Therapeutic Targets For Type 2 Diabetes Mellitus Research Articles

Targeting gut microbiota as a therapeutic target in T2DM: A review of multi-target interactions of probiotics, prebiotics, postbiotics, and synbiotics with the intestinal barrier

The global epidemic of type 2 diabetes mellitus (T2DM) imposes a substantial burden on public health and healthcare expenditures, thereby driving the pursuit of cost-effective preventive and therapeutic strategies. Emerging evidence suggests a potential association between dysbiosis of gut microbiota and its metabolites with T2DM, indicating that targeted interventions aimed at modulating gut microbiota may represent a promising therapeutic approach for the management of T2DM. In this review, we concentrated on the multifaceted interactions between the gut microbiota and the intestinal barrier in the context of T2DM. We systematically summarized that the imbalance of beneficial gut microbiota and its metabolites may constitute a viable therapeutic approach for the management of T2DM. Meanwhile, the mechanisms by which gut microbiota interventions, such as probiotics, prebiotics, postbiotics, and synbiotics, synergistically improve insulin resistance in T2DM are summarized. These mechanisms include the restoration of gut microbiota structure, upregulation of intestinal epithelial cell proliferation and differentiation, enhancement of tight junction protein expression, promotion of mucin secretion by goblet cells, and the immunosuppressive functions of regulatory T cells (Treg) and M2 macrophages. Collectively, these actions contribute to the amelioration of the body's metabolic inflammatory status. Our objective is to furnish evidence that supports the clinical application of probiotics, prebiotics, and postbiotics in the management of T2DM.

Plasma proteomic signatures for type 2 diabetes mellitus and related traits in the UK Biobank cohort.

The plasma proteome holds promise as a diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict type 2 diabetes mellitus (T2DM) and related traits. Clinical, genetic, and high-throughput proteomic data from three subcohorts of UK Biobank participants were analyzed for association with dual-energy x-ray absorptiometry (DXA) derived truncal fat (in the adiposity subcohort), estimated maximum oxygen consumption (VO2max) (in the fitness subcohort), and incident T2DM (in the T2DM subcohort). We used least absolute shrinkage and selection operator (LASSO) regression to assess the relative ability of non-proteomic and proteomic variables to associate with each trait by comparing variance explained (R2) and area under the curve (AUC) statistics between data types. Stability selection with randomized LASSO regression identified the most robustly associated proteins for each trait. The benefit of proteomic signatures (PSs) over QDiabetes, a T2DM clinical risk score, was evaluated through the derivation of delta (Δ) AUC values. We also assessed the incremental gain in model performance metrics using proteomic datasets with varying numbers of proteins. A series of two-sample Mendelian randomization (MR) analyses were conducted to identify potentially causal proteins for adiposity, fitness, and T2DM. Across all three subcohorts, the mean age was 56.7 years and 54.9% were female. In the T2DM subcohort, 5.8% developed incident T2DM over a median follow-up of 7.6 years. LASSO-derived PSs increased the R2 of truncal fat and VO2max over clinical and genetic factors by 0.074 and 0.057, respectively. We observed a similar improvement in T2DM prediction over the QDiabetes score [Δ AUC: 0.016 (95% CI 0.008, 0.024)] when using a robust PS derived strictly from the T2DM outcome versus a model further augmented with non-overlapping proteins associated with adiposity and fitness. A small number of proteins (29 for truncal adiposity, 18 for VO2max, and 26 for T2DM) identified by stability selection algorithms offered most of the improvement in prediction of each outcome. Filtered and clustered versions of the full proteomic dataset supplied by the UK Biobank (ranging between 600-1,500 proteins) performed comparably to the full dataset for T2DM prediction. Using MR, we identified 4 proteins as potentially causal for adiposity, 1 as potentially causal for fitness, and 4 as potentially causal for T2DM. Plasma PSs modestly improve the prediction of incident T2DM over that possible with clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of these signatures in predicting the risk of T2DM over the standard practice of using the QDiabetes score. Candidate causally associated proteins identified through MR deserve further study as potential novel therapeutic targets for T2DM.

Decreased plasma myonectin levels in female patients with type 2 diabetes mellitus and its correlation with lipid and glycemic parameters.

