Pathogenesis Of Type 2 Diabetes Mellitus Research Articles

Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus.

Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.

Establishment of type 2 diabetes mellitus models using streptozotocin after 3 months high-fat diet in Bama minipigs

In the past twenty years, the number of adults with diabetes has tripled. Most studies have been conducted using rodent models of type 2 diabetes mellitus (T2DM), and the developed drugs have low clinical conversion efficiency. Therefore, it is urgent to establish a more human-like large animal model to explore T2DM pathogenesis and formulate new disease prevention and control strategies. This study was designed to establish and validate a T2DM model using minipigs fed a high-fat or high-cholesterol/high-fat diet and injected with low-dose streptozotocin (STZ). We examined the influence of the STZ injection timing with a diet high in fat (HFD) compared with one high in cholesterol and fat (HCFD) on the atherosclerotic lesions accelerated by T2DM. Male Bama minipigs (n = 24) were randomly divided into five groups. The control group was fed a normal diet for 9 months. The STZ + HFD and STZ + HCFD groups were infused with 90 mg/kg STZ and then fed a high-fat diet or high-cholesterol and high-fat diet for 9 months, respectively. The HFD + STZ and HCFD + STZ groups were fed a high-fat diet or a high-cholesterol and high-fat diet, respectively, for 9 months (after 3 months, these pigs were injected intravenously with 90 mg/kg STZ). During the induction period, animal body weight, BMI, and serum GLU, INS, TG, TC, HDL-C, LDL-C, FFA, ALT, AST, CRE, and BUN were detected monthly intervals. IVGTT and insulin release tests were performed at 3-month intervals. At the end of the test, the coronary artery and abdominal aorta were examined by computed tomography and pathological observations, and the thickness of the basement membrane of the capillary of the retina and kidney glomerulus was measured under a transmission electron microscope. The serum glucose concentrations were normal in all groups except the HFD + STZ and HCFD + STZ groups. Animals fed an HFD for 9 months did not develop apparent atherosclerotic lesions, but atherosclerotic lesions were seen in the animals fed an HCFD. Hyperglycemia accelerated the formation of atherosclerotic lesions on the intimal surface of the abdominal aorta. Low-dose STZ after 3 months of HFD or HCFD successfully established a T2DM model in minipigs. The HFD did not induce apparent atherosclerotic lesions, but these were seen with the HCFD. Hyperglycemia accelerated atherosclerosis in the minipigs.

The Role of Nutritional Factors in the Modulation of the Composition of the Gut Microbiota in People with Autoimmune Diabetes.

Type 1 diabetes mellitus (T1DM) is a disease marked by oxidative stress, chronic inflammation, and the presence of autoantibodies. The gut microbiota has been shown to be involved in the alleviation of oxidative stress and inflammation as well as strengthening immunity, thus its’ possible involvement in the pathogenesis of T1DM has been highlighted. The goal of the present study is to analyze information on the relationship between the structure of the intestinal microbiome and the occurrence of T1DM. The modification of the intestinal microbiota can increase the proportion of SCFA-producing bacteria, which could in turn be effective in the prevention and/or treatment of T1DM. The increased daily intake of soluble and non-soluble fibers, as well as the inclusion of pro-biotics, prebiotics, herbs, spices, and teas that are sources of phytobiotics, in the diet, could be important in improving the composition and activity of the microbiota and thus in the prevention of metabolic disorders. Understanding how the microbiota interacts with immune cells to create immune tolerance could enable the development of new therapeutic strategies for T1DM and improve the quality of life of people with T1DM.

Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice.

Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age-dependent impairment of glucose tolerance and glucose-stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80-positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP-1 and TNF-α), part of the senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 β-cells to MGO confirms its casual role on β-cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.

Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson's Disease: Insights into Mechanisms and Pathological Consequences.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemic conditions. A higher risk of developing Parkinson's disease (PD) in patients with T2DM has become evident in recent years. However, the molecular mechanisms underlying the interplay between T2DM and PD pathogenesis remain unknown. Nevertheless, emerging epidemiological studies have demonstrated many common molecular pathways that play an essential role in regulating normal cellular functioning are independently implicated in the progression and etiopathogenesis of T2DM and PD. This review summarizes some common shared pathophysiological mechanisms, including insulin resistance, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), autophagy, and the ubiquitin-proteasome system (UPS) that independently mediate the onset and etiopathogenesis of T2DM and PD. In this review, we summarize the studies that have reported the relationship between T2DM and PD. This review will provide insights into the common involvement of molecular pathways that may provide alternative treatment strategies for both T2DM and PD.

