Pathogenesis Of Type 2 Diabetes Mellitus Research Articles

Dietary Polyphenols and Gene Expression in Molecular Pathways Associated with Type 2 Diabetes Mellitus: A Review.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder with various contributing factors including genetics, epigenetics, environment and lifestyle such as diet. The hallmarks of T2DM are insulin deficiency (also referred to as β-cell dysfunction) and insulin resistance. Robust evidence suggests that the major mechanism driving impaired β-cell function and insulin signalling is through the action of intracellular reactive oxygen species (ROS)-induced stress. Chronic high blood glucose (hyperglycaemia) and hyperlipidaemia appear to be the primary activators of these pathways. Reactive oxygen species can disrupt intracellular signalling pathways, thereby dysregulating the expression of genes associated with insulin secretion and signalling. Plant-based diets, containing phenolic compounds, have been shown to exhibit remedial benefits by ameliorating insulin secretion and insulin resistance. The literature also provides evidence that polyphenol-rich diets can modulate the expression of genes involved in insulin secretion, insulin signalling, and liver gluconeogenesis pathways. However, whether various polyphenols and phenolic compounds can target specific cellular signalling pathways involved in the pathogenesis of T2DM has not been elucidated. This review aims to evaluate the modulating effects of various polyphenols and phenolic compounds on genes involved in cellular signalling pathways (both in vitro and in vivo from human, animal and cell models) leading to the pathogenesis of T2DM.

Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism

Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce H2O2 and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6−/−). Metabolic parameters, like carbon dioxide (VCO2) production, oxygen consumption (VO2), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6−/− mice showed weight gain and higher food and drink intake compared to controls. VO2 consumption and VCO2 production decreased in PRDX6−/− mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6−/− mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6−/− mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6−/− mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6−/− mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.

Role of rs7903146 polymorphism and adropin serum level in patients with diabetes mellitus; a case–control study from Isfahan, Iran

Background Type-2 diabetes mellitus (T2DM) is the common endocrinopathy which characterised by insulin resistance, insufficient expression or secretion of insulin and decrement of insulin effectiveness. Although T2DM has unknown aetiology, the strongest susceptible gene in this disease is TCF7L2. Adropin peptide may have roles in T2DM pathogenesis due to several roles in glucose tolerance, decrement of insulin resistance, lipid metabolism and energy homoeostasis. Aim To evaluate the serum level of adropin in T2DM patients and comparing with healthy individuals as well as assessing frequency of rs7903146 genotypes/alleles in patients and control groups. Methods We analysed the frequency of rs7903146 genotypes/alleles in 93 patients with T2DM disease and 53 healthy individuals by the method of polymerase chain reaction–restriction fragment length polymorphism analysis. The serum level of adropin was measured by using enzyme-linked immunosorbent assay technique. Results The mean serum level of adropin was 12.32 ± 2.98 and 9.51 ± 2.73 in patients and control groups, respectively (p value < .001). Also, there were significant difference in frequency of genotypes and alleles of rs7903146 in patients and controls groups (p < .001). The rs7903146T/T and rs7903146C/T genotypes increased risk of T2DM disease (OR: 6.035 and OR: 3.082, respectively). Interestingly, the highest level of adropin was detected in T2DMpatients with rs7903146T/T genotype. Conclusion Our analysis showed higher level of adropin in T2DM patients and increased risk of T2DM with rs7903146T/T and rs7903146C/T genotypes.

The relationship of vitamin D status with the development and course of diabetes mellitus type 1

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that develops as a result of a genetic predisposition and environmental factors. Literature data indicate that the suboptimal status of vitamin D can be considered as a risk factor for the development of T1DM, especially at some stages of life. Adequate vitamin D supplementation in childhood may provide a protective effect and reduce the risk of developing T1DM at a later age. Pathogenesis of T1DM predisposes to abnormalities in the metabolism of vitamin D, including the development of vitamin D deficiency. Moreover, the immunomodulating effect of calcitriol (induction of immune tolerance and T-cell anergy, impaired B-cell activity and antibodies production) suggests the therapeutic potential of vitamin D in autoimmune diseases, including T1DM. A number of studies have demonstrated the positive clinical effects of various vitamin D preparations with respect to maintaining residual -cell function, improving glycemia control in patients with T1DM. Determining the optimal doses of vitamin D for patients with T1DM may contribute to disease control and prevention of complications.

