Onset Of Diabetes Mellitus Research Articles

Patterns and Characteristics of Diabetic Ketoacidosis in Children With Type I Diabetes in Saudi Arabia.

Type 1 diabetes mellitus (T1DM) in children, a significant public health concern, often leads to diabetic ketoacidosis (DKA). The prevalence of T1DM is increasing globally, with Saudi Arabia recording high rates of DKA at T1DM onset. This study aimed to evaluate the characteristics and risk factors of pediatric T1DM patients presenting with DKA in the emergency roomin Saudi Arabia and quantify intensive care unit (ICU) admission incidences reflecting DKA severity. This retrospective chart review, conducted at Medina Maternity and Children's Hospital, Saudi Arabia, analyzed data from 2017 to 2022. The study included children and adolescents under 18 presenting with DKA, using non-probability consecutive sampling. Patient medical records provided demographic, medical, and laboratory data, and the analysis employed SPSS for statistical assessment. The study enrolled 70 participants, predominantly female (n = 42, 60%) and Saudi nationals (n = 63, 90%). The average age at diabetes mellitus (DM) onset was 6.9 years, with a mean hospital stay of 3.31 days. About 18.57%(n = 13) were newly diagnosed with DM, and 81.43% (n = 57) were known cases of DM. Most participants (n = 59, 86.8%) had no comorbidities, while 7.4% (n = 5) had celiac disease. The recovery rate was high (n = 67, 95.7%), with 80% (n = 56) experiencing no complications. Notably, 44.3% (n = 31) were admitted to a ward, and 12.9% (n = 9) required ICU admission. Weight was found to be a significant predictor of ICU admission (OR = 1.26, 95% CI: 1.05 to 1.5; p = 0.011). This study highlights the importance of personalized insulin therapy and weight management in pediatric T1DM patients presenting with DKA. It suggests that early and effective management in emergency settings can significantly improve patient outcomes. The study also calls for further research into long-term management strategies and the impact of targeted educational programs.

RISK FACTORS FOR DIABETES MELLITUS ACCORDING TO THE INDIVIDUAL REGISTRATION OF PRIMARY CARE IN A MUNICIPALITY IN THE NORTH OF MINAS GERAIS-MG

Objective: To analyze the completion of the individual e-SUS registration form and identify the completion of the factors that correlate to the onset of diabetes mellitus. Methods: Descriptive study based on documents, in which the individual registration forms of users assigned to an area covered by the Family Health Strategy were used for analysis. Results: It was identified that data such as family history, anthropometric measurements, dietary components, and frequency of physical exercise are not addressed in the registration forms, factors considered predisposing to the disease. There is an underreporting of risk factors for diabetes mellitus since there is no adequate description of them. Conclusion: The individual registration forms of primary care show inconsistencies in the face of factors correlated to the development of metabolic diseases, especially DM, leading to an underreporting of these factors.

A case report of chronic hepatitis-C genotype 4c infection: Non-specific symptoms can become contextually relevant in clinical diagnosis

Chronic hepatitis C (CHC) infection is one of the leading causes of liver disease worldwide and its early diagnosis is often considered a challenge because of its non-symptomatic presentation until late disease progression stages. We report the case of a 52-year-old, South-Indian male with CHC genotype 4c infection. We start with the patient’s initial presentation 12 weeks before the diagnosis with seemingly non-specific symptoms of pedal edema, purpura, peripheral neuropathy, arthralgia, and recent onset of diabetes mellitus (DM). We then present the employed direct-acting antiviral (DAA) management regimen and the patient’s response over the span of 48 weeks. Correlating with observations from recent literature highlighting CHC’s extra-hepatic role in inducing cryoglobulinemic vasculitis (CV) and pancreatic dysfunction, we discuss some educational perspectives on how CV and DM-related symptoms may sometimes become contextually specific in clinically suspecting, assessing risk, and warranting CHC screening and diagnostic confirmation.

Pancreatic cancer and diabetes: The effects of race and genes.