Characterization of lncRNA Profiles of Plasma-Derived Exosomes From Type 1 Diabetes Mellitus.

BackgroundsExosomes contain several types of transcripts, including long non-coding RNAs (lncRNAs), and have been shown to exert important effects in human diseases. However, the roles of exosomal lncRNAs in type 1 diabetes mellitus (T1DM) have not been well investigated. In the present study, we characterized the plasma-derived exosomal lncRNAs expression profiles of T1DM and predict their potential function in the pathogenesis of T1DM.Material and MethodsExosomal lncRNA expression profiles were detected by Illumina Hiseq platform (T1DM subjects N=10; age-, sex- matched Control subjects N=10). Six exosomal lncRNAs were selected to validate their expression level by using quantitative real-time PCR (qRT-PCR) (T1DM subjects N=30; age-, sex- matched Control subjects N=30). Bioinformatics analysis approaches were carried out to explore the potential biological function of differentially expressed lncRNAs.ResultsA total of 162 differentially expressed exosomal lncRNAs were identified in T1DM patients compared with control subjects, among which 77 up-regulated and 85 down-regulated. The expression level of the selected six lncRNAs didn’t show significant difference in the following qRT-PCR analysis. Gene Ontology analysis enriched terms such as activation of phospholipase D activity, neuronal cell body membrane, and calcium sensitive guanylate cyclase activator activity for cis-acting genes of lncRNAs, and metal ion binding for trans-acting genes. The most enriched Kyoto Encyclopedia of Genes and Genomes pathways for the lncRNAs were associated with oxidative phosphorylation and Parkinson’s disease for cis-acting genes, and pathways in cancer as well as focal adhesion for trans-acting genes.ConclusionsThis study characterized the lncRNA profiles of plasma-derived exosomes from T1DM for the first time and these results highlighted the potential role of exosomal lncRNAs in T1DM pathogenesis. A better understanding of exosomal lncRNA profiling will provide novel insights into its molecular mechanisms.

Pathophysiology, phenotypes and management of type 2 diabetes mellitus in Indian and Chinese populations.

Nearly half of all adults with type 2 diabetes mellitus (T2DM) live in India and China. These populations have an underlying predisposition to deficient insulin secretion, which has a key role in the pathogenesis of T2DM. Indian and Chinese people might be more susceptible to hepatic or skeletal muscle insulin resistance, respectively, than other populations, resulting in specific forms of insulin deficiency. Cluster-based phenotypic analyses demonstrate a higher frequency of severe insulin-deficient diabetes mellitus and younger ages at diagnosis, lower β-cell function, lower insulin resistance and lower BMI among Indian and Chinese people compared with European people. Individuals diagnosed earliest in life have the most aggressive course of disease and the highest risk of complications. These characteristics might contribute to distinctive responses to glucose-lowering medications. Incretin-based agents are particularly effective for lowering glucose levels in these populations; they enhance incretin-augmented insulin secretion and suppress glucagon secretion. Sodium–glucose cotransporter 2 inhibitors might also lower blood levels of glucose especially effectively among Asian people, while α-glucosidase inhibitors are better tolerated in east Asian populations versus other populations. Further research is needed to better characterize and address the pathophysiology and phenotypes of T2DM in Indian and Chinese populations, and to further develop individualized treatment strategies.

Protein N-glycosylation aberrations and glycoproteomic network alterations in osteoarthritis and osteoarthritis with type 2 diabetes

