Pathogenesis Of Type 2 Diabetes Mellitus Research Articles

Transversion and transition mutations of interleukin-6 gene -174 (G/C) in patients with type-2 diabetes mellitus

IL-6 is a cytokine that has essential effects on the regulation of immune system in addition to its effects on non-immune events in cellular and histological levels outside immune system. In the last decade, there was a lot of evidence that has shown the relationship between the pathogenesis of type-2 diabetes mellitus (T2DM) and immune-related mechanisms and factors. In the current study, we analyze the mutational changes related to polymorphisms of IL-6-174 (G/C) gene among 64 type-2 diabetic patients and 26 individuals as a control group. Patients and controls were from Wasit province in Iraq. The allele-specific PCR (ARMS-PCR) technique was used to detect the IL-6-174 (G/C) gene polymorphism (rs2243250). PCR products for IL-6-174 (G/C) and primers were prepared for sequencing analysis in order to detect mutations and alterations in IL-6-174 (G/C) gene of patients with T2DM. After alignment of product amplification of "IL-6-174 (G/C)GG,CC" or CG genotypes, there are five transversion and two transition substitution mutations in patients with diabetes mellitus. All five transversion substitution mutations are: guanine to cytosine G > C in site 4880.The two transition mutations are: adenine to guanine A > G in site 4876. We conclude that different transversion and transition mutations at IL-6-174 (G/C) gene are associated with type-2 diabetes mellitus.

Amylin as a potential link between type 2 diabetes and alzheimer disease.

Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and β-amyloid (Aβ) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aβ and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aβ interact with amylin in either the pancreas or brain of these subjects. Cytoplasmic tau and Aβ protein deposits were detected in pancreatic β cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aβ and tau in both the pancreas and hippocampus. The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.

Serum Fetuin-A and Adipsin Levels in Type II Diabetes Patients

Background: Fetuin-A is a glycoprotein known as a biomarker for diabetes risk. Adipsin or complement factor D (CFD) plays a role in glucose tolerance, and metabolism. Objectives: This study aimed to investigate the concentration of fetuin-A and adipsin in patients with type 2 diabetes mellitus (T2DM) and healthy subjects. Patients and Methods: This case–control study was carried out on 43 patients with T2DM and 41 healthy subjects. Biochemical parameters were determined. Fetuin-A and adipsin levels were measured using ELISA kits. Lipid profile and biochemical factors were measured by spectrophotometric methods. Results: The results showed a trend toward lower fetuin-A and CFD concentrations between the two groups (P < 0.05). There was a significant correlation between the levels of fetuin- A and adipsin (P < 0.0001), FBS and HbA1C (P = 0.02), FBS and creatinine (P = 0.03), and BUN (P < 0.001).There was significant differences according to biochemical levels between the two groups (P < 0.001). Conclusions: The findings suggest that fetuin-A and adipsin levels were decreased in T2DM. It seems that the result of fetuin-A and adipsin levels in the diabetes depends on numerous vague factors. Nevertheless, in comparison with published data the changes of fetuin and adipsin levels in patients with T2DM indicate a complex but not complete role of fetuin-A and adipsin in the pathogenesis of T2DM.

