Acetylcholine-Mediated Vasorelaxation in Zucker Diabetic Fatty (ZDF) Rat Aorta: A Monogenic Model of Obesity-Induced Type 2 Diabetes.

Several reports, including our previous studies, indicate that hyperglycemia and diabetes mellitus exert differential effects on vascular function in males and females. This study examines sex differences in the vascular effects of type 2 diabetes (T2D) in an established monogenic model of obesity-induced T2D, Zucker Diabetic Fatty (ZDF) rats. Acetylcholine (ACh) responses were assessed in phenylephrine pre-contracted rings before and after apocynin, a NADPH oxidase (NOX) inhibitor. The mRNA expressions of aortic endothelial NOS (eNOS), and key NOX isoforms were also measured. We demonstrated the following: (1) diabetes had contrasting effects on aortic vasorelaxation in ZDF rats, impairing relaxation to ACh in females while enhancing it in male ZDF rats; (2) inhibition of NOX, a major source of superoxide in vasculature, restored aortic vasorelaxation in female ZDF rats; and (3) eNOS and NOX4 mRNA expressions were elevated in female (but not male) ZDF rat aortas compared to their respective leans. This study highlights sexual dimorphism in ACh-mediated vasorelaxation in the aorta of ZDF rats, suggesting that superoxide may play a role in the impaired vasorelaxation observed in female ZDF rats.

Efficacy and safety of cofrogliptin once every 2 weeks in Chinese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, phase 3 trial.

We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D). Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups. Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D. Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851).

Association of initial serum sodium change and clinical outcome in patients with diabetes receiving sodium-glucose cotransporter-2 inhibitor therapy: A multicentre database analysis in Taiwan.

The study aimed to assess the impact of varying degrees of initial serum sodium change among patients with type 2 diabetes (T2D) starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy and their subsequent clinical outcome. We used medical data from a multicentre health care provider in Taiwan and recruited 4400 patients with T2D with baseline normal serum sodium (135-145 mmol/L) and follow-up serum sodium measures available after 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2021. After a median of 2.9 (2.4, 3.4) months of SGLT2i treatment, overall, there was a minimal change in serum sodium levels (from 139.6 ± 2.4 to 139.5 ± 3.7 mmol/L). Most patients (87.8%) maintained normal sodium levels, while 8.6% (n = 378) experienced hyponatraemia (<135 mmol/L) and 3.6% (n = 158) hypernatraemia (>145 mmol/L). Factors independently associated with hyponatraemia included cancer history, chronic lung disease, insulin use, higher glycated haemoglobin, impaired liver function, lower baseline sodium and greater initial decline in kidney function. Conversely, factors linked to hypernatraemia included older age, absence of cancer history, loop diuretic and non-steroidal anti-inflammatory drug use, higher baseline sodium and a lesser initial decline in kidney function. Over a median of 26.0 months of follow-up, hyponatraemia shortly after starting SGLT2i therapy was associated with significantly increased risks of major adverse cardiovascular events [hazard ratio (HR): 2.52; 95% confidence interval (CI): 1.83-3.48], heart failure for hospitalization (HR: 1.66; 95% CI: 1.16-2.37), major adverse renal events (HR: 2.27; 95% CI: 1.73-2.96) and all-cause death (HR: 2.98; 95% CI: 2.17-4.11) after adjusting for clinically relevant factors. Non-linear analysis indicated that a more pronounced initial decline in serum sodium levels correlated steeply with higher risks of these adverse events. While most patients with T2D maintain stable serum sodium homeostasis on SGLT2i therapy, a subset may experience dysnatraemic events with potential worse clinical consequences. Physicians should be vigilant about monitoring sodium levels and considering the associated risks when initiating SGLT2i therapy in patients with risk.