Whether the relationship between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) can be solely attributed to the shared risk factors, such as obesity, remains controversial. Several studies have revealed the critical role of abnormal glycosylation in the pathogenesis of OA and T2DM. Therefore, we speculate that T2DM may contribute to the pathogenesis of OA through the intrinsic mechanisms of N-glycosylation aberrations. Using N-glycoproteomics, we compared the changes in N-glycosylated protein abundance in cartilage samples from patients with OA without and with T2DM (DM-OA), and from patients with traumatic joint injury (NC) as controls. We identified 847 N-glycosylation sites corresponding to 729 peptides fragments from 374 proteins. The number of N-glycosylated proteins in the DM-OA group tended to decrease compared with that in the OA and NC groups. We identified 22 upregulated and 1 down-regulated N-glycosylated peptides in the OA group compared to the NC group, while only fibronectin 1 (FN1) at position N1007, cartilage intermediate layer protein 1 (CILP) at N346, and collagen type VI alpha 1 chain (COL6A1) at N804, were also identified in the DM-OA group. Compared to the OA group, the downregulation of secreted protein acidic and rich in cysteine (SPARC) at N116, collagen type VI alpha 1 chain (COL6A2) at N785, and asporin (ASPN) at N282, and the upregulation of complement component C8 alpha chain (C8α) at N437, were the most remarkable alterations in the DM-OA group. The differentially expressed N-glycosylated proteins between the OA and DM-OA groups were mainly located extracellularly and enriched in the KEGG pathways involving PI3K/Akt signaling, focal adhesion, and ECM-receptor interaction. Their predicted protein–protein interactions were also depicted. We were thus able to show the general characteristics of N-glycosylation aberrations in OA and DM-OA. Moreover, the upregulated glycosylated complement C8α in the DM-OA group might augment membrane attack complex activity, thereby exacerbating cartilage destruction. Although further confirmation is required, our hypothesis proposes a possible explanation for the deduction that T2DM is an independent risk factor for OA.

Loneliness and its Relationship with Diabetes Mellitus

Loneliness is highly prevalent globally and has been noted in all age groups. Loneliness is associated with significant physical and mental health risks. These individuals have a poor quality of life. Lonely individuals also demonstrate a high mortality rate and incur more health care costs. Type 2 diabetes mellitus (T2DM). a common chronic disease. Worldwide, it is expected to affect 629 individuals in 2045. Several studies have established an incriminating role of loneliness in the pathogenesis and progression of T2DM. It is estimated that the risk of developing a high HbA1c is almost fivefold in lonely people. This increased risk is independent of other confounding factors. Although increased inflammation and reduced immunity play a role, the main mechanism appears to be an increase in the hypothalamic-pituitary adrenocortical activity. Loneliness also increases unhealthy lifestyles, which also contribute to this deleterious loneliness-diabetes link. Lonely people are also more burdened with chronic diseases, which further increase the diabetic risk and its worsening. They also tend to be more non-adherent to healthcare recommendations. On the other hand, diabetic patients face a multitude of issues with daily living and healthcare, and these tend to increase loneliness. The causative factors and their mechanisms underlying this bidirectional relationship between loneliness and T2DM is narratively reviewed in this manuscript.

Identification of Key Genes and Pathways in Peripheral Blood Mononuclear Cells of Type 1 Diabetes Mellitus by Integrated Bioinformatics Analysis.

Background The onset and progression of type 1 diabetes mellitus (T1DM) is closely related to autoimmunity. Effective monitoring of the immune system and developing targeted therapies are frontier fields in T1DM treatment. Currently, the most available tissue that reflects the immune system is peripheral blood mononuclear cells (PBMCs). Thus, the aim of this study was to identify key PBMC biomarkers of T1DM.Methods Common differentially expressed genes (DEGs) were screened from the Gene Expression Omnibus (GEO) datasets GSE9006, GSE72377, and GSE55098, and PBMC mRNA expression in T1DM patients was compared with that in healthy participants by GEO2R. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses of DEGs were performed using the Cytoscape, DAVID, and STRING databases. The vital hub genes were validated by reverse transcription-polymerase chain reaction using clinical samples. The disease-gene-drug interaction network was built using the Comparative Toxicogenomics Database (CTD) and Drug Gene Interaction Database (DGIdb).Results We found that various biological functions or pathways related to the immune system and glucose metabolism changed in PBMCs from T1DM patients. In the PPI network, the DEGs of module 1 were significantly enriched in processes including inflammatory and immune responses and in pathways of proteoglycans in cancer. Moreover, we focused on four vital hub genes, namely, chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine ligand 1 (CXCL1), matrix metallopeptidase 9 (MMP9), and granzyme B (GZMB), and confirmed them in clinical PBMC samples. Furthermore, the disease-gene-drug interaction network revealed the potential of key genes as reference markers in T1DM.Conclusion These results provide new insight into T1DM pathogenesis and novel biomarkers that could be widely representative reference indicators or potential therapeutic targets for clinical applications.