Potential association between type 1 diabetes mellitus and gender dysphoria.

Multiple factors have been proposed to explain the increasing prevalence of type 1 diabetes mellitus (T1DM), including psychological stress. The prevalence of gender dysphoria (GD) in youth is also growing. Identifying environmental triggers, such as psychological minority stress experienced by youth with GD, that may influence the pathogenesis and management of T1DM could have important clinical implications. The objective of this study was to determine the prevalence of concurrent diagnosis of T1DM and GD in adolescents evaluated at a university-based children's hospital. An electronic data extraction was conducted at the University of Wisconsin Hospital and Clinics from 1 November 2007 to 1 November 2017. Inclusion criteria included age 10 to 21 years and diagnosis of T1DM and/or GD. Prevalence rates were calculated for T1DM and GD. For adolescents with T1DM and GD, information related to diagnosis, treatment, and psychiatric history was collected. The prevalence for T1DM was 2.69 per 1000; the prevalence for GD was 0.42 per 1000. Eight adolescents had T1DM and GD. In adolescents with GD, the prevalence of T1DM was 9.4-fold higher than the prevalence of T1DM alone (24.77 vs 2.68 per 1000). Five adolescents were seen in GD clinic and their glycemic control initially improved after the first GD clinic visit. There was an increased prevalence of a concurrent diagnosis of T1DM in those with GD compared to the general population. Glycemic control improved after the first GD clinic visit in adolescents with T1DM and GD, which may be secondary to stress reduction.

Role of Epigenetics in the Pathogenesis and Management of Type 2 Diabetes Mellitus

The need to reverse the growing incidence and burden of diabetes mellitus (DM) worldwide has led to more studies on the possible causes of the disease. Genetic and environmental factors had long been suspected in the pathogenesis of a form of the disease known as the Type 2 diabetes mellitus (T2DM). However, more recent studies suggest epigenetic changes could also be involved in the onset of the disease. This review highlights the role of epigenetic modifications in the pathogenesis and management of T2DM. Peer reviewed studies on the subject were retrieved from reputable sources over the internet, and the majority of the studies unanimously implicated epigenetic modifications in the pathogenesis of some cases of the disease. DNA methylation, histone modification and microRNAs mediated pathways were observed to be the main mechanisms of epigenetic changes. These mechanisms are triggered by certain environmental factors such as diets, microbial and pollutant exposure, lifestyles, among others, prior to the onset of T2DM. Epigenetic changes can modify the expressions and functions of certain genes involved in insulin biosynthesis and glucose metabolism, leading to hyperglycemia and insulin resistance, which are hallmarks of T2DM. Fortunately, epigenetic changes can be reversed by blocking or activating the modulating enzymes, thus if the epigenetic aetiology of a diabetic condition is identified, it can be used as a therapeutic strategy.

Association of serum adropin with risk and severity of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus

BackgroundDiabetic peripheral neuropathy (DPN) is the major microvascular complication of type 2 diabetes mellitus (T2DM). Adropin is a peptide hormone that has essential roles in metabolic homeostasis and the pathogenesis of T2DM and its complications. This study was designed to estimate serum adropin levels in patients with T2DM in correlation with risk factors of DPN. The authors also aimed to investigate the association between serum adropin level and clinical and electrophysiological tests of DPN.Patients and methodsThis case–control study enrolled 100 patients with T2DM (40 diabetic cases without DPN and 60 diabetic cases with DPN) and 50 controls. All participants were subjected to a complete neurological examination. The motor and sensory conduction velocities of the median nerve, ulnar nerve, and common peroneal nerve were measured. The severity of DPN was assessed by Toronto clinical scoring system (TCSS). Serum adropin levels were assessed using an enzyme-linked immunosorbent assay.ResultsOur results revealed decreased circulating serum adropin levels in patients with T2DM (3.5±1.2), especially diabetic patients with DPN (3.1±1.07), compared with controls (6.1±0.89). There is a negative correlation between serum adropin level and TCSS as well as electrophysiological tests: motor nerve conduction velocity of median and ulnar nerve, sensory nerve conduction velocity of median and ulnar nerve, compound muscle action potential amplitude (median and ulnar nerve), and sensory nerve action potential amplitude (median, ulnar, and perception threshold nerve) (P<0.001*).ConclusionDiabetic patients with DPN had lower values of serum adropin than diabetic patients without DPN, and serum adropin levels were negatively correlated with metabolic risk factors, TCSS, as well as electrophysiological tests of DPN.