627 Background: Pancreatic cancer and diabetes mellitus (DM) have been shown to be connected, but the genetic associations between the two have not been well characterized. The goal of this study was to identify racial and genomic patterns that relate the timing of DM onset with a pancreatic cancer diagnosis. Methods: Consecutive pancreatic cancer patients treated at the University of Cincinnati Cancer Center with available tumor genomic profiles were studied. Descriptive statistics for 133 genes, patient characteristics, cancer stage, treatment details, and family history were analyzed. Categorical variables were compared using the Pearson Chi-square test for contingency tables (or Fisher’s exact test when the expected frequency within any cell was less than 5 in the contingency table), and the t-test or ANOVA was used for continuous variables. For overall survival, we generated Kaplan-Meier curves by DM diagnosis, and fit univariable Cox Proportional-Hazard models for each interest variable for all patients, and multivariable Cox models, which included only significant variables. Results: Of 147 individuals with pancreatic cancer (median age 67 years, 49% female, 12% Black), 46.3% had a DM diagnosis. Of these, 62% had chronic DM, while 38% were diagnosed within one year of their pancreatic cancer diagnosis. Black individuals were more likely to have DM diagnosed (76.5% vs 41.7%, p = 0.007), and were more likely to have been diagnosed within a year of pancreatic cancer (69.2% vs 30.2%, p = 0.023), compared with White individuals. There were 15 genes found to be upregulated in those with DM and pancreatic cancer, and 11 genes found to be downregulated. RNF43 mutation was more prevalent in pancreatic cancer patients with chronic DM than those without DM (71.4% vs 32.5%, p = 0.048), although absolute number of individuals with the mutation were low. No other genomic association on the timing of DM and pancreatic cancer was found. A SMAD4 mutation was associated with a 121% increased risk of mortality (HR = 2.21, 95% CI 1.16-4.19, p=0.016). Conclusions: In a cohort of pancreatic cancer patients at a single center, Black individuals were more likely to have DM diagnosed closer to pancreatic cancer diagnosis (rather than earlier), compared with other races. No remarkable genomic association was found. This highlights that a diagnosis of diabetes may be related to inequities in healthcare, as opposed to true genomic differences, and needs to be explored in larger datasets.

New Onset Diabetes Mellitus With COVID-19 Infection in a 5-Month Old.

New Onset Diabetes Mellitus With COVID-19 Infection in a 5-Month Old.

Comparative analysis of hemodialysis and peritoneal dialysis on the risk of new onset diabetes mellitus

BackgroundDiabetes mellitus is a significant risk factor for cardiovascular events and mortality in dialysis patients. The impact of different dialysis modalities on the risk of new onset diabetes mellitus (NODM) remains a subject of debate. Previous studies did not adequately account for critical confounding factors such as pre-dialysis glycemic status, medication use, and nutritional status, which may influence the association between dialysis modality and NODM risk. MethodsWe conducted a retrospective cohort study of 1426 non-diabetic end-stage renal disease (ESRD) patients who underwent either hemodialysis (HD) or peritoneal dialysis (PD) at a single medical center. We used different statistical methods, adjusting for potential confounding factors, and accounted for competing risk of death. ResultsOver 12 years, 331 patients (23 %) developed NODM. After adjusting for potential confounding factors and mortality, PD patients had a significantly higher risk of NODM compared to HD patients (adjusted HR 1.52, p = 0.001). A propensity-matched cohort sensitivity analysis yielded similar results. Among patients with prediabetes, those receiving PD had a 2.93 times higher risk of developing NODM than those receiving HD (p for interaction <0.001), whereas no significant difference was observed among euglycemic patients. NODM was also associated with a 1.78 times increased risk of major cardiovascular events. ConclusionOur study provides evidence that PD treatment may increase the risk of NODM in ESRD patients, particularly among those with preexisting prediabetes. These findings highlight the importance of personalized treatment approaches, and nephrologists should consider prediabetes when choosing the dialysis modality for their patients.

Optical coherence tomography-angiography findings of prediabetic patients.