In vivo functional profiling and structural characterisation of the human Glp1r A316T variant.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a highly effective therapy class for type 2 diabetes (T2D) and obesity, yet there are variable patient responses. Variation in the human Glp1r gene leading to altered receptor structure, signal transduction, and function might be directly linked to therapeutic responses in patients. A naturally occurring, low-frequency, gain-of-function missense variant, rs10305492 G>A (A316T), protects against T2D and cardiovascular disease. Here we employ CRISPR/Cas9 technology to generate a humanised knock-in mouse model bearing the homozygous Glp1r A316T substitution. Human Glp1r A316T/A316T mice displayed lower fasting blood glucose levels and improved glucose tolerance, as well as increased plasma insulin levels and insulin secretion responses, even under metabolic stress. They also exhibited alterations in islet cytoarchitecture and β-cell identity indicative of compensatory mechanisms under a high-fat, high-sucrose (HFHS) diet challenge. Across all models investigated, the human Glp1r A316T variant exhibited characteristics of constitutive activation but blunted incretin-induced responses. Our results are further supported by cryo-EM analysis and molecular dynamics (MD) simulations of the GLP-1R A316T structure, demonstrating that the A316T Glp1r variant governs basal receptor activity and pharmacological responses to GLP-1R-targeting anti-diabetic therapies, highlighting the importance of the precise molecular characterisation of human Glp1r variants to predict individual therapy responses.

Glucagon-like Peptide 1 Receptor Agonists in Cardio-Oncology: Pathophysiology of Cardiometabolic Outcomes in Cancer Patients.

Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.

Evidence for the Quercetin Binding Site of Glycogen Phosphorylase as a Target for Liver-Isoform-Selective Inhibitors against Glioblastoma: Investigation of Flavanols Epigallocatechin Gallate and Epigallocatechin.

Glycogen phosphorylase (GP) is the rate-determining enzyme in glycogenolysis, and its druggability has been extensively studied over the years for the development of therapeutics against type 2 diabetes (T2D) and, more recently, cancer. However, the conservation of binding sites between the liver and muscle isoforms makes the inhibitor selectivity challenging. Using a combination of kinetic, crystallographic, modeling, and cellular studies, we have probed the binding of dietary flavonoids epigallocatechin gallate (EGCG) and epigallocatechin (EGC) to GP isoforms. The structures of rmGPb-EGCG and rmGPb-EGC complexes were determined by X-ray crystallography, showing binding at the quercetin binding site (QBS) in agreement with kinetic studies that revealed both compounds as noncompetitive inhibitors of GP, with EGCG also causing a significant reduction in cell viability and migration of U87-MG glioblastoma cells. Interestingly, EGCG exhibits different binding modes to GP isoforms, revealing QBS as a promising site for GP targeting, offering new opportunities for the design of liver-selective GP inhibitors.

Pancreatic β-cells package double C2-like domain beta protein into extracellular vesicles via tandem C2 domains.

Double C2-like domain beta (DOC2B) is a vesicle priming protein critical for glucose-stimulated insulin secretion in β-cells. Individuals with type 1 diabetes (T1D) have lower levels of DOC2B in their residual functional β-cell mass and platelets, a phenotype also observed in a mouse model of T1D. Thus, DOC2B levels could provide important information on β-cell dys(function). Our objective was to evaluate the DOC2B secretome of β-cells. In addition to soluble extracellular protein, we assessed DOC2B localized within membrane-delimited nanoparticles - extracellular vesicles (EVs). Moreover, in rat clonal β-cells, we probed domains required for DOC2B sorting into EVs. Using Single Extracellular VEsicle Nanoscopy, we quantified EVs derived from clonal β-cells (human EndoC-βH1, rat INS-1 832/13, and mouse MIN6); two other cell types known to regulate glucose homeostasis and functionally utilize DOC2B (skeletal muscle rat myotube L6-GLUT4myc and human neuronal-like SH-SY5Y cells); and human islets sourced from individuals with no diabetes (ND). EVs derived from ND human plasma, ND human islets, and cell lines were isolated with either size exclusion chromatography or differential centrifugation. Isolated EVs were comprehensively characterized using dotblots, transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting. DOC2B was present within EVs derived from ND human plasma, ND human islets, and INS-1 832/13 β-cells. Compared to neuronal-like SH-SY5Y cells and L6-GLUT4myc myotubes, clonal β-cells (EndoC-βH1, INS-1 832/13, and MIN6) produced significantly more EVs. DOC2B levels in EVs (over whole cell lysates) were higher in INS-1 832/13 β-cells compared to L6-GLUT4myc myotubes; SH-SY5Y neuronal-like cells did not release appreciable DOC2B. Mechanistically, we show that DOC2B was localized to the EV lumen; the tandem C2 domains were sufficient to confer sorting to INS-1 832/13 β-cell EVs. Clonal β-cells and ND human islets produce abundant EVs. In cell culture, appreciable DOC2B can be packaged into EVs, and a small fraction is excreted as a soluble protein. While DOC2B-laden EVs and soluble protein are present in ND plasma, further studies will be necessary to determine if DOC2B originating from β-cells significantly contributes to the plasma secretome.