Investigation of association of biomarkers of iron metabolism and insulin resistance in Egyptian patients with impaired glucose metabolism and type 2 diabetes

IntroductionType 2 diabetes is an expanding overall medical issue. A large portion of the enthusiasm for the job of supplements in diabetes is fixated on macronutrients, yet a micronutrient, iron, is additionally closely connected with diabetes.AimTo study biomarkers of iron metabolism, including serum ferritin, transferrin saturation, iron, and insulin resistance, in diabetic and prediabetes patients.Patients and methodsThis is a cross-sectional study directed on a cohort of 50 patients, comprising 25 patients with impaired glucose tolerance and 25 patients recently discovered to have type 2 diabetes mellitus (T2DM), as well as 20 healthy controls of matched age and both sexes. All patients enrolled in the study were subjected to full history taking, full examination, laboratory investigations including iron, total iron-binding capacity, ferritin, insulin, lipid profile, fasting blood glucose, 2-h postprandial glucose, urea, creatinine, complete blood count, alanine aminotransferase, and aspartate aminotransferase.ResultsWe found that patients with T2DM have significant higher body weight and BMI than prediabetes patients and controls, and also statistically significant difference in serum iron between the studied groups, but no statistical significance in serum ferritin between the studied groups. In addition, we found a positive correlation of serum iron and insulin resistance in T2DM, a significant positive correlation of serum ferritin with low-density lipoprotein and negative correlation with high-density lipoprotein in T2DM, positive correlation of ferritin with cholesterol and triglycerides in impaired glucose tolerance group. Moreover, transferrin saturation was negatively correlated with glycated hemoglobin, BMI, and total iron-binding capacity and is positively correlated with iron and creatinine and hemoglobin among the studied groups.ConclusionThe distinguished relationship of several markers of iron metabolism with hyperglycemia and insulin resistance recommends that iron stores add to the pathogenesis of IGM and T2DM.

Knowledge and Awareness Regarding T1DM in Primary Health care Providers

Background: Diabetes is one of the commonest non-communicable diseases in the world. Type 1 Diabetes Mellitus (T1DM) is relatively less common but it is associated with greater morbidity and mortality. It is important to have the knowledge and awareness of T1DM especially in primary care providers (PCPs) to save the lives of children and young adults with T1DM.&#x0D; Methods: A cross sectional study was performed by distributing questionnaires amongst the doctors belonging to the field of General Medicine working at the primary care level with practices comprising approximately 10% of diabetic patients. Responses were recorded on a questionnaire and the data was analyzed by SPSS versions 20.&#x0D; Results: Only 62% doctors were aware about the correct pathogenesis of T1DM. Regarding the most important and fatal complications of T1DM i.e. diabetic ketoacidosis (DKA), 88.9% came up with correct answer. However when asked about the mortality related to T1DM only 22% PCPs gave the right answer. Only 40% of the PCPs could give correct answer regarding the mechanism of action of insulin. 55.6% PCPs were aware of the variation in blood glucose levels and had knowledge how to adjust them. Only 55.6% doctors were aware of cause of hypoglycemia.&#x0D; Conclusion: Most of the PCPs had suboptimal knowledge regarding T1DM, its pathogenesis, complications and mechanism of action of insulin. This study had identified the need for further improvement in PCPs practices for treating and educating diabetes and recommended that awareness and educational programs are necessary to update the PCPs on screening, effective treatment of T1DM, and prevention of its complications.