The purpose of this study was to evaluate prediabetic patients for microvascular changes using optical coherence tomography-angiography (OCT-A) and compare with diabetic patients and healthy controls. OCT-A images of 60 eyes of 30 patients with diabetes mellitus (DM), 72 eyes of 36 prediabetic patients, and 108 eyes of 54 healthy controls were retrospectively evaluated and compared in this study. A swept-source OCTA (Triton, Topcon) instrument was used for collecting OCT-A images. Duration of the diabetic or prediabetic period, glycated hemoglobin, fasting blood glucose level, postprandial glucose (PPG) level, high-density lipoprotein, low-density lipoprotein, triglyceride, and creatinine values of all participants were recorded. Microaneurysm, nonperfusion areas, perifoveal capillary disruption, and capillary network disorganization were detected in both prediabetics and diabetics but statistically more common in diabetic patients. Neovascularization and intraretinal microvascular anomalies were detected only in diabetic patients. OCT-A seemed to be effective in detecting microvascular changes in diabetic patients. More importantly, results showed us that in prediabetic patients, microvascular changes can be seen before the onset of DM and before or concurrently with neurodegenerative changes.

Clinical Evidence of the Relationship Between Alanine Aminotransferase and Diabetic Kidney Disease.

Multiple studies have investigated the association between alanine aminotransferase (ALT) and diabetes mellitus (DM); however, only a few studies have specifically examined the relationship between ALT and diabetic kidney disease (DKD). This study aimed to investigate the relationship between ALT and DKD using clinical data. A cross-sectional study was conducted on 668 individuals that included non-DM (N=281), DM without DKD (N=160), and DKD (N=227) patients. A generalized additive model (GAM) was used to examine the dose-response relationship between ALT and DKD risk. We also analyzed the data from the US National Health and Nutrition Examination Survey (NHANES) 2015-2018 using the same statistical methods; 4481, 1110, and 671 individuals were included in the non-DM, DM without DKD, and DKD groups, respectively. The changes in ALT activity among the non-DM, DM without DKD, and DKD groups showed a similar pattern in both our clinical data and the NHANES dataset. ALT activity increases with the onset of DM, whereas ALT activity decreases when DM progresses to DKD. The GAM revealed a nonlinear U-shaped relationship between ALT and DKD risk in the two datasets, and the lowest range of ALT was 40-50 IU/L. Both lower (<40 IU/L) and higher (>50 IU/L) ALT activity were found to be positively associated with DKD risk. A U-shaped nonlinear association between ALT and DKD was found in our clinical data and NHANES data. DKD risk was increased by both lower or higher ALT activity. To confirm the causality of nonlinear relationship, larger prospective studies or Mendelian randomization analysis are required.

Diabetes mellitus progression in β-thalassaemia major patients: The impact of iron overload

ABSTRACT Regular blood transfusion therapy and enhanced iron absorption in patients with β-thalassemia major lead to progressive accumulation of iron in the patient’s tissues. Iron overload disrupts the function of pancreatic β-cell, deteriorates insulin resistance, increases blood glucose levels, and precipitates diabetes mellitus (DM). A family history of DM, obesity, sedentary lifestyle, and age increase the risk of DM in β-thalassemia patients. The prevalence of DM among individuals with β-thalassemia major is on the rise despite considerable screening and management efforts. Therefore, more research is still warranted to fully understand the molecular underpinnings linking β-thalassemia major and the onset and progression of DM to develop more robust screening and management approaches. In this context, no reliable biomarkers are currently available to predict or detect DM in such patients. In this review, we elaborate on key tentative links between thalassemia and DM and expand on established metabolic alterations that associate with DM in patients with β-thalassemia major. The review also addresses the prevalence rates and patient management strategies and underscores the need for identifying DM-related predictive and diagnostic biomarkers in β-thalassemia major patients.

Delayed menarche in children and adolescents with type 1 diabetes mellitus: a systematic review and meta-analysis.