OXIDATIVE STRESS LEVELS ARE INCREASED IN TYPE 2 DIABETES MELLITUS AND OBESITY

Objective: The relationship between obesity, type 2 diabetes mellitus (T2DM) and oxidative stress (OS) is complex and insufficiently studied. Chronic hyperglycemia causes endothelial damage by increasing reactive oxygen species (ROS) production and decreasing the activity of antioxidant enzymes, explaining why OS is a main contributor in T2DM pathogenesis. The adipose tissue is also a source of ROS via low-grade chronic inflammation and deregulation of adipokine secretion. Thus, we aimed to evaluate OS levels in obese T2DM subjects and obese non-T2DM subjects vs. controls. Design and method: OS was measured in 20 T2DM obese patients (mean age 64.85 ± 7.74 years), 20 obese non-T2DM patients (mean age 61.30 ± 10.59 years) and 20 non-obese non-T2DM controls (mean age 64.10 ± 2.26 years). ROS were evaluated via the Free Oxygen Radical Testing (FORT; normal range: < = 2.3 mmol/L H2O2) assay. The total antioxidant capacity was measured by the Free Oxygen Radical Defense (FORD; normal range: 1.07 – 1.53 mmol/L Trolox) test. Results: T2DM obese subjects registered higher FORT (3.33 ± 0.30 vs. 3.10 ± 0.34; p = 0.017) and lower FORD (0.60 ± 0.10 vs. 0.71 ± 0.15; p = 0.008) values compared to their obese non-T2DM counterparts. Both obese T2DM subjects and obese non-T2DM subjects depicted higher FORT and lower FORD values vs. controls (p < 0.001) (Table 1). In obese T2DM subjects, FORT values correlated positively with BMI, LDL-cholesterol, total cholesterol, triglycerides, uric acid and HDL/cholesterol value and negatively with age. FORD values evolved oppositely (Table 2).Conclusions: Obese T2DM subjects recorded higher FORT and lower FORD values vs. obese non-T2DM. In both obese T2DM and obese non-T2DM subjects, OS levels were higher vs. controls. In obese T2DM subjects, ROS levels correlated positively with lipid values, BMI, uric acid and, surprisingly, negatively with age. The total antioxidant capacity evolved oppositely. The negative correlation between age and ROS levels and the positive correlation between FORD and age are paradoxical since the ageing process is associated with higher ROS and lower antioxidant values.

Opportunities and options for surrogate assessment of insulin resistance

The high prevalence of type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular diseases (CVD) determines the need for early detection and correction of key markers of cardio-metabolic risk (CMR). This prophylactic direction is closely related to metabolic syndrome (MS) based on the concept of insulin resistance (IR). At the same time, IR is the first link in the pathogenesis of T2DM and is a recognized risk factor for atherothrombosis. Therefore, early diagnosis of IR is of practical importance both for the detection of early disorders of carbohydrate metabolism (DCM) and prognosis of T2DM, and cardiological risk. Alternative indicators have been proposed for evaluating IR with the inclusion of lipid and anthropometric parameters, the diagnostic and prognostic significance of which in terms of CMR (DCM and CVD) has been evaluated in randomized clinical trials in comparison with the HOMA-IR index and clamp. The TyG index (calculated on the basis of plasma glucose and triglycerides) is consistent with the phenomenon of glucolipotoxicity with subsequent metabolic disorders in target organs. Its derivatives are proposed: TyG-WC (TyG / waist circumference) and TYG-BMI (TyG / BMI). Apply LAP indices (lipid accumulation index) and VAI (visceral obesity index), as well as TG / HDL (TG / HDL). Their ethnic and gender differences were revealed, attempts were made to calculate the cut-off points for these indices.

1725-P: Hsa-circ-000094 in Peripheral Blood Can Be Used as a Biomarker for the Diagnosis of Type 2 Diabetes