Milk exosomal miRNAs: potential drivers of AMPK-to-mTORC1 switching in \u03b2-cell de-differentiation of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) steadily increases in prevalence since the 1950’s, the period of widespread distribution of refrigerated pasteurized cow’s milk. Whereas breastfeeding protects against the development of T2DM in later life, accumulating epidemiological evidence underlines the role of cow’s milk consumption in T2DM. Recent studies in rodent models demonstrate that during the breastfeeding period pancreatic β-cells are metabolically immature and preferentially proliferate by activation of mechanistic target of rapamycin complex 1 (mTORC1) and suppression of AMP-activated protein kinase (AMPK). Weaning determines a metabolic switch of β-cells from a proliferating, immature phenotype with low insulin secretion to a differentiated mature phenotype with glucose-stimulated insulin secretion, less proliferation, reduced mTORC1- but increased AMPK activity. Translational evidence presented in this perspective implies for the first time that termination of milk miRNA transfer is the driver of this metabolic switch. miRNA-148a is a key inhibitor of AMPK and phosphatase and tensin homolog, crucial suppressors of mTORC1. β-Cells of diabetic patients return to the postnatal phenotype with high mTORC1 and low AMPK activity, explained by continuous transfer of bovine milk miRNAs to the human milk consumer. Bovine milk miRNA-148a apparently promotes β-cell de-differentiation to the immature mTORC1-high/AMPK-low phenotype with functional impairments in insulin secretion, increased mTORC1-driven endoplasmic reticulum stress, reduced autophagy and early β-cell apoptosis. In contrast to pasteurized cow’s milk, milk’s miRNAs are inactivated by bacterial fermentation, boiling and ultra-heat treatment and are missing in current infant formula. Persistent milk miRNA signaling adds a new perspective to the pathogenesis of T2DM and explains the protective role of breastfeeding but the diabetogenic effect of continued milk miRNA signaling by persistent consumption of pasteurized cow’s milk.

Association between CUBN gene variants, type 2 diabetes and vitamin D concentrations in an elderly Greek population

Accumulating evidence suggests a potential implication of vitamin D biological network in the pathogenesis of diabetes mellitus. The megalin-cubilin endocytotic system constitutes a key transport structure, with a modulating role in vitamin D metabolism. We aimed to assess the contribution of variants in the CUBN gene to the genetic risk of Type 2 Diabetes Mellitus (T2DM). 95 polymorphisms within CUBN were genotyped in 716 patients with T2DM and 542 controls of Greek origin. Samples were analyzed on Illumina Human PsychArray. Permutation test analysis was implemented to determine statistical significance. Twenty-five-hydroxy-vitamin-D [25(OH)D)] levels were measured in a sub-group of participants (n = 276). Permutation analysis associated rs11254375_G/T (pemp = 0.00049, OR = 1.482), rs6602175_G/T (pemp = 0.016, OR = 0.822), rs1801224_G/T (pemp = 0.025, OR = 0.830), rs4366393_A/G (pemp = 0.028, OR = 0.829) and rs7071576_A/G (pemp = 0.04, OR = 1.219) with T2DM. Mean 25(OH)D concentrations were significantly lower in patients with T2DM compared to controls (16.70 ± 6.69 ng/ml vs 18.51 ± 6.71 ng/ml, p < 0.001), although both groups were vitamin D deficient. In a further quantitative analysis, rs41301097 was strongly associated with higher 25(OH)D concentrations (p = 5.233e-6, beta = 15.95). Our results indicate a potential role of CUBN gene in T2DM genetic susceptibility in the Greek population. These findings may also denote an indirect effect of vitamin D metabolism dysregulation on the pathogenesis of T2DM. Further studies are required to replicate our findings and clarify the complex underlying mechanisms.

Plasma fibroblast growth factor 21 levels increase with ectopic fat accumulation and its receptor levels are decreased in the visceral fat of patients with type 2 diabetes

BackgroundFibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has beneficial effects on glucose and lipid metabolism. However, plasma FGF21 levels are paradoxically increased in type 2 diabetes...

Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling.