Nutraceutical Synergy in the Treatment of Polymorbid Pathology: Black Seed Supplementation in Hypertension, Diabetes, Knee Osteoarthritis and Anxiety - A Case Study

Introduction: Investigate combining black seed (Nigella sativa) and honey to manage hypertension, type-2 diabetes, knee osteoarthritis, and anxiety in a middle-aged woman. Case Presentation: A 55-year-old woman, poorly controlled on allopathic meds for 4 months, had her BP and blood sugar monitored for 2 weeks. She then started a black seed-honey mix, and BP and blood sugar were monitored for another 2 weeks. Significant reductions in BP and blood sugar levels were observed. The knee osteoarthritis score was halved, and anxiety was reduced from moderate to none. The patient continued the supplement with adjusted meds and experienced no adverse effects. Conclusion: The black seed-honey mix shows promise as an adjunctive therapy for multiple conditions and warrants further investigation.

Association between RBC folate and diabetic nephropathy in Type2 diabetes mellitus patients: a cross-sectional study

Folates play a crucial role as cofactors in metabolic pathways, influencing biological methylation and nucleotide synthesis, which has a significant impact on overall health and disease susceptibility. Diabetic nephropathy (DN) is a prevalent and severe complication of diabetes mellitus (DM). The correlation between RBC folate and DN remains unclear currently. This study aims to assess whether RBC folate is associated with DN. Based on data from the NHANES (2011–2018), we conducted a cross-sectional study involving 3070 adults with type 2 DM (T2DM). Demographic factors, levels of folate and vitamin B12, dietary folate intakes, and relevant laboratory data were obtained from all participants. Logistic regression, fitting smooth curves, interaction effects were utilized to support the research objectives. Regression analyses demonstrated a positive relation between RBC folate and DN. (P < 0.001). A positive association between levels of RBC folate and the risk of DN was observed after full adjustment for all the confounding variables (odds ratio: 1.38, 95% confidence interval: 1.27–1.49, P < 0.001). Similar patterns of association were observed for subgroup analysis (all P values for interaction > 0.05). In addition, curve fitting after adjusting for all the confounding variables demonstrated that there was a linear relationship between RBC folate and DN (P for non-linearity = 0.147). Increased RBC folate levels were linked to a higher risk of DN in type 2 diabetes. RBC folate should be considered as a crucial indicator for folate status in DN.

The impact of Serum Amylin on Body mass index in Children with type1 Diabetes Mellitus newly diagnosis

Background: Pancreatic β cells' inability to synthesize insulin is the defining feature of type 1 diabetes mellitus (T1DM), an endocrine illness. This action involves the peptide hormone amylin, which is co-secreted with insulin and plays a key role in controlling glucose homeostasis and appetite. It also influences body weight, calorie intake, stomach emptying, glucagon release suppression, and satiety. Subjects, Material, and Method: This study included 120 pediatric individuals aged between( 2-14) years. They were divided into four groups. Group one contains 40 lean patients with T1DM, with a BMI≥85 percentile, and group two contains 40 underweight patients with (T1DM) with a BMI≥5 percentile. The Group contains 40 healthy pediatrics and ages matched with the patients subdivided into (group three, lean control with a BMI less than 85 percentile. The group numbered 22, and four groups, underweight control with BMI≥5 percentile, consisted of 18 pediatric underweight healthy as controls. They were analyzed for fasting serum glucose, amylin, and HbA1c. Results: The levels of Amylin in the control group(lean and underweight) were higher than in the patients with diabetes mellitus(lean and underweight). Also, fast blood glucose( FBG) was found in the Lean DM group. Similarly, the Underweight DM group was higher than those observed in the Lean Control and Underweight Control groups. For HbA1c%, the Lean DM group. The Underweight DM group exhibited a higher mean HbA1c%. In contrast, the Lean Control and Underweight Control groups had significantly lower mean HbA1c% values. Conclusion: The control group had higher Amylin levels, a potential biomarker for metabolic status in children with T1DM, and could inform therapeutic strategies to optimize glycemic control and body weight management. In comparison, the patient group had higher FBG values. The Lean DM group had higher HbA1c% values, while the Underweight DM group had slightly higher values. Both control groups had significantly lower HbA1c% values.