Myonectin is a novel myokine which has significant implications on diabetes. This study aimed to investigate plasma myonectin levels in patients with type 2 diabetes mellitus (T2DM), and their correlation with body composition, lipid and glycemic parameters. The study participants included 40 diabetic and 33 non-diabetic healthy adult Saudi females matched for their BMI and age. Body composition was assessed by bioelectrical impedance analysis. Fasting blood samples were used to investigate plasma myonectin levels by ELISA, along with lipid and glycemic parameters. We found that plasma myonectin levels were significantly decreased in diabetic patients (40.90±4.13 ng/ml, p<0.05) compared to non-diabetic participants (59.58±4.41). Diabetic patients with poor glycemic parameters had significantly decreased myonectin levels (35.18±4.03 ng/ml p<0.05) compared to non-diabetic healthy subjects. There was no significant difference in myonectin levels between diabetic patients with good glycemic control (55.76±8.09 ng/ml p>0.05) and non-diabetic healthy participants. Pearson correlation analysis indicated a significant negative correlation with fasting blood sugar (R=-0.366, p=0.001), HbA1c (R=-0.406, p<0.0001), triglycerides (R=-0.264, p=0.024), insulin (R=-0.278, p=0.017), and HOMA-IR (R=-0.409, p<0.0001). Our findings highlight an important aspect of myonectin in the pathophysiology of T2DM. They also show that myonectin has the potential to be a useful biomarker and therapeutic target in T2DM.

Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus.

White adipose tissue (WAT) plays a pivotal role in the onset of type 2 diabetes mellitus (T2DM) and obesity. Despite its significance the underlying pathogenesis and key genes associated with it remain elusive. In our study, we screened the differentially expressed genes (DEGs) in intra-abdominal WAT of T2DM patients with obesity, as well as those with simple obesity, aiming to lay a foundational theory for an in-depth investigation of T2DM pathogenesis and the identification of novel therapeutic targets. Gene expression datasets (GSE16415 and GSE71416) were retrieved from the Gene Expression Omnibus (GEO) database. We employed R for screening DEGs and conducted a functional enrichment analysis using the Metascape database. Combined Lasso regression and Boruta feature selection algorithms were used to identify key DEGs. Subsequently, these were cross-verified using the GSE29231 dataset. Samples and medical records were collected from clinical study participants. The mRNA and protein expressions of the key DEGs were verified using qRT-PCR and western blotting, respectively. We discerned a total of 130 DEGs, with 40 being upregulated and 90 downregulated. Functional and pathway enrichment analyses illuminated that these genes are instrumental in mediating metabolite and energy production, neutrophil-mediated immunity, and other associated biological processes. This includes their involvement in the tricarboxylic acid cycle, glycolysis/gluconeogenesis, peroxisome proliferator-activated receptors, and other signalling pathways. Two genes, CIDEA and FSCN1 emerged as key DEGs. The low expression of CIDEA and high expression of FSCN1 in the T2DM and obesity group were verified in clinical samples (P < 0.05). We established that CIDEA and FSCN1 manifest significant differential expression in T2DM patients who are obese. This suggests their potential as risk assessment markers and therapeutic targets for T2DM.

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes.

Autophagy, an innate safeguard mechanism for protecting the organism against harmful agents, is implicated in the survival of pancreatic â cells and the development of type 2 diabetes mellitus (T2DM). Potential autophagy-related genes (ARGs) may serve as potential biomarkers for T2DM treatment. The GSE25724 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and ARGs were obtained from the Human Autophagy Database. The differentially expressed autophagy-related genes (DEARGs) were screened at the intersection of ARGs and differentially expressed genes (DEGs) between T2DM and non-diabetic islet samples, which were subjected to functional enrichment analyses. A protein-protein interaction (PPI) network was constructed to identify hub DEARGs. Expressions of top 10 DEARGs were validated in human pancreatic â-cell line NES2Y and rat pancreatic INS-1 cells using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and insulin secretion were measured after cell transfection with lentiviral vector EIF2AK3 or RB1CC1 into islet cells. In total, we discovered 1,270 DEGs (266 upregulated and 1,004 downregulated genes) and 30 DEARGs enriched in autophagy- and mitophagy-related pathways. In addition, we identified GAPDH, ITPR1, EIF2AK3, FOXO3, HSPA5, RB1CC1, LAMP2, GABARAPL2, RAB7A, and WIPI1 genes as the hub ARGs. Next, qRT-PCR analysis revealed that expressions of hub DEARGs were consistent with findings from bioinformatics analysis. EIF2AK3, GABARAPL2, HSPA5, LAMP2, and RB1CC1 were both differentially expressed in the two cell types. Overexpression of EIF2AK3 or RB1CC1 promoted cell viability of islet cells and increased the insulin secretion. This study provides potential biomarkers as therapeutic targets for T2DM.