PurposeType 1 diabetes mellitus (T1DM) is characterized by irreversible islet β cell destruction. Accumulative evidence indicated that Cdc42 and Wnt/β-catenin signaling both play a critical role in the pathogenesis and development of T1DM. Further, bio-molecular mechanisms in adipose-derived mesenchymal stem cells (ADSCs)-derived insulin-producing cells (IPCs) remain largely unknown. Our aim was to investigate the underlying mechanism of Cdc42/Wnt/β-catenin pathway in ADSC-derived IPCs, which may provide new insights into the therapeutic strategy for T1DM patients.MethodsADSC induction was accomplished with DMSO under high-glucose condition. ML141 (Cdc42 inhibitor) and Wnt-3a (Wnt signaling activator) were administered to ADSCs from day 2 until the induction finished. Morphological changes were determined by an inverted microscope. Dithizone staining was employed to evaluate the induction of ADSC-derived IPCs. qPCR and Western blotting were employed to measure the mRNA and protein expression level of islet cell development-related genes and Wnt signaling-related genes. The proliferation ability of ADSC-derived IPCs was also detected with a cell counting kit (CCK) assay. The expression and secretion of Insulin were detected with immunofluorescence test and enzyme-linked immunosorbent assay (ELISA) respectively.ResultsDuring induction, morphological characters of ADSCs changed into spindle and round shape, and formed islet-line cell clusters, with brown dithizone–stained cytoplasm. Expression levels of islet cell development-related genes were up-regulated in ADSC-derived IPCs. Wnt-3a promoted Wnt signaling markers and islet cell development-related gene expression at mRNA and protein levels, while ML141 played a negative effect. Wnt-3a promoted ADSC-derived IPC proliferation and glucose-stimulated insulin secretion (GSIS), while ML141 played a negative effect.ConclusionOur research demonstrated that DMSO and high-glucose condition can induce ADSCs into IPCs, and Wnt signaling promotes the induction. Cdc42 may promote IPC induction, IPC proliferation and insulin secretion via Wnt/β-catenin pathway, meaning that Cdc42 may be regarded as a potential target in the treatment of T1DM.

Preparation of a new type 2 diabetic miniature pig model via the CRISPR/Cas9 system

Diabetes has become one of the major noninfectious diseases that seriously endanger public health. The formation of islet amyloid polypeptide (IAPP) affects the normal physiological functions of the body, such as glucose metabolism and lipid metabolism. The mature human IAPP protein (hIAPP) has a strong tendency to misfold and is considered to be one of the major causes of amyloid changes in islets. Deposition of hIAPP is considered to be one of the leading causes of type 2 diabetes mellitus (T2DM). Miniature pigs are experimental animal models that are well suited for research on gene function and human diabetes. In our study, we obtained IAPP gene-humanized miniature pigs via the CRISPR/Cas9 system and somatic cell nuclear transfer (SCNT) technology. The hIAPP pigs can be used to further study the pathogenesis and related complications of T2DM and to lay a solid foundation for the prevention and treatment of T2DM.

Flavonoids extracted from mulberry (Morus alba L.) leaf improve skeletal muscle mitochondrial function by activating AMPK in type 2 diabetes.

