Non-obese Type 2 Diabetes Mellitus Research Articles

TG: A Mediator of the Relationship of Serum Uric Acid to Creatinine Ratio and Nonalcoholic Fatty Liver Disease in Non-Obese Patients with Type 2 Diabetes.

The study estimated the association between NAFLD and SUA/Cr in Chinese non-obese patients with type 2 diabetes mellitus (T2DM) and also investigated mediating effect of TG. All patients were divided into NAFLD group (n = 420) and non-NAFLD group (n = 347). The differences of biochemical indicators between the two groups were compared. The link between SUA/Cr and other parameters was checked through Spearman correlation analysis. Differences in the incidence rate of NAFLD between SUA/Cr and TG 3 tertile subgroups were tested by chi-squared. To explore the independent influence of SUA/Cr and TG on NAFLD, logistic regression was performed. The predictive value of SUA/Cr and SUA/Cr combined with BMI for NAFLD was analyzed using ROC curves. In addition, to confirm whether TG has a mediating effect on the link of SUA/Cr and NAFLD, we conducted a mediating analysis. NAFLD group had higher SUA/Cr values than individuals without NAFLD (P < 0.01). SUA/Cr was linked with TC and TG (r = 0.081, 0.215 respectively). NAFLD prevalence increased progressively from quartile 1 to quartile 3 of SUA/Cr (44% vs 57% vs 62%). Prevalence of NAFLD increased from quartile 1 to quartile 3 of TG (35.8% vs 58.7% vs 69.9%). Analysis of the logistic regression revealed that SUA/Cr and TG were statistically linked with NAFLD. The ROC curve pointed out that the area under the curve (AUC), sensitivity and specificity of SUA/Cr were 0.59, 0.629 and 0.522, respectively. The AUC, sensitivity and specificity for SUA/Cr combined with BMI were 0.719, 0.644 and 0.677, separately. The mediation analysis showed a statistically direct effect of SUA/Cr on NAFLD (β=0.148, 95% CI: 0.0393, 0.2585). The function of SUA/Cr on NAFLD partially mediated by TG (β=0.1571, 95% CI: 0.0704, 0.2869). SUA/Cr was significantly associated with NAFLD in non-obese T2DM patients, and TG partially mediated this association. SUA/Cr can be applied to predict for NAFLD.

MiR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD

Abstract Previous studies have shown that microRNAs (miRNAs) are involved in the regulation of a variety of metabolic diseases, which related to some important signal pathways. Our aim was to explore the possible mechanism of miRNAs by revealing the differential expression of serum miRNAs in different BMI of type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). We found that miR-29 decreased liver aminotransferase gamma-GGT and uric acid levels by inhibiting the expression of JNK-1 in non-obese T2DM patients with NAFLD, and down-regulated the expression of atherosclerosis-related factor lipoprotein phospholipase A2 (Lp-PLA2). Combined with bioinformatics analysis, we speculate that this may be mediated by the AMPK signaling. These findings suggest that miR-29 may be a potential targeted therapeutic strategy in T2DM patients with NAFLD.

CORRELATION BETWEEN THYROID FUNCTION AND OBESITY IN TYPE 2 DIABETES INDIVIDUALS

Objectives: In the present study, it is aimed to investigate the prevalence of thyroid dysfunction and blood glucose parameters and their correlation in Type 2 diabetes mellitus (T2DM) obese patients. Methods: The present study was a cross-sectional and observational study conducted for a period of 1 year January 2020–January 2022. The patient demographic data, age, and gender were collected from the medical records. After an overnight fast, venous blood samples were collected in the morning for laboratory tests. Electrochemiluminescence immunoassays were used to assess serum free T3 (FT3), FT4, and thyroid stimulating hormone (TSH). Fasting blood glucose, postprandial blood glucose, and random sugar levels were measured using enzymatic method. Body mass index (BMI) was calculated as weight (kg) divided by squared height (m). Results: In the present study, the mean values of thyroid harmones T3, T4 between the obese and non-obese individuals showed that no much significant variations might be due to low sample size. However, the mean values of TSH values were significantly higher 8.7ng/dl for obese individuals than non-obese individuals. There was a significant positive correlation that was identified for thyroid parameters TSH between obese and non-obese T2DM patients. On the other hand, there was a significant influence of postprandial blood sugar, random blood sugar, hemoglobin A1C, and BMI in obese and non-obese T2DM patients and insignificant influence for thyroid parameters T3 and T4. However, the results also showed that there was a highly significant influence of THS levels in obese T2DM patients. Conclusion: The findings of the present investigation showed a high correlation between thyroid function, mainly TSH levels, and Type 2 diabetes, particularly in obese persons.