IDF21-0185 Prevalence of autoimmune diseases in young patients with type 1 diabetes

Background: Autoimmunity and viral infections are the main etiopathological factors implicated in the pathogenesis of T1DM on the background of genetic predisposition. Type 1 diabetes mellitus (T1DM) is associated with various autoimmune disorders like celiac disease, thyroid disorder, adrenal failure, etc. However, how common is this association in Indian children is not clearly known. Aim: This cross-sectional study was planned to investigate the prevalence of autoimmune disorders like autoimmune thyroid disorders, celiac disease, and other autoimmune disorders in T1DM. Method: In this cross-sectional study, patients requiring insulin and ketosis-prone diabetic and with history of diabetic ketoacidosis/undetectable fasting C-peptide levels were included. Beside demographic and clinical data, detailed biochemistry evaluations were performed. Celiac disease was diagnosed as per the ESPGHAN diagnostic criteria. ACTH stimulation test was done to confirm the adrenal insufficiency in patients with basal serum cortisol <5 μg/dL. Thyroid function test (TSH) and anti-TPO antibody were assessed in all patients. Screening for other autoimmune disorders was done only when clinically indicated or symptoms or family history was suggestive of presence of such disorder. Results: Among 200 patients enrolled, 65% were males and mean age was 12.37 ± 3.34 years. Mean age at diagnosis of T1DM was 10.1 ± 3.58 years and duration of diabetes was 3.52 ± 3.21 years. The prevalence of antibodies positive against autoimmune diseases was anti-tTG IgA (21%), anti-TPO (34%), anti-CCP ab (1.5%), and ANA (0.8%). Significantly higher proportion of females had raised anti-TPO antibodies than males (48.1% vs. 26.4%, P = 0.005). Celiac disease was most common association (25.4%) followed by hypothyroidism (13.8%) and Grave's disease (3.2%). Significantly higher proportion of females had hypothyroidism than males (26.1% vs. 8.6%, respectively, P = 0.006). Prevalence of raised anti-tTG and anti-TPO did not differ significantly by the age (P = 0.841 and P = 0.067) or duration of T1DM (P = 0.493 and P = 0.399). Discussion: In this part of country, celiac disease, hypothyroidism, and Graves's disease are common associations in children with T1DM. This study also emphasizes the importance of total IgA estimation and duodenal biopsy in IgA anti-tTG-negative patients having strong suspicion of celiac disease on the basis of history. This study reinforces a call to improve the quality of healthcare services, including implementation of universal screening for thyroid dysfunction and celiac disease in children with T1DM.

The Impact of Intestinal Microorganisms and Their Metabolites on Type 1 Diabetes Mellitus.

BackgroundType 1 diabetes mellitus (T1DM) is an autoimmune disease with a complex etiology comprising numerous genetic and environmental factors; however, many of the mechanisms underlying disease development remain unclear. Nevertheless, a critical role has recently been assigned to intestinal microorganisms in T1DM disease pathogenesis. In particular, a decrease in intestinal microbial diversity, increase in intestinal permeability, and the translocation of intestinal bacteria to the pancreas have been reported in patients and animal models with T1DM. Moreover, intestinal microbial metabolites differ between healthy individuals and patients with T1DM. Specifically, short-chain fatty acid (SCFA) production, which contributes to intestinal barrier integrity and immune response regulation, is significantly reduced in patients with T1DM. Considering this correlation between intestinal microorganisms and T1DM, many studies have investigated the potential of intestinal microbiota in preventive and therapeutic strategies for T1DM.ObjectiveThe aim of this review is to provide further support for the notion that intestinal microbiota contributes to the regulation of T1DM occurrence and development. In particular, this article reviews the involvement of the intestinal microbiota and the associated metabolites in T1DM pathogenesis, as well as recent studies on the involvement of the intestinal microbiota in T1DM prevention and treatment.ConclusionIntestinal microbes and their metabolites contribute to T1DM occurrence and development and may become a potential target for novel therapeutics.