Several studies have reported an association between age at menarche and the onset of type-1 diabetes mellitus (T1DM). This review compared the age at menarche in patients who had menarche after T1DM diagnosis with that of patients who were healthy and/or had menarche before T1DM diagnosis. Searches were conducted using four databases. The outcome was the age at menarche of patients who had menarche after T1DM diagnosis and patients who were healthy and/or had menarche before T1DM diagnosis. A qualitative analysis was performed using the JBI (Joanna Briggs Institute) Critical Appraisal. Quantitative analysis of the mean differences was performed using Revman 5.4 tool. A total of 1952 studies were obtained from the initial search. The final results were 13 articles that met the inclusion criteria for the qualitative assessment and eight for the quantitative assessment. Eight studies included 1030 patients who had menarche after being diagnosed with T1DM and 1282 patients who were healthy and/or had menarche before T1DM diagnosis. The meta-analysis showed a cumulative effect on a mean difference of 0.87 (95% CI: 0.75; 0.99, p-value < 0.00001), indicating a later age at menarche in patients who had menarche after T1DM diagnosis. The age at menarche was later in patients who had menarche after T1DM diagnosis compared to healthy subjects and those who had menarche beforehand.

Study of Profile of Young Diabetics with Special Reference to Type 2 Diabetes Mellitus

Abstract Background: Data about the frequency of type 2 diabetes mellitus (T2DM) among young subjects below 25 years of age are sparse in the Indian subcontinent. Aims and Objectives: The objective of this study was to study the frequency and clinical profile of T2DM among young diabetics. Materials and Methods: The study was a prospective observational study conducted in the Department of General Medicine and Pediatrics in JSS Hospital, Mysuru, Karnataka, India. The subjects with age of onset of diabetes mellitus below 25 years were included in the study. They were categorized according to the C-peptide values as type 1 diabetes mellitus (T1DM) and T2DM. The statistical analyses were performed using Statistical Package for the Social Sciences (SPSS version 25) computer program. Results: Of the 250 patients included in the study, 208 (83.2%) subjects had T1DM, 38 (15.2%) T2DM, and 4 (1.6%) maturity-onset diabetes of the young. The mean age of onset of T1DM was 13.7 ± 6.201 years and T2DM was 23.28 ± 3.68 years. Body mass index and waist circumference of young T2DM patients were more compared to T1DM, which were statistically significant (P &lt; 0.0001), and family history showed strong positivity in patients with young T2DM compared to T1DM. Low-density lipoprotein-cholesterol, triglyceride, and total cholesterol were more in young T2DM patients compared to T1DM, which were statistically significant with P = 0.003, P = 0.0015, and P = 0.03, respectively. Conclusion: T2DM is now commonly occurring in young adults and children, probably due to a growing epidemic of childhood obesity and lifestyle. Obesity and dyslipidemia were more in T2DM compared to T1DM among young diabetics.

Metformin enhances METTL14-Mediated m6A methylation to alleviate NIT-1 cells apoptosis induced by hydrogen peroxide

Injuries to pancreatic β-cells are intricately linked to the onset of diabetes mellitus (DM). Metformin (Met), one of the most widely prescribed medications for diabetes and metabolic disorders, has been extensively studied for its antioxidant, anti-aging, anti-glycation, and hepatoprotective activities. N6-methyladenosine (m6A) plays a crucial role in the regulation of β-cell growth and development, and its dysregulation is associated with metabolic disorders. This study aimed to elucidate the mechanistic basis of m6A involvement in the protective effects of Met against oxidative damage in pancreatic β-cells. Hydrogen peroxide (H2O2) was employed to induce β-cell damage. Remarkably, Met treatment effectively increased methylation levels and the expression of the methyltransferase METTL14, subsequently reducing H2O2-induced apoptosis. Knocking down METTL14 expression using siRNA significantly compromised cell viability. Conversely, targeted overexpression of METTL14 specifically in β-cells substantially enhanced their capacity to withstand H2O2-induced stress. Molecular evidence suggests that the anti-apoptotic properties of Met may be mediated through Bcl-xL and Bim proteins. In conclusion, our findings indicate that Met induces METTL14-mediated alterations in m6A methylation levels, thereby shielding β-cells from apoptosis and oxidative damage induced by oxidative stress.

Lipemic serum in a child with new onset diabetes mellitus presenting in severe diabetic ketoacidosis: A case report

Abstract Diabetic Ketoacidosis (DKA) presents as an acute emergency in children with type 1 diabetes mellitus. The mortality associated with DKA is more in developing countries and in children less than 5 years of age. Cerebral edema, sepsis, shock and renal failure are the identified causes for mortality. Severe hyperlipidemia and pancreatitis are less recognised causes for mortality in children with DKA. We report a 6-year-old female child who presented with lipemic serum due to severe hyperlipidemia associated with DKA. With adequate management of DKA as per the guidelines, hyperlipidemia also resolved and no further episodes were noted on follow up. Knowledge about this rare entity could help the clinicians regarding the prompt recognition, evaluation and management of hyperlipidemia and thus help in reduction of mortality associated with the same.