Mulberry (Morus alba L.) leaves have been widely applied to controlling blood glucose as a efficacious traditional Chinese medicine or salutary medical supplement. The extracts of mulberry leaf suppress inflammatory mediators and oxidative stress, protect the pancreatic β-cells and modulate glucose metabolism in diabetic rats. Our previous studies and others have shown that mulberry leaf extract has excellent therapeutic effects on type 2 diabetes mellitus (T2DM), however, the underlying mechanism remains to be studied. Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of T2DM. The aim of this study was to investigate the effects and mechanisms of Mulberry leaf flavonoids (MLF) in L6 skeletal muscle cells and db/db mice. L6 skeletal muscle cells were cultured and treated with/without MLF for in vitro studies. For in vivo studies, the db/db mice with/without MLF therapy were used. Coomassie brilliant blue staining and α-SMA immunofluorescence staining were used to identify the differentiated L6 cells. Glucose level and ATP level of L6 myotubes were performed by optical density detection and cell viability was performed by MTT method. Mitochondrial membrane potential of L6 myotubes was detected by JC-1 fluorescent staining. ROS level of L6 myotubes was detected by DCFH-DA fluorescent staining. The body weight, food intake, and blood glucose of the mice were measured in different treatment days. Oral glucose tolerance test (OGTT), starch glucose tolerance test (STT) and insulin tolerance test (ITT) were performed in mice. Glycated hemoglobin, glycated serum protein, insulin, liver and muscle glycogen, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) of the mice were detected by corresponding kit. The pathologic change of pancreas and skeletal muscle of mice were performed by H & E staining. Immunohistochemistry staining was used to detect the GLUT4 and p-AMPK expressions in skeletal muscle in mice. GLUT4, CPT-1, NRF1, COXIV, PGC-1α, and p-AMPK expression levels in L6 cells and mice were detected by western bolt assay. MLF and metformin significantly ameliorated muscle glucose uptake and mitochondrial function in L6 muscle cells. MLF also increased the phosphorylation of AMPK and the expression of PGC-1α, and up-regulated the protein levels of m-GLUT4 and T-GLUT4. These effects were reversed by the AMPK inhibitor compound C. In db/db mice, MLF improve diabetes symptoms and insulin resistance. Moreover, MLF elevated the levels of p-AMPK and PGC-1α, raised m-GLUT4 and T-GLUT4 protein expression, and ameliorated mitochondrial function in skeletal muscle of db/db mice. MLF significantly improved skeletal muscle insulin resistance and mitochondrial function in db/db mice and L6 myocytes through AMPK-PGC-1α signaling pathway, and our findings support the therapeutic effects of MLF on type 2 diabetes.

Clinical Features and Microvascular Complications Risk Factors of Early-onset Type 2 Diabetes Mellitus.

The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus (T2DM). We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital. Subjects were divided into early-onset T2DM group (diagnostic age <40 years) and late-onset T2DM group (diagnostic age >40 years). All subjects underwent a standardized assessment of microvascular complications. Data were compared with independent-samples t test or Chi-square test. Multiple logistic regression was used to determine the risk factors of microvascular complications. Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure (SBP), a longer duration of diabetes and higher levels of body mass index (BMI), uric acid (UA), fasting plasma glucose (FPG), total cholesterol (TC)- triglyceride (TG) and glycosylated hemoglobin (HbA1c) than those with late-onset T2DM (P<0.05). The prevalence of diabetic retinopathy (DR) was significantly higher and that of diabetic peripheral neuropathy (DPN) was significantly lower in early-onset group than in late-onset group (P<0.05). For DN, UA was an independent risk factor in early-onset T2DM. SBP and TG were independent risk factors in late-onset T2DM. For DR, duration of diabetes and SBP were independent risk factors in early-onset T2DM. Duration of diabetes, SBP and HbA1c were independent risk factors in late-onset T2DM. This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders, including glucose metabolism, lipid metabolism and amino acid metabolism. Early-onset T2DM was more likely to be associated with DR. The potential pathogenesis of early and late-onset T2DM might be different. The management of metabolic risk factors especially HbA1c, SBP, TG and UA is advised to be performed in the early stage of diabetes.

Genetic aspects of type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic beta-cells in genetically predisposed individuals, eventually resulting in severe insulin deficiency. It is the most common form of diabetes in children and adolescents. Genetic susceptibility plays a crucial role in development of T1DM. The human leukocyte antigen complex plays a key role in the pathogenesis of T1DM. Furthermore, genome-wide association studies and linkage analysis have recently made a significant contribution to current knowledge relative to the impact of genetics on T1DM development and progression. This review focuses on current knowledge of genetics as a pathogenesis for T1DM. It also discusses mechanisms by which genes influence the risk of developing T1DM as well as the clinical and research applications of genetic risk scores in T1DM.