Generation of an induced pluripotent stem cell lines NSHDMUi001-A from patients with type 2 diabetes

Type 2 diabetes mellitus (T2DM) is common in China, and its aetiology and pathogenesis are still unclear. We reprogrammed pEP4EO2SEN2K and pEP4EO2SET2K, pCEP4-M2L was electrotransfected in T2DM patients with pEP4EO2SEN2K, and pCEP4-M2L was electrotransfected in T2DM patients expressing the OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT transcription factors to obtain induced pluripotent stem cells (iPSCs). The obtained iPSCs have been verified to have pluripotency, normal karyotype and differentiation potential; therefore, these cells can be used in the study of disease pathophysiology and drug development to create new therapeutic targets for T2DM and associated central nervous system damage.

U-shaped association between serum IGF2BP3 and T2DM: A cross-sectional study in Chinese population.

To clarify the expression of N6-methyladenosine (m6 A) modulators involved in the pathogenesis of type 2 diabetes mellitus (T2DM). We further explored the association of serum insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) levels and odds of T2DM in a high-risk population. The gene expression data set GSE25724 was obtained from the Gene Expression Omnibus, and a cluster heatmap was generated by using the R package ComplexHeatmap. Differential expression analysis for 13 m6 A RNA methylation regulators between nondiabetic controls and T2DM subjects was performed using an unpaired t test. A cross-sectional design, including 393 subjects (131 patients with newly diagnosed T2DM, 131 age- and sex-matched subjects with prediabetes, and 131 healthy controls), was carried out. The associations between serum IGF2BP3 concentrations and T2DM were modeled by restricted cubic spline and logistic regression models. Two upregulated (IGF2BP2 and IGF2BP3) and 5 downregulated (methyltransferase-like 3 [METTL3], alkylation repair homolog protein 1 [ALKBH1], YTH domain family 2 [YTHDF2], YTHDF3, and heterogeneous nuclear ribonucleoprotein [HNRNPC]) m6 A-related genes were found in islet samples of T2DM patients. A U-shaped association existed between serum IGF2BP3 levels and odds of T2DM according to cubic natural spline analysis models, after adjustment for body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyeride. Multivariate logistic regression showed that progressively higher odds of T2DM were observed when serum IGF2BP3 levels were below 0.62 ng/mL (odds ratio 3.03 [95% confidence interval 1.23-7.47]) in model 4. Seven significantly altered m6 A RNA methylation genes were identified in T2DM. There was a U-shaped association between serum IGF2BP3 levels and odds of T2DM in the general Chinese adult population. This study provides important evidence for further examination of the role of m6 A RNA methylation, especially serum IGF2BP3 in T2DM risk assessment.

The Potential Role of R4 Regulators of G Protein Signaling (RGS) Proteins in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a complex and heterogeneous disease that primarily results from impaired insulin secretion or insulin resistance (IR). G protein-coupled receptors (GPCRs) are proposed as therapeutic targets for T2DM. GPCRs transduce signals via the Gα protein, playing an integral role in insulin secretion and IR. The regulators of G protein signaling (RGS) family proteins can bind to Gα proteins and function as GTPase-activating proteins (GAP) to accelerate GTP hydrolysis, thereby terminating Gα protein signaling. Thus, RGS proteins determine the size and duration of cellular responses to GPCR stimulation. RGSs are becoming popular targeting sites for modulating the signaling of GPCRs and related diseases. The R4 subfamily is the largest RGS family. This review will summarize the research progress on the mechanisms of R4 RGS subfamily proteins in insulin secretion and insulin resistance and analyze their potential value in the treatment of T2DM.

Remission as an Emerging Therapeutic Target in Type 2 Diabetes in the Era of New Glucose-Lowering Agents: Benefits, Challenges, and Treatment Approaches.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.

Dipeptidyl peptidase-4 inhibitory potentials of Glycyrrhiza uralensis and its bioactive compounds licochalcone A and licochalcone B: An in silico and in vitro study.

Type 2 diabetes mellitus (T2DM) is a growing global public health issue, and dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target in T2DM. Several synthetic anti-DPP-4 medications can be used to treat T2DM. However, because of adverse effects, there is an unmet demand for the development of safe and effective medications. Natural medicines are receiving greater interest due to the inherent safety of natural compounds. Glycyrrhiza uralensis (licorice) is widely consumed and used as medicine. In this study, we investigated the abilities of a crude water extract (CWE) of G. uralensis and two of its constituents (licochalcone A (LicA) and licochalcone B (LicB)) to inhibit the enzymatic activity of DPP-4 in silico and in vitro. In silico studies showed that LicA and LicB bind tightly to the catalytic site of DPP-4 and have 11 amino acid residue interactions in common with the control inhibitor sitagliptin. Protein-protein interactions studies of LicA-DPP4 and LicB-DPP4 complexes with GLP1 and GIP reduced the DPP-4 to GLP1 and GIP interactions, indicated that these constituents might reduce the degradations of GLP1 and GIP. In addition, molecular dynamics simulations revealed that LicA and LicB stably bound to DPP-4 enzyme. Furthermore, DPP-4 enzyme assay showed the CWE of G. uralensis, LicA, and LicB concentration-dependently inhibited DPP-4; LicA and LicB had an estimated IC50 values of 347.93 and 797.84 μM, respectively. LicA and LicB inhibited DPP-4 at high concentrations, suggesting that these compounds could be used as functional food ingredients to manage T2DM.