Physical Activity as a Lifestyle Modification in Patients With Multiple Comorbidities: Emphasizing More on Obese, Prediabetic, and Type 2 Diabetes Mellitus Patients.

In this research, physical activity (PA) was shown to be inversely associated with the incidence of diabetes. This emphasizes the relevance of PA in diabetes prevention lifestyle intervention initiatives and encourages healthcare practitioners to advise high-risk patients on a healthy lifestyle combining PA for the reduction of weight in prediabetic, obese, and type 2 diabetes mellitus (T2DM) patients. The link between PA and diabetes was stronger in people with moderate or higher baseline PA, reflecting national recommendations that imply increasing activity levels may provide larger advantages for those who are comparatively less active. An intensive lifestyle intervention of eating healthier foods and increasing PA resulted in an effective decrease in weight and waist circumference after one year, which has high potential in the long term to prevent T2DM and different comorbidities such as obesity. Studies such as PRomotion Of Physical activity through structured Education with differing Levels of ongoing Support for those with prediabetes (PROPELS) demonstrate that the combination of PA interventions with telemedicine follow-ups results in ambulatory activity changes in the first year, but these changes do not last longer than four years. Acute PA practicing regularly will reduce postprandial glucose excursions. However, it is unknown what type of PA routine will benefit the most from reducing postprandial glucose levels. There are no discernible variations in the effects of different disciplines of training on glucose levels, mainly when the data are compared across time. The combination of a healthy diet and lifestyle with programs based on diabetes prevention results in comparable and clinically significant mean weight reduction with cardiometabolic advantages. Based on the reviewed and cited studies, PA in patients at high risk of T2DM and obese and non-obese patientswith T2DM results infavorable outcomes in the first few months. There is a large gap in investigations of the effects of PA in these patients and the benefits of other lifestyle modifications in long-term-based studies. However, in this study, we emphasize the importance of lifestyle modifications, putting in perspective principally the PA that the majority of patients with comorbidities do not practice, especially those with obesity, prediabetes, and T2DM. Thus, it would be necessary to conduct long-interval studies such as randomized clinical trials, where a better outcome can be given about intervals based on daily exercise times and the type of exercise in conjunction with diets that will have the greatest benefit, focusing more on the subjects that our research mentioned.

Comparison of Plasma Exosome Proteomes Between Obese and Non-Obese Patients with Type 2 Diabetes Mellitus.

Obesity is considered a promoter of type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unclear. This study aimed to identify plasma exosome differentially expressed proteins (DEPs) that are potentially involved in the development of obesity-related T2DM. Exosomes were isolated from the plasma of obese and non-obese T2DM patients (n = 10 for each group). A label-free quantitative mass spectrometry analysis was applied to identify plasma exosome DEPs in obese patients compared with non-obese patients, followed by bioinformatics analysis including GO annotation, KEGG analysis, subcellular localization prediction, transcription factor analysis, and protein-protein interaction (PPI) prediction. We identified 2 significantly upregulated proteins (C9 and PON1) and 5 significantly downregulated proteins (HPX, A1BG, CFHR1, ANG, and CALM) in obese patients compared with those in non-obese patients. KEGG analysis demonstrated that the insulin signaling pathway was one of the pathways that significantly correlated with the DEPs. The DEPs were primarily localized in the extracellular space (5 out of 7). HMG-box and NF-Y beta might regulate the transcription of the DEPs. C9, PON1, HPX, and CFHR1 were present in the PPI network. The plasma exosome DEPs are potentially responsible for the development of obesity-related T2DM possibly through the insulin signaling pathway and the interaction with other proteins. Our study may guide future research direction toward the pathogenesis of obesity-related T2DM.

The multiscale characterization and constitutive modeling of healthy and type 2 diabetes mellitus Sprague Dawley rat skin.