Objective: To investigate the differential expression of circRNAs in human blood, as a diagnostic marker for type 2 diabetes mellitus (T2DM) and to explore the mechanism of action of circRNA on miRNA and its target genes. Methods: Circular RNA microarrays were performed to identify T2DM-related circRNAs. qPCR assays were performed to detect circRNA expression pattern in clinical samples. TargetScan and miRBase program was used to predict circRNA/miRNA interaction. Dual luciferase reporter gene assay to detect the mechanism of action of circRNA on miRNA.A total of 1,439 up-regulated expressed circRNAs were found in microarray analysis. Nine of the carcRNAs were selected by qPCR in pre-research.Blood collected from normal people(NC, N=20), prediabetes(pre-DM, n=20) and T2DM(DM, N=20) for qPCR test. Results: The results showed that the difference expression of hsa-circ-000094 among the nine circRNAs were the most obvious in the three groups, the area under the maximum curve was found by ROC curve analysis, Spre-DM =0.8025 (95% CI, 0.6655-0.9395, p=0.001); ST2DM=0.77(95% CI,0.624-0.916, p=0.003). In order to verify the clinical diagnostic ability of hsa-circ-000094, the sample were expanded to 60 in each three groups. The results showed that the expression of hsa-circ-000094 in the three groups were different, the difference and ROC curve analysis were statistically significant, Spre-DM =0.6733 (95% CI, 0.5757-0.7710, P&amp;lt;0.001);ST2DM=0.7231 (95% CI,0.6327-0.8134, P&amp;lt;0.001). The results of Dual luciferase reporter gene assay showed that the fluorescence activity was reduced by about 40% after transfection of hsa-circ-000094 WT and hsa-miR-370-5p mimic into cells. It suggests that hsa-circ-000094 acted as miR-370 sponge to inhabit miR-370 activity. Conclusions: CircRNAs are involved in T2DM pathogenesis, and thus serve as a potential biomarkers of T2DM diagnosis. Disclosure C. Zhu: None. L. Wei: None. Y. Xiao: None. Funding National Natural Science Foundation of China (81500615)

2490-PUB: The Relationship between Circulatory Levels of Fractalkine, Omentin, and the Mass of Adipose Tissue and Their Role in the Pathogenesis of Diabetes Mellitus Type 2

Objective: To examine the extent to which circulating levels of omentin and fractalkine are dependent on the degree of adipose tissue accumulation, waist circumference, plasma insulin and НО??-IR in representatives of Ukrainian population. Materials and Methods: 250 individuals mean age of 65.48±11.86 years were examined; waist circumference was measured; adipose tissue mass was assessed by bio-impedance with relative body weight. Content of insulin, blood fractalkine and omentin were determined by immune enzyme method and НО??-IR index was calculated. Results: There was an inverse correlation between blood fractalkine and omentin levels(r = -0.863, p&amp;lt;0.001). Blood fractalkine level correlates positively with adipose mass of the body(r=0.5341, p&amp;lt;0.001)); waist circumference- (r =0.4542, p&amp;lt;0.001); insulinemia (r =0.7798, p&amp;lt;0.001) and НО??-IR levels (r= 0.745, p&amp;lt;0.001). Omentin level correlates negatively with adipose body mass(r = -0.609, p&amp;lt;0.001); waist circumference- (r = -0.397, p&amp;lt;0.001); insulinemia (r = -0.799, p&amp;lt;0.001) and НО??-IR levels (r = -0.7706, p&amp;lt;0.001). The data also showed that accumulation of adipose mass greater than 25% of total body mass determines an increase in blood fractalkine levels up to750 ng/mL and higher, and НО??-IR&amp;gt; 2.77 is associated with decreased omentin levels down to500 ng/mL and less. Conclusion: These data indicate strong associations, which suggest that there may be an important role for fractalkine and omentin in markers of diabetes mellitus and obesity. Disclosure O. Lavrynenko: None. N. Kravchun: None. K. Misura: None. O. Zemlianitsyna: None. I. Dunaeva: None. P. Kravchun: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None. I. Karachentsev: None.

Neuroimaging endophenotypes of type 2 diabetes mellitus: a discordant sibling pair study.