Manipulation of the miR-378a/mt-ATP6 regulatory axis rescues ATP synthase in the diabetic heart and offers a novel role for lncRNA Kcnq1ot1.

Diabetes mellitus has been linked to an increase in mitochondrial microRNA-378a (miR-378a) content. Enhanced miR-378a content has been associated with a reduction in mitochondrial genome-encoded mt-ATP6 abundance, supporting the hypothesis that miR-378a inhibition may be a therapeutic option for maintaining ATP synthase functionality during diabetes mellitus. Evidence also suggests that long noncoding RNAs (lncRNAs), including lncRNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (Kcnq1ot1), participate in regulatory axes with microRNAs (miRs). Prediction analyses indicate that Kcnq1ot1 has the potential to bind miR-378a. This study aimed to determine if loss of miR-378a in a genetic mouse model could ameliorate cardiac dysfunction in type 2 diabetes mellitus (T2DM) and to ascertain whether Kcnq1ot1 interacts with miR-378a to impact ATP synthase functionality by preserving mt-ATP6 levels. MiR-378a was significantly higher in patients with T2DM and 25-wk-old Db/Db mouse mitochondria, whereas mt-ATP6 and Kcnq1ot1 levels were significantly reduced when compared with controls. Twenty-five-week-old miR-378a knockout Db/Db mice displayed preserved mt-ATP6 and ATP synthase protein content, ATP synthase activity, and preserved cardiac function, implicating miR-378a as a potential therapeutic target in T2DM. Assessments following overexpression of the 500-bp Kcnq1ot1 fragment in established mouse cardiomyocyte cell line (HL-1) cardiomyocytes overexpressing miR-378a revealed that Kcnq1ot1 may bind and significantly reduce miR-378a levels, and rescue mt-ATP6 and ATP synthase protein content. Together, these data suggest that Kcnq1ot1 and miR-378a may act as constituents in an axis that regulates mt-ATP6 content, and that manipulation of this axis may provide benefit to ATP synthase functionality in type 2 diabetic heart.

The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Role of Intrinsic Disorder in Alternatively Spliced Sortilin Variants in 3T3L1 Adipocytes

Type 2 diabetes mellitus (T2DM) is a metabolic disorder defined by systemic insulin resistance affecting more than 400 million people worldwide. Adipose tissue is an important regulator of glucose metabolism as well as an endocrine organ secreting hormones and cytokines. Defective signaling in insulin resistant adipocytes leads to impaired trafficking of main glucose transporter 4 (Glut4) thus leading to reduced glucose uptake and hyperglycemia. Notably, trafficking protein sortilin has an important role in regulating Glut4 movement in adipocytes thereby affecting glucose levels. We demonstrate that in mouse 3T3L1 adipocytes, alternative splicing generates a sortilin splice variant with an included exon 17b (Sort17b) expressed along with SortWT. Insulin resistance induced by high serum increases expression levels of Sort17b. Further, our results demonstrate that increased Sort17b decreases Glut4 translocation and glucose uptake. Using bioinformatic analysis we show inclusion of exon 17b introduces a novel intrinsic disorder region in a crucial ligand binding regulation site. Since intrinsic disorder is a measure of lack of protein folding potentially affecting ligand binding and protein interactions, we performed molecular modeling of both sortilin variants (Sort17b and SortWT) and analyzed flexibility of protein backbone (RMSD) and individual residues (RMSF). Our results show increased flexibility in Sort17b within the amino acids of exon 17b. Using co-immunoprecipitation assays we demonstrate that Sort17b binds robustly to Glut4 and the binding efficiency is increased in insulin resistant adipocytes. Overall, the results demonstrate that the novel splice variant of sortilin in mouse 3T3L1 adipocytes contains an intrinsically disordered region that affects glucose metabolism and may be a potential therapeutic target in T2DM.

Identification of a potentially functional circRNA-miRNA-mRNA regulatory network in type 2 diabetes mellitus by integrated microarray analysis.