In type 2 diabetes mellitus (T2DM), elevated glucose level impairs the biochemistry of the skin which may result in alteration of its mechanical and structural properties. The several aspects of structural and mechanical changes in skin due to T2DM remain poorly understood. To fill these research gaps, we developed a non-obese T2DM rat (Sprague Dawley (SD)) model for investigating the effect of T2DM on the in vivo strain stress state, mechanical and structural properties of skin. In vivo strain and mechanical anisotropy of healthy and T2DM skin were measured using the digital imaging correlation (DIC) technique and DIC coupled bulge experiment, respectively. Fluorescence microscopy and histology were used to assess the collagen and elastin fibers microstructure whereas nanoscale structure was captured through atomic force microscopy (AFM). Based on the microstructural observations, skin was modeled as a multilayer membrane where in and out of plane distribution of collagen fibers and planar distribution of elastin fibers were cast in constitutive model. Further, the state of in vivo stresses of healthy and T2DM were measured using model parameters and in vivo strain in the constitutive model. The results showed that T2DM causes significant loss in in vivo stresses (p < 0.01) and increase in anisotropy (p < 0.001) of skin. These changes were found in good correlation with T2DM associated alteration in skin microstructure. Statistical analysis emphasized that increase in blood glucose concentration (HbA1c) was the main cause of impaired biomechanical properties of skin. The presented data in this study can help to understand the skin pathology and to simulate the skin related clinical procedures. STATEMENT OF SIGNIFICANCE: Our study is significant as it presents findings related to the effect of T2DM on the physiologic stress strain, structural and mechanical response of SD rat skin. In this study, we developed a non-obese T2DM SD rat model which mimics the phenotype of Asian type 2 diabetics (non-obese). Several structural and mechanical characterization techniques were explored for multiscale characterization of healthy and T2DM skin. Further, based on microstructural information, we presented the constitutive models that incorporate the real microstructure of skin. The presented results can be helpful to simulate the realistic mechanical response of skin during various clinical trials.

Effect of duodenal-jejunal bypass on diabetes in the early postoperative period

Metabolic surgery is an effective treatment for patients with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the effect of duodenal-jejunal bypass (DJB) in a rat model of T2DM during the early postoperative period. A rat model of non-obese T2DM was allocated to two groups: a sham group and a DJB group. On postoperative day 1 (1POD), oral glucose tolerance testing (OGTT) was performed and the changes of glucose transporter expressions in the small intestine was evaluated. [18F]-fluorodeoxyglucose ([18]-FDG) uptake was measured in sham- and DJB-operated rats using positron emission tomography-computed tomography (PET-CT). DJB improved the glucose tolerance of the rats on 1POD. The expression of sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 1 (GLUT1) was high, and that of GLUT2 was low in the alimentary limb (AL) of rats in the DJB group. PET-CT showed that [18F]-FDG uptake was high in the proximal jejunum of DJB-operated rats. These results may show that DJB improve glucose tolerance in very early postoperative period as the result of glucose accumulation in the AL because of changes in glucose transporter expression.

Evaluation of miRNA-143 and miRNA-145 Expression and Their Association with Vitamin-D Status Among Obese and Non-Obese Type-2 Diabetic Patients.

Growing epidemics of type-2 diabetes mellitus (T2DM) and obesity have become a serious health concern. Since miRNAs and vitamin levels affect the development and progression of numerous pathogenic diseases, including diabetes, the present study aimed to evaluate miRNA-143 and miRNA-145 expression and vitamin-D status among obese and non-obese T2DM patients. The study included 100 clinically confirmed newly diagnosed obese and non-obese T2DM cases and 100 healthy subjects. Total RNA was extracted from collected blood samples and 100 ng of RNA was used for cDNA synthesis, then TaqMan assay was performed to evaluate the miRNA-143 and miRNA-145 relative expression. T2DM cases with hypertension (4.08 fold, p=0.01; 5.36 fold, p=0.009), fatigue (5.07 fold, p=0.04; 5.32 fold, p=0.03) and blurred vision (5.15 fold, p=0.01) showed higher miRNA-143 and miRNA-145 relative expression compared with their counterparts, respectively. A positive correlation was observed between miRNA-143 and miRNA-145 expression and decreased vitamin-D status in T2DM had significant association with impaired blood glucose fasting (p=0.001) and HDL level (p<0.0001). Obese T2DM cases showed higher miRNA-143 and miRNA-145 expression compared with their counterparts. Vitamin-D deficient T2DM cases had higher miRNA-143 and miRNA-145 expression (5.69 fold, 5.91 fold) compared with insufficient (4.27 fold, p=0.03; 4.61 fold, p=0.03) and sufficient (4.08 fold, p=0.002; 4.29 fold, p=0.003). ROC curve for miRNA-143 and miRNA-145 between obese T2DM vs non-obese T2DM cases, at best possible cutoff value of 4.39 fold, 4.0 fold showed increased miRNA-143 and miRNA-145 expression, the sensitivity and specificity were 85%, 88% and 61%, 53% respectively (AUC=0.83, p<0.0001; AUC=0.81, p<0.0001). Higher miRNA-143 and miRNA-145 expression could be a predictive indicator for obese T2DM cases, decreased status of vitamin-D was also significantly associated with impaired fasting blood sugar and HDL level, therefore it is important to evaluate the vitamin-D status among T2DM cases for better clinical outcome during the intervention.