Type 2 diabetes mellitus (T2DM) is characterized by notable familial aggregation involving common variants of many genes, and its heritability leads to a high prevalence in the siblings of affected individuals compared with the general population. Endophenotypes are objective, heritable, quantitative traits that appear to reflect the genetic risk for polygenic disorders at more biologically tractable levels. Based on a sibling pair design, we aimed to find the neuroimaging endophenotypes of T2DM and investigate the role of inherent neurological disorders in the pathogenesis and deterioration of T2DM. Twenty-six pairs of diagnosed T2DM patients with unaffected siblings and 26 unrelated controls were included in this study. Both high-resolution structural MRI and three-dimensional pseudo-continuous arterial spin labelling (3D-pCASL) MRI data were acquired with a 3.0 T MRI system. Voxel-based morphometry (VBM) analysis was performed on the structural T1W images, and cerebral blood flow (CBF) maps were obtained. All data were processed with the SPM8 package under the MATLAB 7.6 operation environment. The T2DM patients and their unaffected siblings shared significant atrophy in the right inferior/middle temporal gyrus, and left insula, in addition to elevated CBF in the right prefrontal lobe. Several regions with abnormal CBF in siblings, including the right inferior/middle temporal gyrus, left insula, left operculum, right supramarginal gyrus, right prefrontal lobe, and bilateral anterior cingulate cortex, also presented significant atrophy in T2DM patients. The shared brain regions with grey matter (GM) loss and CBF increases may serve as neuroimaging endophenotypes of T2DM, and the regions with abnormal CBF in siblings indicate an increased risk for T2DM.

Microbiota signatures in type-2 diabetic patients with chronic kidney disease - A Pilot Study

The human microbiota is paramount for normal host physiology. Altered host-microbiome interactions are part of the pathogenesis of numerous common ailments. Currently, much emphasis is placed on the involvement of the microbiome in the pathogenesis of type-2 diabetes mellitus (T2DM), impaired glucose tolerance, and other metabolic disorders (i.e. obesity). Several studies found highly significant correlations of specific intestinal bacteria with T2DM. A better understanding of the role of the microbiome in diabetes and its complications might provide new insights in the development of new therapeutic principles.

Circulating neuromedin U levels are similar in subjects with NGT and newly diagnosed T2DM and do not correlate with insulin secretion

AimsNeuromedin U (NMU), a highly conserved peptide, is implicated in energy homeostasis and is involved in regulating insulin secretion as a decretin hormone in animals. However, there have been no reports on the relationship between NMU and type 2 diabetes mellitus (T2DM). The aim of this study was to investigate circulating NMU concentrations in healthy subjects and T2DM patients and to evaluate the association between serum NMU levels and glucose-stimulated insulin secretion. MethodsWe used ELISA to analyze NMU concentrations in blood samples from newly diagnosed T2DM patients (n = 57) and age-, sex- and BMI-matched healthy control subjects (n = 50). Anthropometric parameters, oral glucose tolerance, glycosylated hemoglobin, blood lipids, insulin sensitivity, and insulin secretion were measured. ResultsNo difference was observed in serum NMU levels between control subjects and newly diagnosed T2DM patients (p = 0.788). The oral glucose tolerance test (OGTT) results indicated that serum NMU concentrations did not change and did not correlate with insulin levels at fasting and 1 h, 2 h and 3 h after glucose load in both healthy controls and newly diagnosed T2DM patients. ConclusionCirculating NMU concentrations were similar in control subjects and newly diagnosed T2DM patients and were not associated with glucose-stimulated insulin secretion. Serum NMU is not a human decretin hormone and may not play a role in the pathogenesis of T2DM.

SUN-156 Exosomal MicroRNA Profile in Korean Obese Subjects with Prediabetes and Those with Type 2 Diabetes Mellitus