Combining bioinformatics and machine learning algorithms to identify and analyze shared biomarkers and pathways in COVID-19 convalescence and diabetes mellitus.

Most patients who had coronavirus disease 2019 (COVID-19) fully recovered, but many others experienced acute sequelae or persistent symptoms. It is possible that acute COVID-19 recovery is just the beginning of a chronic condition. Even after COVID-19 recovery, it may lead to the exacerbation of hyperglycemia process or a new onset of diabetes mellitus (DM). In this study, we used a combination of bioinformatics and machine learning algorithms to investigate shared pathways and biomarkers in DM and COVID-19 convalescence. Gene transcriptome datasets of COVID-19 convalescence and diabetes mellitus from Gene Expression Omnibus (GEO) were integrated using bioinformatics methods and differentially expressed genes (DEGs) were found using the R programme. These genes were also subjected to Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to find potential pathways. The hub DEGs genes were then identified by combining protein-protein interaction (PPI) networks and machine learning algorithms. And transcription factors (TFs) and miRNAs were predicted for DM after COVID-19 convalescence. In addition, the inflammatory and immune status of diabetes after COVID-19 convalescence was assessed by single-sample gene set enrichment analysis (ssGSEA). In this study, we developed genetic diagnostic models for 6 core DEGs beteen type 1 DM (T1DM) and COVID-19 convalescence and 2 core DEGs between type 2 DM (T2DM) and COVID-19 convalescence and demonstrated statistically significant differences (p<0.05) and diagnostic validity in the validation set. Analysis of immune cell infiltration suggests that a variety of immune cells may be involved in the development of DM after COVID-19 convalescence. We identified a genetic diagnostic model for COVID-19 convalescence and DM containing 8 core DEGs and constructed a nomogram for the diagnosis of COVID-19 convalescence DM.

EFEKTIFAS EDUKASI DALAM PENCEGAHAN DIABETES MELITUS DI DESA GENENG POLOKARTO SUKOHARJO

Background: Diabetes Mellitus (DM) is a metabolic syndrome due to impaired quantity and function of insulin which causes high blood glucose levels (hyperglycemia). Early prevention needs to be done for early detection of chronic diseases such as DM which have good risk factors due to unhealthy lifestyles and heredity. Early detection of DM can be done through screening by checking blood sugar levels at the time. In addition, success in preventing the onset of DM and controlling blood sugar levels in people with DM depends on people's behavior. Changes in behavior towards a healthy lifestyle in the context of correct DM prevention and control will be realized if the community has sufficient knowledge about DM and its prevention. The purpose of this activity is to add health information to the public about education on the prevention of Diabetes Mellitus. The method is carried out by lectures, discussions and questions and answers while the media uses leaflets. The education delivered increases public knowledge about diabetes risk prevention education, so that people can independently prevent the risk of diabetes mellitus which is a degenerative disease and is predicted to increase every year.

Pediatric diabetes mellitus hospitalizations and COVID-19 pandemic response measures