Association Between Triglyceride-Glucose Index and Serum Uric Acid Levels: A Biochemical Study on Anthropometry in Non-Obese Type 2 Diabetes Mellitus Patients.

The triglyceride-glucose index (TyG) is positively correlated with serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). However, whether this relationship exists in non-obese T2DM patients remains unknown. The study investigated the relationship between TyG and SUA in Chinese non-obese T2DM patients and examined the prognostic value of TyG in hyperuricemia (HUA). In total, 719 T2DM patients who were not obese were enrolled from among those who visited the Hebei General Hospital. The patients were categorized into groups according to their SUA levels. The relationship between TyG and clinical parameters was examined through correlation analysis. To consider covariates and examine the independent impact of TyG on HUA, logistic regression was performed. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of TyG and homeostasis model assessment of insulin resistance (HOMA-IR) for HUA. The HUA prevalence was 12.10%. TyG was statistically different among the four SUA groups, with lower TyG levels in the Q1, Q2, and Q3 groups than that in the Q4 group. TyG was positively correlated with SUA (r = 0.176, P < 0.001). Logistic regression exhibited that TyG and SUA were independently correlated (OR = 2.427, 95% CI = 1.134-5.195, P = 0.022) even after adjustment for confounding factors. The ROC curve showed that the predictive value of TyG for HUA was higher than that of HOMA-IR (AUROC = 0.613, P = 0.001). TyG was positively correlated with SUA in non-obese T2DM patients. TyG may better predict HUA in non-obese T2DM patients than HOMA-IR.

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells.

Identification and epidemiological characterization of Type-2 diabetes sub-population using an unsupervised machine learning approach

BackgroundStudies on Type-2 Diabetes Mellitus (T2DM) have revealed heterogeneous sub-populations in terms of underlying pathologies. However, the identification of sub-populations in epidemiological datasets remains unexplored. We here focus on the detection of T2DM clusters in epidemiological data, specifically analysing the National Family Health Survey-4 (NFHS-4) dataset from India containing a wide spectrum of features, including medical history, dietary and addiction habits, socio-economic and lifestyle patterns of 10,125 T2DM patients.MethodsEpidemiological data provide challenges for analysis due to the diverse types of features in it. In this case, applying the state-of-the-art dimension reduction tool UMAP conventionally was found to be ineffective for the NFHS-4 dataset, which contains diverse feature types. We implemented a distributed clustering workflow combining different similarity measure settings of UMAP, for clustering continuous, ordinal and nominal features separately. We integrated the reduced dimensions from each feature-type-distributed clustering to obtain interpretable and unbiased clustering of the data.ResultsOur analysis reveals four significant clusters, with two of them comprising mainly of non-obese T2DM patients. These non-obese clusters have lower mean age and majorly comprises of rural residents. Surprisingly, one of the obese clusters had 90% of the T2DM patients practising a non-vegetarian diet though they did not show an increased intake of plant-based protein-rich foods.ConclusionsFrom a methodological perspective, we show that for diverse data types, frequent in epidemiological datasets, feature-type-distributed clustering using UMAP is effective as opposed to the conventional use of the UMAP algorithm. The application of UMAP-based clustering workflow for this type of dataset is novel in itself. Our findings demonstrate the presence of heterogeneity among Indian T2DM patients with regard to socio-demography and dietary patterns. From our analysis, we conclude that the existence of significant non-obese T2DM sub-populations characterized by younger age groups and economic disadvantage raises the need for different screening criteria for T2DM among rural Indian residents.