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Recent evidence has shown that altered expression of miRNAs is associated with various pathophysiological processes, including type 2 diabetes mellitus (T2DM), cancer and other metabolic diseases. Circulating miRNAs are packaged inside exosomes, microvesicles of 20-150 nm, which are known to transfer miRNAs between cells. In this study, we aimed to compare exosomal miRNA profile between Korean obese subjects with prediabetes and those with T2DM.Sixteen subjects with prediabetes (mean A1c 5.8%, body-mass index [BMI] 39.9 ± 4.7 kg/m2) and 13 subjects with T2DM (mean A1c 7.1%, BMI 38.0 ± 6.4 kg/m2) were participated in our study. We measured circulating levels of exosomal miRNAs by next generation sequencing (NGS) and compared miRNA levels between the two groups.NGS has shown similar expression patterns of exosomal miRNAs between prediabetes and T2DM. However, we have identified more than 20 miRNAs which were differentially expressed (fold change > 2.0 or < -2.0) between the two groups. Whereas expression of miR-4792, miR-4485-5p, miR-6739-5p was significantly increased, expression of miR-199b-5p, miR-33a-5p, miR-424-5p was decreased in subjects with T2DM compared to those with prediabetes. In addition, expression of miR-6751-3p found to be decreased in subjects with prediabetes compared to non-obese controls was further decreased in those with T2DM.We have found the differential expression profile of circulating exosomal miRNAs between Korean obese subjects with prediabetes and those with T2DM. Further extensive studies will help identify the possible role of exosomal miRNAs on the pathogenesis of T2DM in obesity.

Boolean network modeling of \u03b2-cell apoptosis and insulin resistance in type 2 diabetes mellitus

BackgroundMajor alteration in lifestyle of human population has promoted Type 2 diabetes mellitus (T2DM) to the level of an epidemic. This metabolic disorder is characterized by insulin resistance and pancreatic β-cell dysfunction and apoptosis, triggered by endoplasmic reticulum (ER) stress, oxidative stress and cytokines. Computational modeling is necessary to consolidate information from various sources in order to obtain a comprehensive understanding of the pathogenesis of T2DM and to investigate possible interventions by performing in silico simulations.ResultsIn this paper, we propose a Boolean network model integrating the insulin resistance pathway with pancreatic β-cell apoptosis pathway which are responsible for T2DM. The model has five input signals, i.e. ER stress, oxidative stress, tumor necrosis factor α (TNF α), Fas ligand (FasL), and interleukin-6 (IL-6). We performed dynamical simulations using random order asynchronous update and with different combinations of the input signals. From the results, we observed that the proposed model made predictions that closely resemble the expression levels of genes in T2DM as reported in the literature.ConclusionThe proposed model can make predictions about expression levels of genes in T2DM that are in concordance with literature. Although experimental validation of the model is beyond the scope of this study, the model can be useful for understanding the aetiology of T2DM and discovery of therapeutic intervention for this prevalent complex disease. The files of our model and results are available at https://github.com/JieZheng-ShanghaiTech/boolean-t2dm.

Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome.

Individuals widely use non-nutritive sweeteners (NNS) in attempts to lower their overall daily caloric intake, lose weight, and sustain a healthy diet. There are insufficient scientific data that support the safety of consuming NNS. However, recent studies have suggested that NNS consumption can induce gut microbiota dysbiosis and promote glucose intolerance in healthy individuals that may result in the development of type 2 diabetes mellitus (T2DM). This sequence of events may result in changes in the gut microbiota composition through microRNA (miRNA)-mediated changes. The mechanism(s) by which miRNAs alter gene expression of different bacterial species provides a link between the consumption of NNS and the development of metabolic changes. Another potential mechanism that connects NNS to metabolic changes is the molecular crosstalk between the insulin receptor (IR) and G protein-coupled receptors (GPCRs). Here, we aim to highlight the role of NNS in obesity and discuss IR-GPCR crosstalk and miRNA-mediated changes, in the manipulation of the gut microbiota composition and T2DM pathogenesis.