IDF21-0426 Carbamylated LDL and soluble LOX-1 – potential serum biomarkers for coronary artery disease in type 2 diabetes mellitus

Background: Carbamylated low-density lipoprotein (cLDL) is the most abundant modified LDL isoform in human blood, but it has been investigated only in the context of chronic kidney disease since uremia provides a favourable chemical environment for this posttranslational modification. However, it has been discovered that the proinflammatory enzyme myeloperoxidase catalyses an alternative urea-independent mechanism of carbamylation. Most of the proatherogenic properties of cLDL are mediated by the scavenger lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 has been delineated as a critical player in vascular inflammation and in atherosclerotic plaque formation, destabilization, erosion and rupture. The cLDL-LOX-1 interaction triggers prooxidative and proinflammatory responses. Moreover, LOX-1 has also been identified as a receptor for C-reactive protein (CRP), a classic acute-phase reactant widely used in the clinical practice as a cardiovascular risk biomarker. The soluble form of LOX-1 (sLOX-1) reflects the expression of the membrane receptor and it has recently been suggested as a biomarker of vascular diseases. It is well-established that type 2 diabetes mellitus (T2DM) is a prominent risk factor for coronary artery disease (CAD) and inflammation is involved in the pathogenesis of both T2DM and atherosclerosis. However, the possible role and relationships between cLDL, sLOX-1 and CRP in T2DM with and without CAD have not been investigated yet. Aim: To explore the possible role of cLDL and sLOX-1 as potential biomarkers for CAD in T2DM patients and to evaluate the correlations between serum cLDL, sLOX-1 and high-sensitivity-CRP (hs-CRP). Method: The serum levels of cLDL, sLOX-1 and hs-CRP were measured by ELISA in 44 heathy controls, 67 patients with uncomplicated T2DM and 36 diabetic subjects complicated by CAD but without renal impairments. Results: Patients with uncomplicated T2DM had significantly higher serum levels of both cLDL and hs-CRP than the healthy controls, but lower in comparison to T2DM + CAD subjects. In contrast, there was no significant difference in sLOX-1 concentrations between T2DM patient and the healthy volunteers, but T2DM + CAD cohort had higher serum levels of sLOX-1 compared both to the control and uncomplicated T2DM groups. The receiver-operating characteristic analysis showed that cLDL and sLOX-1 had a significant potential to identify CAD among the diabetic patients with diagnostic sensitivity and specificity similar to those of hs-CRP. Elevated serum levels of cLDL and sLOX-1 were associated with a higher risk of CAD development among T2DM subjects (OR 4.07; 95% CI: 1.71 – 9.69, p = 0.001 and OR 2.82; 95% CI: 1.22 – 6.57, p = 0.014, respectively). Furthermore, the level of cLDL correlated positively and significantly with hs-CRP(r = 0.345, p = 0.039) and tended to correlate positively with sLOX-1 (r = 0.317, p = 0.059) only in T2DM + CAD subjects. Discussion: In conclusion, a positive feedback might exist between cLDL, CRP and LOX-1 and the interplay between them might be involved in the development of CAD in diabetic patients. The present study also elucidates the potential of cLDL and sLOX-1 as biomarkers for the diagnosis and risk assessment of CAD among T2DM population.

Identification of the Shared Gene Signatures and Biological Mechanism in Type 2 Diabetes and Pancreatic Cancer.

BackgroundThe relationship between pancreatic cancer (PC) and type 2 diabetes mellitus (T2DM) has long been widely recognized, but the interaction mechanisms are still unknown. This study was aimed to investigate the shared gene signatures and molecular processes between PC and T2DM.MethodsThe Gene Expression Omnibus (GEO) database was used to retrieve the RNA sequence and patient information of PC and T2DM. Weighted gene co-expression network analysis (WGCNA) was performed to discover a co-expression network associated with PC and T2DM. Enrichment analysis of shared genes present in PC and T2DM was performed by ClueGO software. These results were validated in the other four cohorts based on differential gene analysis. The predictive significance of S100A6 in PC was evaluated using univariate and multivariate Cox analyses, as well as Kaplan–Meier plots. The biological process of S100A6 enrichment in PC was detected using Gene Set Enrichment Analysis (GSEA). The involvement of S100A6 in the tumor immune microenvironment (TIME) was assessed by CIBERSORT. In vitro assays were used to further confirm the function of S100A6 in PC.ResultsWGCNA recognized three major modules for T2DM and two major modules for PC. There were 44 shared genes identified for PC and T2DM, and Gene Ontology (GO) analysis showed that regulation of endodermal cell fate specification was primarily enriched. In addition, a key shared gene S100A6 was derived in the validation tests. S100A6 was shown to be highly expressed in PC compared to non-tumor tissues. PC patients with high S100A6 expression had worse overall survival (OS) than those with low expression. GSEA revealed that S100A6 is involved in cancer-related pathways and glycometabolism-related pathways. There is a strong relationship between S100A6 and TIME. In vitro functional assays showed that S100A6 helped to induce the PC cells’ proliferation and migration. We also proposed a diagram of common mechanisms of PC and T2DM.ConclusionsThis study firstly revealed that the regulation of endodermal cell fate specification may be common pathogenesis of PC and T2DM and identified S100A6 as a possible biomarker and therapeutic target for PC and T2DM patients.