Clinical significance of high mobility group box 1/toll-like receptor 4 in obese diabetic patients.

High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.

Incidence and Cardiovascular Risk Factors Profile in Obese and Non-obese Type 2 Diabetes Mellitus subjects aged between 30 and 80 years in the polyclinic, in an Omani Population: ICD OMAN a Decade-Long Bawshar Study

Background: Coronary heart disease (CHD) and stroke are the major cardiovascular diseases (CVD) among populations with Type 2 diabetes mellitus (T2DM), leading to significant morbidity and mortality. Objective: To identify the incidence and cardiovascular risk factor profiles of obese and non-obese Omani T2DM patients aged between 30 and 80 years followed since ten years in the polyclinic. Design: An observational longitudinal retrospective cohort design was used. Setting: A secondary care polyclinic in Bawshar, Muscat, Oman, was utilized where DM patients were seen three days a week. Sample Size: A Convenient sample of 130 patients with T2DM between 1st November 2019 to 31st January 2020, who were free of CVD at baseline (January 2010) were involved in the study. Materials and Methods: Socio-demographic data and CVD risk factor assessments at the baseline were retrieved from patient’s records. The first CVD outcomes were traced from the date of diagnosis of T2DM to January 31st 2020. The study compared the CVD risk factors among obese and non-obese T2DM patients at baseline. Data were analyzed using Statistical Package for social sciences (SPSS)Statistics Inc., Chicago, US version 25.0. Incidence was expressed in percentage with 95% confidence intervals (CI). p-value&lt; 0.05 was considered Statistically significant. Results: The overall cumulative incidence of CVD was 16.15% over 10 years period. Middle aged (46 to 65years) individuals developed CVD with p value of 0.0028, p&lt; 0.05. Out of 23 middle aged obese women 8 developed CVD compared to non-obese middle aged women with p value of 0.0375, p &lt;0.05. Obese patients had uncontrolled Glycosylated hemoglobin (HbA1c) more than 8 mmol/l with calculated p value of 0.0018, p&lt;0.05. Conclusion: The study revealed higher cumulative incidence of CVD, 16.15% with incidence density of 16 per 1000 persons per year with no gender difference and higher prevalence of CVD risk factors among Omani T2DM patients. Middle aged patients with no gender difference and obese women compared to non-obese women had higher incidence of CVD. Obese patients had uncontrolled HbA1c with no gender difference. Limitations: The study was retrospective in nature, and the sample recruited was a convenient sample which could cause selection bias. Recommendations: The outcomes of the study recommend the Ministry of Health, Oman, to provide GLP-1 agonists for middle-aged obese women to reduce the incidence of CVD by weight reduction and better glycemic control which is currently unavailable in the institution.

Association of rs10830963 MTNR1B and rs841853 SLC2A1 Polymorphism with Obesity on Type 2 Diabetes Patients: An Overview of Melatonin Receptor and Transporter

BACKGROUND: One of the hormones that plays a role in glucose metabolism of Type 2 Diabetes Mellitus (T2DM) is melatonin. Its genetic variation is believed to play a significant role in the pathophysiology of obese and non-obese T2DM. The role of MTNR1B (melatonin receptor coding gene) and SLC2A1 (Glucose transporter 1/GLUT 1 transporter coding gene) on the risk of obese and non-obese T2DM patients is controversial. This study aims to analyze the association between the rs10830963 MTNR1B and rs841853 SLC2A1 polymorphism to the risk of Javanese obese T2DM.METHODS: This was a cross-sectional study that involved 107 Javanese T2DM patients from primary heath care in Semarang. Furthermore, obese T2DM was defined by a body mass index (BMI) more than 25 kg/m2. The genetic variations examined were rs10830963 MTNR1B and rs841853 SLC2A1 polymorphism by PCR-RFLP methods. Blood biochemistry parameters were also examined. Allele and genotype frequencies of rs10830963 MTNR1B and rs841853 SLC2A1 polymorphisms were analyzed using the x2 test with p≤0.05 and 95% CI.RESULTS: There was a significant association between rs10830963 MTNR1B polymorphisms in obese and nonobese T2DM (p=0.044) and the CG genotype increased the risk of obese T2DM. Furthermore, the allele and genotype frequency of rs841853 SLC2A1 polymorphism in both group had no significant difference, with a p=0.756 and p=0.802, respectively. There was also no significant difference in the biochemical parameters' in both groups of the two genetic variants studied.CONCLUSION: The rs10830963 MTNR1B polymorphism is associated with the risk of obesity in Javanese T2DM patients but not for the rs841853 SLC2A1 polymorphism.KEYWORDS: polymorphism, MTNR1B, SLC2A1, obese, diabetes mellitus