AimsIn the United States, evidence suggests that during the COVID-19 pandemic, admissions of patients with diabetes mellitus (DM) have increased. This study assessed hospital admission rates for pediatric type 1 (T1DM) and type 2 (T2DM) diabetes mellitus during 2019–2021, and the potential influence of the timing of various pandemic response measures. MethodsRetrospective chart reviews were conducted of 854 T1DM and 135 T2DM hospital admissions between January 2019 and December 2021 in patients < 20 years old to collect demographic data, admission type, body mass index (BMI), and area deprivation index (ADI, a measure of socioeconomic vulnerability). Patients were divided into three cohorts based on their admission year: 2019 (Pre-pandemic), 2020 (Pandemic, Pre-vaccine), and 2021 (Pandemic, Post-vaccine). Admissions were categorized within each cohort by diagnosis (T1DM or T2DM) and clinical presentation (new onset, diabetic ketoacidosis: DKA). Cohorts were compared using an independent samples t-test for continuous variables or a chi-square test for categorical variables. ResultsThe incidence of T2DM hospitalizations tripled during the pandemic, increasing from 18 in 2019 (Pre-pandemic), to 55 in 2020 (Pandemic, Pre-vaccine), and 62 in 2021 (Pandemic, Post-vaccine). The rate of patients presenting with DKA was 15.4 % (95 % CI: 4 %-26.9 %) higher in 2020 (Pandemic, Pre-vaccine) among patients with new-onset T1DM (72/139 vs. 52/143), and 22.5 % (95 % CI: 9.6 %-35.4 %) higher in 2020 (Pandemic, Pre-vaccine) among T2DM patients (9/40 vs. 0/14). This increased rate of new onset T2DM significantly correlated with younger age (P = 0.046) and higher ADI score (P = 0.017), but not with BMI. ConclusionThe incidence of T1DM hospitalizations did not increase during the pandemic; however, they tripled for T2DM patients. All new onset DM pediatric patients during the pandemic were more likely to present in DKA. Patients admitted with new onset T2DM were socioeconomically more vulnerable. For T1DM, the peak of local pediatric diabetes admissions in 2020 occurred slightly later coinciding with the reopening of primary care physicians (PCP) offices and schools.

Predictive modeling for the development of diabetes mellitus using key factors in various machine learning approaches

AimsMachine learning (ML) approaches are beneficial when automatic identification of relevant features among numerous candidates is desired. We investigated the predictive ability of several ML models for new onset of diabetes mellitus. MethodsIn 10,248 subjects who received annual health examinations, 58 candidates including fatty liver index (FLI), which is calculated by using waist circumference, body mass index and levels of triglycerides and γ-glutamyl transferase, were used. ResultsDuring a 10-year follow-up period (mean period: 6.9 years), 322 subjects (6.5 %) in the training group (70 %, n=7,173) and 127 subjects (6.2 %) in the test group (30 %, n=3,075) had new onset of diabetes mellitus. Hemoglobin A1c, fasting glucose and FLI were identified as the top 3 predictors by random forest feature selection with 10-fold cross-validation. When hemoglobin A1c and FLI were used as the selected features, C-statistics analogous in receiver operating characteristic curve analysis in ML models including logistic regression, naïve Bayes, extreme gradient boosting and artificial neural network were 0.874, 0.869, 0.856 and 0.869, respectively. There was no significant difference in the discriminatory capacity among the ML models. ConclusionsML models incorporating hemoglobin A1c and FLI provide an accurate and straightforward approach for predicting the development of diabetes mellitus.

An alternative approach using hs-CRP levels and age of onset in diagnostics of HNF1A-MODY.

The aim is to identify people with HNF1A-MODY among individuals in diabetic cohort solely based on low hs-CRP serum level and early diabetes onset. In 3537 participants, we analyzed the hs-CRP levels. We analyzed the HNF1A gene in 50 participants (1.4% of the cohort) with type 1 or type 2 diabetes who had hs-CRP ≤0.25 mg/L and were diagnosed with diabetes mellitus (DM) at the age of 8-40 years. We functionally characterized two identified missense variants. Three participants had a rare variant in the HNF1A gene, two of which we classified as likely pathogenic: c.1369_1384dup (p.Val462Aspfs*92) and c.737T>G (p.Val246Gly), and one as likely benign: c.1573A>T (p.Thr525Ser). Our functional studies revealed that p.Val246Gly decreased HNF1α transactivation activity to ~59% and the DNA binding ability to ~16% of the wild-type, while p.Thr525Ser variant showed no effect on transactivation activity, DNA binding, nor nuclear localization. Based on the two identified HNF1A-MODY patients among 3537 people with diabetes, we estimate 0.057% as the minimal HNF1A-MODY prevalence in Slovakia. A positive predictive value of hs-CRP ≤0.25 mg/L for finding HNF1A-MODY individuals was 4.0% (95% CI 0.7%, 13.5%). Hs-CRP value and age of DM onset could be an alternative approach to current diagnostic criteria with a potential to increase the diagnostic rate of HNF1A-MODY.