Association of polymorphism of NLRP3, ICAM-1, PTPN22, INS genes in childhood onset type 1 diabetes in a Pakistani population.

Type 1 diabetes (T1D) is an organ-specific autoimmune disorder characterized by the destruction of pancreatic β cells, leading to absolute insulin deficiency. The genes NLRP3, ICAM-1, PTPN22, and INS are reportedly associated with T1D in other populations. However, the genetic pattern of T1D in the Pakistani population is not clear. This study aimed to find the association of polymorphisms in the PTPN22, INS, NLRP3, and ICAM-1 genes with T1D susceptibility in the Pakistani population. This case-control study includes 100 T1D patients (3-14 years), recruited randomly from the pediatric endocrinology department of Fatima Memorial Hospital, Lahore, Pakistan and 100 age-matched healthy controls were selected from different localities of the same population. The polymorphisms in PTPN22 (rs601, rs33996649, rs2488457), INS (rs80356664), NLRP3 (rs10754558, rs35829419), and ICAM-1 (rs1799969, rs5498) genes were genotyped by Sanger sequencing. The genotypic and allelic frequencies, haplotypes, and linkage disequilibrium were computed using the genetic toolset PLINK to investigate their relationship to T1D. The results indicate that the occurrence of the GT genotype of the rs33996649 variant is significantly higher in children with T1D compared to a control group of healthy individuals (P = 0.001, OR: 2.0, 95% CI = 0.15-0.45). Furthermore, the CT genotype of rs2488457 was notably associated with T1D patients (P = 0.007, OR: 2.8, 95% CI = 0.56-0.67). The CG genotype of rs80356664 showed a slight association with T1D (P = 0.03, OR: 1.9, 95% CI = 0.35-0.59). The prevalence of the AT genotype of rs10754558 showed a strong association with T1D (P = 0.005, OR: 3.4, 95% CI = 0.45-0.69). The TG genotype of rs5498 was also strongly associated with T1D (P = 0.009, OR: 2.8, 95% CI = 0.75-0.89). The present study provides evidence that SNPs in the PTPN22, INS, NLRP3, and ICAM-1 genes are associated with the development of T1D. Further research is needed to explore their potential use in genetic screening and personalized medication.

Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.

Cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs according to baseline blood pressure in type 2 diabetes: a systematic meta-analysis of cardiovascular outcome trials

Objectives: Using a systematic meta-analysis, we investigated if patients with type 2 diabetes (T2D) and with varying baseline blood pressure (BP) differ in the cardiorenal benefits received from sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Design: Randomized, placebo-controlled, cardiovascular outcome trials (CVOTs) of SGLT-2is and GLP-1RAs were identified from MEDLINE, Embase, and the Cochrane Library up to April 2024. Hazard ratios (HRs) with 95% CIs were pooled. The differential treatment effect by baseline BP category within each trial was estimated as the ratio of the HR (RHR) and pooled. Results: Seventeen publications based on 9 unique CVOTs (4 SGLT-2is and 5 GLP-1RAs) were eligible. In participants with normal baseline BP, comparing SGLT-2is with placebo, the HRs (95% CIs) were 0.88 (0.79-0.97) for major adverse cardiovascular events (MACE), 0.73 (0.59-0.91) for heart failure (HF) hospitalization, 0.78 (0.65-0.94) for composite CVD death/HF hospitalization, and 0.55 (0.41-0.73) for composite renal outcome. The corresponding estimates for participants with higher baseline BP were 0.88 (0.81-0.96), 0.67 (0.57-0.79), 0.73 (0.65-0.82), and 0.61 (0.48-0.77), respectively. In participants with normal baseline BP, GLP-RAs had no strong effect on MACE, stroke and nephropathy, but reduced stroke and nephropathy risk in those with higher baseline BP. Estimated RHRs showed no statistical evidence that baseline BP modified the cardiorenal benefits of SGLT-2is and GLP-1RAs. Conclusions: In patients with T2D, the cardiorenal benefits of treatment with SGLT2-Is and GLP1-RAs were similar in patients with normal baseline BP compared to those with a higher baseline BP.

Translation and Validation of the Diabetes Knowledge Questionnaire in Indonesian Patients With Type 2 Diabetes.