A framework to decipher the genetic architecture of combinations of complex diseases: applications in cardiovascular medicine.

Currently, most genome-wide association studies (GWAS) are studies of a single disease against controls. However, an individual is often affected by more than one condition. For example, coronary artery disease (CAD) is often comorbid with type 2 diabetes mellitus (T2DM). Similarly, it is clinically meaningful to study patients with one disease but without a related comorbidity. For example, obese T2DM may have different pathophysiology from nonobese T2DM. We developed a statistical framework (CombGWAS) to uncover susceptibility variants for comorbid disorders (or a disorder without comorbidity), using GWAS summary statistics only. In essence, we mimicked a case-control GWAS in which the cases are affected with comorbidities or a disease without comorbidity. We extended our methodology to analyze continuous traits with clinically meaningful categories (e.g. lipids), and combination of more than two traits. We verified the feasibility and validity of our method by applying it to simulated scenarios and four cardiometabolic (CM) traits. In total, we identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 CM disease 'subtypes' without a relevant comorbidity. Genetic correlation analysis revealed that some subtypes may be biologically distinct from others. Further Mendelian randomization analysis showed differential causal effects of different subtypes to relevant complications. For example, we found that obese T2DM is causally related to increased risk of CAD (P = 2.62E-11). R code is available at: https://github.com/LiangyingYin/CombGWAS. Supplementary data are available at Bioinformatics online.

Adipose Tissue Levels of DDT as Risk Factor for Obesity and Type 2 Diabetes Mellitus.

Background:Exposure to dichlorodiphenyltrichloroethane (DDT), a potent lipophilic organochlorine pesticide, has long been linked as a risk factor for type 2 diabetes mellitus (T2DM). However, its presence in the adipose tissues of the T2DM subjects has not been explored in the Indian population, where this long-banned pesticide is still in use. The present study was conducted to evaluate the possible association of DDT and its metabolites in obese and non-obese T2DM subjects.Methods:Subjects with normal glucose tolerance (n = 50) and T2DM (n = 50) were divided into equal numbers in obese and non-obese groups. Their plasma glucose levels, HbA1c, and lipid profile were measured. The adipose tissues were collected intraoperatively, and DDT and its metabolites were measured using a gas chromatograph equipped with an electron capture detector.Results:Obese subjects, irrespective of their glycemic status, and T2DM subjects had higher concentrations of DDT. p, p’ DDT was found to increase the odds for diabetes, and o, p’ DDT for central obesity. p, p’ DDD was also strongly correlated with central obesity, glycemic parameters, and triglycerides.Conclusion:The excess deposition of p, p’ DDD, o, p’ DDT, and p, p’ DDT in obese subjects may proceed to T2DM by disrupting triglycerides and glycemic parameters.

Plasma Alarin Level and Its Influencing Factors in Obese Newly Diagnosed Type 2 Diabetes Patients.