Proteomic Analysis of Serum Lysine Acetylation in Uyghur Patients With T2DM

Lysine acetylation is a reversible modification process after protein translation, which plays a key regulatory role in various metabolic diseases such as diabetes. The prevalence of type 2 diabetes mellitus (T2DM) in the Uyghur population is high, but the acetylation status of proteomics in Uyghur with T2DM is still unclear. Herein, we performed a quantitative proteomic study of lysine acetylation in T2DM patients using Tandem Mass Tags (TMTs) labeling, acetylation enrichment techniques, and high-resolution liquid chromatography-tandem mass spectrometry. We quantified 422 acetylation sites on 120 proteins, of which 347 sites of 103 proteins contained quantitative information. Compared with the control, we found that a total of eight acetylated sites within proteins were significantly differentially expressed with three upregulated and five downregulated, including histones H4 and H3.3C. Meanwhile, we completed bioinformatics analysis, including protein annotation, functional classification, functional enrichment, and cluster analysis, based on functional enrichment. In addition, the mRNA (ApoB-100, histones H4 and H3.3C) and protein (histones H4 and H3.3C) levels were verified through 60 samples. Besides, we also performed histone H4 chromatin immunoprecipitation analysis at the level of INS-1 cells. These could be potentially useful markers for the prediction of prediabetes and also provided a basis for the pathogenesis of T2DM.

Association of Auto-Antigen SLC30A8 Gene Variants with Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus (T1DM), is a genetic disease, the prevalence of which is increasing due to delays in the diagnosis because of the absence of standard antibodies. Therefore, there is a need for a molecular variant that can help in early diagnosis in these patients. The polymorphism in the SLC30A8 gene can identify the people at risk of T1DM. However, there is a controversy in the association of the SLC30A8 gene in the pathogenesis of T1DM and a dearth of data in our part of the world. Therefore, we aimed to determine the most frequent autoantigen SLC30A8 genotype and its association with T1DM in the Pakistani population. This case-control study was carried out at Ziauddin Medical University (ZMU) jointly with Baqai Institute of Diabetology and Endocrinology (Baqai Medical University) from June to October 2019. A total of 50 subjects were enrolled (25 cases and 25 controls) in the study. Cases included 25 diagnosed patients of T1DM meeting American Diabetes Association (ADA) new criteria and controls were their first-degree relatives. Blood was drawn, DNA was extracted and amplified through PCR. The RFLP of PCR product was done using a restriction enzyme, Alu I for genotyping. The most frequently observed genotype was CC among cases as well as controls. The CC genotype of rs13266634 was not found significantly associated with T1DM (p=0.08) but the OR was 2.7; CI=0.86 -9.00. Similarly other genotypes were also not found statistically significant. However, HbA1C and Fasting Blood Sugar (FBS) were found statistically significant (p=0.001, p=0.000) in T1DM patients compared to controls. The autoantigenic variants of SLC30A8 of rs13266634 were not found statistically significant with T1DM. The role of this variant as a susceptibility gene in T1DM development should be further confirmed by carrying out studies with a larger sample size.

Single Nucleotide Polymorphisms at +45 T&gt;G and at +276 G&gt;T of the Adiponectin Gene and Plasma Adiponectin Level in Myanmar Type 2 Diabetic Patients