The purpose of the study was to translate and cross-culturally adapt the 24-item Diabetes Knowledge Questionnaire (DKQ) for Indonesian patients with type 2 diabetes (T2D) and evaluate its psychometric properties. Forward-backward translation, adaptation involving 7 experts, and pretesting to develop the Indonesian version of DKQ were conducted. Psychometric analysis was carried out among T2D patients from 40 primary health care centers in Indonesia. Known-group, convergent and discriminant validity, internal consistency and test-retest reliability were assessed. Additionally, a descriptive item analysis was conducted. In total, 39 patients participated in the pretesting and 304 patients in the validation process and descriptive analysis. Of the 24 items, 2 were adjusted during the adaptation process, and 1 item was deleted because it did not adequately reflect the original item. Known-group validity was demonstrated because patients with younger ages, higher educational levels, and longer diabetes duration had significantly higher DKQ scores. Convergent validity was demonstrated by a significant positive correlation of the DKQ scores with overall treatment satisfaction. The 23-item DKQ Bahasa Indonesia showed satisfactory internal consistency (Cronbach's α = 0.73; omega total = 0.72) and good test-retest reliability (intraclass correlation coefficient = 0.87 in a sample of 27 patients). No floor and ceiling effects were found in the item analysis. The study demonstrates adequate validity and reliability of the 23-item DKQ Bahasa Indonesia for assessing diabetes knowledge in Indonesian primary care patients with T2D. This instrument can be used to identify room for improvement and develop diabetes education programs.

OS RISCOS DO USO DE ANTI-INFLAMATÓRIOS NÃO ESTERÓIDES PELO PACIENTE DIABÉTICO NO BRASIL

Introduction: Diabetes mellitus (DM) is a chronic non-communicable disease characterized by hyperglycemia. The types of diabetes have different symptoms and treatments and can cause various chronic complications. Diabetic nephropathy and cardiovascular diseases stand out in this article. Anti-inflammatories are divided into two classifications: steroids and non-steroids (NSAIDs). NSAIDs can treat inflammation, pain, edema, osteoarthritis, rheumatoid arthritis, and musculoskeletal disorders. Still, they cause side effects, some of which can cause problems in the renal system and cardiovascular systems, systems that may already be at risk of suffering complications in diabetic patients. Despite these effects, some NSAIDs are Over-the-Counter Medications (OTC) and this facilitates self-medication and irrational use of these medications. Objective: To analyze the risks related to the use of NSAIDs by diabetics in Brazil. Methodology: The method was descriptive and quantitative research through a bibliographic review. Conclusion: Due to the prevalence of diabetics in Brazil and the common use of non-prescription NSAIDs, diabetics must avoid self-medication and be made aware and guided by health professionals.

NADPH oxidase 5 is a novel susceptibility gene for type 2 diabetes mellitus.

This pilot study investigated whether single nucleotide polymorphisms (SNP) in the NOX5 gene (NADPH oxidase 5) are associated with the type 2 diabetes (T2D) risk. A total of 1579 patients with T2D and 1627 age- and sex-matched healthy subjects were recruited for this study. Genotyping of common SNPs, namely rs35672233, rs3743093, rs2036343, rs311886, and rs438866, was performed using the MassArray-4 system. SNP rs35672233 was associated with an increased risk of T2D (OR = 1.67, 95% CI 1.29-2.17, FDR = 0.003). The H3 haplotype (rs35672233T-rs3743093G-rs2036343A-rs311886C-rs438866C) increased T2D risk (OR = 1.65, 95% CI 1.27-2.13, FDR = 0.001). The rs35672233 polymorphism and H3 haplotype were found to have an association with T2D risk only in subjects with a body mass index greater than 25 kg/m2 (FDR < 0.01). Environmental risk factors, such as chronic psycho-emotional stress, sedentary lifestyle, high-calorie diet and SNP rs35672233 were jointly associated with T2D susceptibility. A haplotype comprising the allele rs35672233-C and conferring protection against T2D, was associated with elevated levels of antioxidants such as total glutathione and uric acid, as well as reduced levels of two-hour postprandial glucose in the plasma of patients. The NOX5 polymorphisms showed no associations with diabetic complications. The present study is the first to establish associations between polymorphisms in NOX5 and the risk of type 2 diabetes mellitus, and provides a new line of evidence for the crucial role of oxidative stress-related genes in disease susceptibility.