ObjectiveTo investigate the plasma alarin level in newly diagnosed obese type 2 diabetes mellitus (T2DM) and its correlation with glucose and lipid metabolism and insulin resistance.MethodsFrom October 2018 to June 2020, 239 newly diagnosed T2DM patients were collected. According to obesity, patients were divided into T2DM obese group (n=135) and T2DM non-obese group (n =104). Gender, age, body mass index (BMI), blood lipids, blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin (FINS), plasma alarin concentration, homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment for β-cell function (HOMA-β) and other clinical data were collected and analyzed.ResultsBMI, triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), fasting blood glucose (FPG), HbA1c, FINS, plasma alarin levels and HOMA-IR in the control group, T2DM non-obese group and T2DM obese group increased sequentially, and high-density lipoprotein-cholesterol (HDL-L) and HOMA-β decreased sequentially (P<0.05). Correlation analysis results showed that plasma alarin levels in T2DM patients were positively correlated with waistline, BMI, TC, LDL-C, FPG, HbA1c, FINS and HOMA-IR (P<0.05), and negatively correlated with HDL-C and HOMA-β (P <0.05), and the correlation coefficient of T2DM obese group was significantly higher than that of T2DM non-obese group (P<0.05). Multiple linear stepwise regression analysis showed that BMI, FPG, HbA1c, HOMA-β, and HOMA-IR were independent factors related to plasma alarin levels in T2DM non-obese and T2DM obese patients, and the correlation coefficient of the T2DM obese group was significantly higher than that of the T2DM non-obese group (P <0.05).ConclusionPlasma alarin levels increase in newly diagnosed T2DM and obese T2DM patients, which are affected by TC, BMI, FPG, HbA1c, HOMA-β and HOMA-IR, and may be involved in development of T2DM.

Abstract 15634: High-fat Diet Consumption Accelerates Cardiometabolic Impairment via Deteriorating Mitochondrial Function in Non-obese Spontaneously Type 2 Diabetic Rats

Introduction: Type 2 Diabetes Mellitus (T2DM) is a complex disease which is related to genetic, environmental, and lifestyle factors. In genetically-induced T2DM rats, normal diet could induce spontaneous diabetes, and induce left ventricular (LV) dysfunction over time. However, the effect of high-fat diet (HFD) in these genetically-induced T2DM rats on the cardiometabolic changes, including LV function and cardiac mitochondrial function has rarely been investigated. Hypothesis: High-fat diet (HFD) consumption accelerates the development of T2DM and LV dysfunction by inducing mitochondrial dysfunction in genetically-induced non-obese T2DM-Spontaneously Diabetic Torii (SDT) rats. Methods: Male SDT rats (n=18/group) were divided into 2 groups to receive either normal diet (ND, 19.77% fat) or HFD (57.60% fat) for 4, 8 or 12 weeks. At each time course, cardiac function determined by echocardiography and the pressure-volume loop determined by invasive intracardiac catheterization were assessed. The heart was removed to study cardiac mitochondrial function at each time-course. Results: The body weight, food intake, and visceral fat were not different between ND and HFD rats at any times. Increased blood glucose was seen earlier at week 4 in HFD rats, but later at week 12 in ND rats. The development of LV contractile dysfunction and decreased stroke volume was observed earlier at week 8 in HFD rats, compared to ND rats and HFD rats at the baseline. Increased cardiac mitochondrial ROS production and decreased mitochondrial membrane potential (i.e. mitochondrial depolarization) was observed earlier at week 8 in HFD rats, compared to ND rats (Fig). Conclusions: High-fat diet accelerates cardiometabolic impairments via impaired cardiac mitochondrial function in genetically-induced non-obese T2DM rats.

Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats

AimsParasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic β-cell volume density (Vβ). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and Vβ and the therapeutic effects of a DPP4 inhibitor (DPP4i) and an SGLT2 inhibitor (SGLT2i) in nonobese type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats (GK) have not been investigated. Materials and methodsWe divided 5-week old male GK and Wistar rats (W) into a DPP4i-treated group (GKTe), SGLT2i-treated group (GKCa), and combination-treated group (GKCaTe). After 25 weeks, the pancreata was pathologically evaluated. ResultsVβ in GK was significantly decreased (p < 0.01 vs. W), whereas Vβ was the most well preserved in GKCaTe (p < 0.05 vs. GKTe), followed by GKTe (p < 0.05 vs. GK). The decreased amount of PNs in the islets and intraepidermal nerve fiber density (IENFD) in GK was significantly improved in the treated groups compared with GK (p < 0.05 vs. GKCa and GKTe and p < 0.01 vs. GKCaTe). PN density and IENFD were significantly correlated with Vβ (r = 0.55, p < 0.01 and r = 0.54, p < 0.01, respectively). IENFD was identified as a surrogate marker for the prediction of Vβ (cutoff value, 16.39). ConclusionsThe combination therapy of DPP4i and SGLT2i improved Vβ accompanied by PNs density and IENFD. IENFD was proportionally correlated with Vβ. Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of Vβ in nonobese T2DM.

Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus.

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans.Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests.Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples.Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.