Introduction: Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic diseases and poses a substantial burden on health care systems globally. There is compelling data that genetic susceptibility to T2DM is polygenic. Genome-wide association studies have identified almost 50 loci associated with T2DM risk. Adiponectin gene polymorphism may be a causal role in the pathogenesis of insulin resistance and T2DM.&#x0D; Aims: The aim of the study was to investigate the association between single nucleotide polymorphisms (SNP) at rs 2241766 (SNP+45 T&gt;G) and at rs 1501299 (SNP+276 G&gt;T) of adiponectin gene and plasma adiponectin level in Myanmar Type 2 Diabetic patients.&#x0D; Study Design: It was a cross-sectional analytical study.&#x0D; Methodology: 100 Type 2 Diabetic patients and 104 non-diabetic subjects were included. Genotype frequencies were determined by PCR-RFLP method and plasma adiponectin level was measured by ELISA method.&#x0D; Results: Carrier groups (TG and GG genotypes of SNP+45) were more likely to develop T2DM risk than non-carrier groups (TT) [OR =1.8 (95% CI = 0.89-3.63, p = 0.09) and OR = 3.51 (95% CI = 1.07-11.54, p =0.04)] respectively. Carrier groups (GT and TT genotypes of SNP+276) were more likely to develop T2DM risk than non-carrier groups (GG) [OR =1.98 (95% CI =1.10-3.55, p = 0.02) and OR = 4.07 (95% CI =1.34-12.3, p = 0.01)] respectively. Therefore, G allele of SNP+45 was found to statistically increase T2DM risk than T allele and T allele of SNP+276 was found to statistically increase T2DM risk than G allele. Mean plasma adiponectin level (27.41±16.7µg/ml) of T2DM patients was significantly lower than that of non-diabetic subjects (37.19±26.77 µg/ml), (p =0.002). Mean plasma adiponectin levels of carrier groups (TG and GG of SNP+45) were significantly lower than that of non-carrier groups (TT). Mean plasma adiponectin levels of carrier groups (GT and TT of SNP+276) were significantly lower than that of non-carrier groups (GG).&#x0D; Conclusion: SNP+45 T&gt;G and +276 G&gt;T of adiponectin gene are significantly associated with low plasma adiponectin level and type 2 diabetes mellitus in this study groups of Myanmar population.

Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice.

Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and Mycobacterium tuberculosis (Mtb) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of Mtb infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that Mtb persists in adipose tissue and that Mtb infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during Mtb infection in adult mice. We also showed that Mtb infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of Mtb infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between Mtb infection and subsequent metabolic syndrome.

Low glucose metabolizing capacity and not insulin resistance is primary etiology of type 2 Diabetes Mellitus: A hypothesis

This paper puts forward the hypothesis that the etiology of type 2 Diabetes Mellitus (T2DM) is low cellular metabolizing capacity for glucose and insulin resistance develops as a protective mechanism when the intercellular glucose load overwhelms this capacity. Failure of intensive glycemic control to demonstrate better outcomes in macrovascular complications indicates that something is missing from our current understanding of pathogenesis of T2DM. This hypothesis is also able to give a simple explanation of multiple phenomena seen in T2DM like double diabetes, Insulin resistance (IR) preceding hyperglycemia, better than expected cardiovascular benefits from SGLT2 (sodium glucose transport protein 2) inhibitors, association of diet and physical activity and the increasing prevalence of the disease in the population. This hypothesis also implies that IR may be a wrong target in management of the disease. Drugs surpassing insulin resistance is likely to cause increased cardiovascular mortality and morbidity. There might be a need to rethink the role of insulin, insulin secretagogues and insulin sensitizing agent in management of T2DM. If the hypothesis is indeed true, it could reveal new drug targets and there is hope that T2DM might become curable in years to come.

Evidence and possible mechanisms of probiotics in the management of type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is one of the most common chronic immune-mediated diseases. The prevalence is worldwide especially among children and young adults. The destruction of the pancreatic β-cells due to some abnormalities in the immune system characterizes T1DM. Considering the high burden of the disease and its impact on human health, researchers have made great efforts during the last decades; investigating the disease pathogenesis and discovering new strategies for its management. Fortunately, probiotics have been found as potential remedies for T1DM. This review aims to explore the potentialities of probiotics in managing T1DM and its complications. Based on the outcomes of human and animal studies carried out from 2016 to 2021, the review hopes to assess the effectiveness of probiotics in the prevention and treatment of T1DM and its complications. We first tried to explain the disease's pathogenesis, and highlighted the possible mechanisms involved in these potentialities of probiotics. We concluded that, probiotics can be used as possible therapeutic tools for the management of T1DM. Possible mechanisms of action of probiotics include; the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of short chain fatty acids (SCFAs), and the regulation ofGLP-1. However, we recommend further studies especially human trials should be carried out to investigate these potentialities of probiotics. • T1DM is highly prevalent worldwide, causing high morbidity and mortality especially among children and young adults• Gut microbiota plays a significant role in the pathogenesis of T1DM via an interconnection with the immune system• Probiotics can be used as possible therapeutic tools for the management of T1DM• Possible mechanisms of action of probiotics include the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of SCFAs, and the regulation ofGLP-1.