Restoring glucose balance: Conditional HMGB1 knockdown mitigates hyperglycemia in a Streptozotocin induced mouse model

Diabetes mellitus (DM) poses a significant global health burden, with hyperglycemia being a primary contributor to complications and high morbidity associated with this disorder. Existing glucose management strategies have shown suboptimal effectiveness, necessitating alternative approaches. In this study, we explored the role of high mobility group box 1 (HMGB1) in hyperglycemia, a protein implicated in initiating inflammation and strongly correlated with DM onset and progression. We hypothesized that HMGB1 knockdown will mitigate hyperglycemia severity and enhance glucose tolerance. To test this hypothesis, we utilized a novel inducible HMGB1 knockout (iHMGB1 KO) mouse model exhibiting systemic HMGB1 knockdown. Hyperglycemic phenotype was induced using low dose streptozotocin (STZ) injections, followed by longitudinal glucose measurements and oral glucose tolerance tests to evaluate the effect of HMGB1 knockdown on glucose metabolism. Our findings showed a substantial reduction in glucose levels and enhanced glucose tolerance in HMGB1 knockdown mice. Additionally, we performed RNA sequencing analyses, which identified potential alternations in genes and molecular pathways within the liver and skeletal muscle tissue that may account for the in vivo phenotypic changes observed in hyperglycemic mice following HMGB1 knockdown. In conclusion, our present study delivers the first direct evidence of a causal relationship between systemic HMGB1 knockdown and hyperglycemia in vivo, an association that had remained unexamined prior to this research. This discovery positions HMGB1 knockdown as a potentially efficacious therapeutic target for addressing hyperglycemia and, by extension, the DM epidemic. Furthermore, we have revealed potential underlying mechanisms, establishing the essential groundwork for subsequent in-depth mechanistic investigations focused on further elucidating and harnessing the promising therapeutic potential of HMGB1 in DM management.

Concordant and antagonistic associations of genetic variants with Alzheimer’s disease and diabetes mellitus through blood glucose and body‐mass index

AbstractBackgroundMounting evidence suggests common etiologies of Alzheimer’s disease (AD) and diabetes mellitus (DM). Genetic mechanisms underlying the risks of AD and DM remain elusive.MethodWe used individual‐level data from four longitudinal studies,—the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study, and UK Biobank,—to examine causal mediation effects in the associations of single nucleotide polymorphisms (SNPs) with AD and DM. We selected 178 lead SNPs representing 74 previously identified AD‐ and/or DM‐associated loci on 20 chromosomes (excluding chromosomes 6 and 21). First, we used marginal structural models to perform a univariate mediation meta‐analysis considering AD or DM as an outcome and blood glucose (BG) or body mass index (BMI) measured before the onset of AD and DM as a mediator. Then, we utilized summary statistics from these univariate analyses to examine pleiotropic mediation effects on AD and DM using an omnibus test.ResultWe identified 56 SNPs in 26 loci on 12 chromosomes attaining p&lt;0.05 in the univariate mediation meta‐analyses and genome‐wide significance (p&lt;5×10−8) in the pleiotropic meta‐analysis of indirect effects on AD and DM through BG and BMI. BG and BMI mediated associations of 27 SNPs—14 loci on nine chromosomes; none in the APOE locus— and 33 SNPs—14 loci on eight chromosomes, including the APOE locus—, respectively. SNPs only from two of 26 loci on chromosomes 7p15.1 (JAZF1 gene) and 10q25.2 (TCF7L2 gene) showed pleiotropic effects through both BG and BMI. Directions of the mediation effects on AD and DM were the same for the same alleles through BG and the opposite through BMI. The exclusion of DM‐affected subjects explained mediation effects on AD through BG in all 14 loci. In contrast, this exclusion improved the significance of the mediation effects on AD through BMI also in all loci by decreasing p‐values 0.5 to 2 orders of magnitude.ConclusionMost of the identified genetic variants increase susceptibility to AD and DM through different mechanisms. The BG‐associated genetic mechanism is common for AD and DM, whereas the BMI‐related genetic mechanism mediates the AD and DM risks in an antagonistic manner.