The Role of Butyrate on Monocyte Migration and Inflammation Response in Patient with Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2DM) is a very serious global problem. In Indonesia, this disease attacks at the most productive age; consequently, it can reduce economic status and life expectancy. The pathogenesis of T2DM is very closely related to inflammation and macrophage accumulation. However, no anti-inflammatory agent has been proven to play a role in the management of T2DM. Butyrate is a short chain fatty acid produced from resistant starch fermentation in the intestinal lumen. It is able to bind to GPR41 and GPR43 receptors on monocytes, so that it can change the pattern of cytokine expression, activation, migration and cell differentiation. Hence, it is interesting to examine the anti-inflammation effect of butyrate and the effect on monocyte migration. A total of 37 subjects were examined in this study. They were divided into two groups, with and without butyrate treatment. We analyzed two pro-inflammatory cytokines (Tumor Necrosis Factor TNF-α and Interleukin IL-6) and one anti-inflammatory cytokine, IL 10. Monocytes were isolated in type 1 collagen gel for migration testing using the µ-slide chemotaxis IBIDI. Image analysis used ImageJ and Chemotaxis tool software. There was a significant difference in the TNFα/IL 10 ratio between healthy groups and T2DM. Butyrate also appears to suppress TNFα cytokine production and increase IL10 production. It also decreases the accumulation distance of monocyte migration in T2DM.

Epigenetic Modifications Associated with the Pathogenesis of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder. Pancreatic β-cell dysfunction and insulin resistance are the most common and crucial events of T2DM. Increasing evidence suggests the association of epigenetic modifications with the pathogenesis of T2DM through the changes in important biological processes including pancreatic β- cell differentiation, development and maintenance of normal β-cell function. Insulin sensitivity by the peripheral glucose uptake tissues is also changed by the altered epigenetic mechanisms. In this review, we discussed the major epigenetic alterations and their effects on β-cell function, insulin secretion and insulin resistance in context of T2DM. We investigated the presently available epigenetic modifications including DNA methylation, posttranslational histone modifications, ATP-dependent chromatin remodeling and non-coding RNAs related to the pathogenesis of T2DM. Published literatures on this topic were searched both on Google Scholar and Pubmed with related keywords and investigated for relevant information. The epigenetic modifications introduce changes in gene expression which are essential for appropriate β-cell development and functions, insulin secretion and sensitivity resulting in the pathogenesis of T2DM. Interestingly, T2DM could also be a prominent reason for the mentioned epigenetic alterations. This review article emphasized on the epigenetic modifications associated with T2DM and discussed the consequences in deterioration of the disease condition.

Micro-RNA 196a2 expression and miR-196a2 (rs11614913) polymorphism in T1DM: a pilot study.

Background Recent emerging evidence supports the role of miR-196a2 in various human diseases. However, its role in type 1 diabetes mellitus (T1DM) is still underestimated. We aimed, for the first time, to investigate the expression of miR-196a2 in T1DM and the association of miR-196a2 (rs11614913) polymorphism with susceptibility of T1DM in a sample of patients from Cairo, Egypt. Methods The study included 150 patients and 150 healthy subjects. Evaluation of rs11614913 genotypes and miR-196a2 expression was done using the allelic discrimination and quantitative reverse transcriptase polymerase chain reaction (PCR) method, respectively. Results The Hardy-Weinberg equilibrium of single nucleotide polymorphism(SNP) was detected among controls (p = 0.2). Our results revealed that the TT genotype was more frequent in patients (22.6%) than controls (10%) while the CC genotype was more frequent in controls (47.3%) than patients (39.3%) (p = 0.01). The frequency of the T allele was significantly higher in patients than in controls (41.7 vs. 31.3%), while the C allele was more frequent in controls (p = 0.008). After adjustment for traditional risk factors, the association of the TT genotype with T1DM remained significant (TT vs. CC, odds ration [OR] = 3.2, 95% confidence interval [CI]: 1.4-7.4, p = 0.005). Power analysis of the data yielded a statistical power of 80% for the miR-196a2 rs11614913 with T1DM. Relative expression of miR-196a2 showed significant decrease in patients compared to controls (median = 0.09, 0.5, interquartile range [IQR] = 0.03-1.6, 0.1-2.1). However, miR-196a2 expression showed no significant difference between different rs11614913 genotypes (p = 0.5). Conclusions Our findings demonstrated that miR-196a rs11614913 is associated with T1DM and decreased expression of miR-196a2 may play a role in pathogenesis of T1DM.