Serum CCN3 levels are increased in type 2 diabetes mellitus and associated with obesity, insulin resistance and inflammation

BackgroudCCN3 is a novel adipokine and has emerged as a potential metabolic regulator. However, information regarding the role of CCN3 in type 2 diabetes mellitus (T2DM) remains unclear. This study measured for the first time serum CCN3 levels in T2DM and explored the correlations between its serum levels and various metabolic parameters in humans. MethodsA total of 219 newly diagnosed T2DM (nT2DM) patients and 205 healthy control subjects, matched for age and sex ratio, were enrolled. Circulating CCN3 and TNF-α, IL-6 and MCP-1 were measured by ELISA. The anthropometric assessment and biochemical evaluation were done in all subjects. OGTT were performed in 34 healthy individuals to investigate the association of CCN3 with glucose. ResultsSerum CCN3 levels were significantly higher in nT2DM patients compared to those of the healthy controls (6.71[4.88, 8.56] vs. 4.51[3.55, 5.99] ng/ml, P < 0.01). Serum CCN3 positively correlated with BMI, WC, FAT%, TG, FPG, 2 h-PG, HbA1c, FIns, HOMA-IR, hs-CRP and TNF-α, IL-6 and MCP-1, but negatively with HOMA-β in all individuals (P < 0.05). Multiple linear regression analysis indicated that BMI, HOMA-IR, TNF-α and MCP-1 were independently associated with CCN3. Multivariate logistic regression analysis demonstrated that CCN3 was correlated with nT2DM. Finally, area under ROC curve of CCN3 (gender and age adjusted) for predicting the presence of nT2DM was 0.725(95% CI: 0.676–0.773). After an oral glucose challenge, there was no obvious change in the circulating levels of CCN3 as compared to 0 min (P > 0.05). ConclusionsElevation of CCN3 in nT2DM supports the hypothesis that CCN3 may serve as a risk factor associated with the pathogenesis of T2DM.

The reconstructed natural history of type 1 diabetes mellitus.

The causes of type 1 diabetes mellitus (T1DM) are unclear; however, a general consensus exists that T1DM is a T cell-mediated autoimmune disease characterized by the selective destruction of insulin-secreting β-cells. Now, two imaging mass cytometry studies of human pancreatic tissue illuminate new biology in the pathogenesis of T1DM.

Comparison of gene expression in cynomolgus monkeys with preclinical type II diabetes induced by different high energy diets.

BackgroundCynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus (T2DM) were established by feeding middle‐aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes‐related genes.MethodsA total of 36 male monkeys were randomly divided into four groups and fed human diets with high sugar, high fat, double high sugar and fat, and a normal diet. The preclinical diabetes phase was determined by monitoring the metabolic characteristic indices and the results of oral glucose tolerance tests (OGTT). The mRNA expression of 45 diabetes‐related genes in peripheral blood leukocytes was analyzed using real‐time PCR.ResultsA total of 22, 25, and 21 genes were significantly up‐regulated (P < 0.05) and 5, 7, and 5 genes were significantly down‐regulated (P < 0.05) in the above three induced groups, respectively, compared with the control group. Of the 45 tested genes, the expression profiles of 21 genes were consistent. Most of the expression levels in the double high sugar‐and‐fat individuals were slightly lower than those in the high glucose and high fat groups, although the expression patterns of the three groups were essentially similar.ConclusionThe different high energy diets all induced diabetes and shared some phenotypic properties with human T2DM. Most of the expression patterns of the related genes were identical. The gene expression profiles could be used as references for the study of early diagnostic indicators and T2DM pathogenesis.

Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis.

Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis. Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays. Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker. Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.

Apoptosis and proliferation ofperipheral blood T-cells as alternative processes in pathogenesis of diabetes mellitus type 1

Apoptosis, along with proliferation, is a form of lymphocyte response to activating stimuli. In the early stages of cell differentiation, the apoptotic response prevails and it results to the formation of tolerance to inductor antigen. Mature lymphocytes proliferate in response to stimulation and it means the initial stage in the development of the immune response. Since in this case apoptosis and proliferation acts as alternative processes, their ratio can serve as a measure of the effectiveness of the cellular response to activating signals. The resistance of autoreactive T-cells to apoptosis is the main key point in the development of type 1 diabetes mellitus (T1DM). Autoreactive T-cells migrates from the bloodstream to the islet tissue of the pancreas and take an active part in b cells destruction. The resistance of autoreactive effector T-cells to apoptosis may suggest their high proliferative potential. Therefore, the comparative evaluation of apoptosis and proliferation of peripheral blood lymphocytes can give a more complete picture of their functional state and thus will help to reveal the causes of ineffective peripheral blood T-ceiis apoptosis in patients with T1DM and will help to understand more deeply the pathogenesis of the disease. in this article, the features of proliferative response of peripheral blood T-cells in patients with T1DM and in individuals with high risk of developing T1DM have been studied. Apoptosis of T-cell subpopulations has been investigated. The correlation between the apoptotic markers and the intensity of spontaneous and activation- induced in vitro T-cells proliferation of was revealed. it was determined, that autoreactive peripheral blood T-cells were resistant to apoptosis and demonstrated the increased proliferative potential in patients with T1DM and in individuals with high risk of developing T1DM.

DNA Methylation Markers of Type 2 Diabetes Mellitus Among Male Veterans With or Without Human Immunodeficiency Virus Infection.

Epigenetic modifications such as DNA methylation are associated with both human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM). We investigated epigenetic associations with T2DM according to HIV infection status and assessed interaction effects among 681 male participants of the Veterans Aging Cohort Study. Methylation at previously reported sites, cg1963031 (TXNIP), cg18181703 (SOCS3), and cg09152259 (PROC), was significantly associated with T2DM in HIV-infected individuals. We identified 3 novel associations with suggestive statistical significance: cg1231141 (ADAMTS2), cg19534769 (HGFAC), and cg13163919 (TLE3). Suggestive interaction with HIV infection status was found at cg17862404 (TSC22D1). The implicated genes are involved in inflammation, pancreatic β-cell function, and T2DM pathogenesis.

Advanced Glycation End Products Enhance M1 Macrophage Polarization by Activating the MAPK Pathway

Background: β-cell dysfunction is one of the core pathogenetic mechanisms of type 2 diabetes mellitus (T2DM). However, there are currently no effective therapeutic strategies to preserve β-cell mass and function. The role of islet macrophage phenotype reprogramming in β-cell dysfunction has attracted great attention. Given that advanced glycation end products (AGEs) are major pathogenic factors in T2DM, we investigated the effect of AGEs on macrophage activation and their role in β-cell dysfunction. Method: We examined cytokine secretion, M1 and M2 macrophage-associated marker expression and MAPK phosphorylation levels in AGEs-stimulated macrophages. MIN6 cells were cocultured with AGEs-pretreated macrophages to study the effect of AGEs-induced macrophage activation on β-cell dysfunction. Findings: We found that AGEs treatment significantly enhanced macrophage secretion of proinflammatory cytokines. The expression of M1 macrophage markers, such as iNOS, ROS and the surface marker CD11c, was significantly upregulated, whereas the expression of M2 macrophage markers, such as Arg1 and CD206, was reciprocally downregulated upon AGEs stimulation. Coculture with AGEs-pretreated macrophages significantly inhibited the expression of genes involved in β-cell function and was accompanied by the impairment of glucose-stimulated insulin secretion (GSIS) in MIN6 cells. In addition, AGEs treatment predominantly activated the MAPK pathway, and the inhibition of the MAPK pathway partially attenuated the AGEs-induced polarization of macrophages. Interpretation: AGEs enhance the expression of proinflammatory molecules by activating the MAPK pathway. Moreover, these data imply that AGEs induce macrophage M1 phenotype polarization but restrain M2 polarization, which might contribute to β-cell dysfunction in the pathogenesis of T2DM. Funding Statement: This study was supported by National Natural Science Foundation of China (81670743, 81970669), Shanghai Municipal Health Commission (201740173) and Shanghai Sailing Program(18YF1415800). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Not required.