Circular RNAs (circRNAs) function as miRNA sponges by adsorbing microRNAs (miRNAs), thereby regulating messenger RNA (mRNA) expression. The circRNA-miRNA-mRNA regulatory network associated with type 2 diabetes mellitus (T2DM) has rarely been explored. A circRNA-miRNA-mRNA regulatory network associated with T2DM was established to help deepen our understanding of the molecular mechanism of and therapeutic targets for T2DM. Differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were derived from the Gene Expression Omnibus (GEO) microarray datasets GSE114248, GSE51674 and GSE95849, respectively. A circRNA-miRNA-mRNA regulatory network associated with T2DM and its subnetwork were constructed. The hub genes were screened using a protein-protein interaction (PPI) network. Finally, a hub gene-related network was constructed. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. The circRNA-miRNA-mRNA network included 9 circRNAs, 24 miRNAs and 320 mRNAs. When four key circRNAs (circMYO9B, circGRAMD1B, circTHAP4 and circTMC7) were chosen, the subnetwork contained 4 circRNAs, 18 miRNAs and 307 mRNAs. Afterwards, 8 hub genes (SIRT1, GNG7, KDR, FOS, SIN3B, STAT1, SP1, and MAPK3) were extracted from the PPI network. GO and KEGG pathway analyses revealed that the network might be involved in oxidative stress responses, regulation of inflammation, neovascularization, endocrine and cancer-related processes, etc. A circRNA-miRNA-hub gene regulatory network was constructed, and the potential functions of the hub genes were analyzed. Four important circRNAs (circMYO9B, circGRAMD1B, circTHAP4 and circTMC7) might be involved in the occurrence and development of T2DM, and this finding provides new insight into the molecular mechanism of and therapeutic targets for T2DM and its complications. Future studies are needed to validate the sponge effects and mechanisms of these 4 circRNAs.

Role of Wnt signaling pathways in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) has become a major global public health issue in the twenty-first century and its incidence has increased each year. Wnt signaling pathways are a set of multi-downstream signaling pathways activated by the binding of Wnt ligands to membrane protein receptors. Wnt signaling pathways regulate protein expression and play important roles in protecting the body's normal physiological metabolism. This review describes Wnt signaling pathways, and then aims to reveal how Wnt signaling pathways participate in the occurrence and development of T2DM. We found that Wnt/c-Jun N-terminal kinase signaling was closely associated with insulin resistance, inflammatory response, and pancreatic β-cell and endothelial dysfunction. β-catenin/transcription factor 7-like 2 (TCF7L2)-mediated and calcineurin/nuclear factor of activated T cells-mediated target genes were involved in insulin synthesis and secretion, insulin degradation, pancreatic β-cell growth and regeneration, and functional application of pancreatic β-cells. In addition, polymorphisms in the TCF7L2 gene could increase risk of T2DM according to previous and the most current results, and the T allele of its variants was a more adverse factor for abnormal pancreatic β-cell function and impaired glucose tolerance in patients with T2DM. These findings indicate a strong correlation between Wnt signaling pathways and T2DM, particularly in terms of pancreatic islet dysfunction and insulin resistance, and new therapeutic targets for T2DM may be identified.

Long Non-coding RNA GAS5 Maintains Insulin Secretion by Regulating Multiple miRNAs in INS-1 832/13 Cells.

Type-2 diabetes mellitus (T2DM) is a complex disease characterized by reduced pancreatic islets β-cell mass and impaired insulin release from these cells. Non-coding RNAs, including microRNAs (miRNA) and long non-coding RNAs (lncRNAs), play a role in the progression of T2DM. Decreased serum lncRNA GAS5 levels were reported to be associated with T2DM. However, the role of GAS5 in regulating islet cell functions remain unknown. In this study, we found that the serum levels of GAS5 were significantly lower in patients with T2DM compared with healthy control subjects, and the low serum GAS5 levels were associated with high levels of HbAlc and fasting glucose in patients with T2DM. In addition, we found that serum GAS5 levels were negatively correlated with the serum levels of miR-29a-3p, miR-96-3p, and miR-208a-3p in patients with T2DM. Consequently, using INS-1 832/13 rat β-cell line, we found that overexpression of GAS5 by lentivirus infection increased glucose-stimulated insulin secretion and insulin content compared with negative control, whereas knockdown of GAS5 expression reduced both them. Moreover, GAS5 interacted with miR-29a-3p, miR-96-3p, and miR-208a-3p in INS-1 832/13 cells, as judged by pull-down assay and dual luciferase reporter assay. GAS5 overexpression caused the decrease in expression of miR-29a-3p, miR-96-3p, and miR-208a-3p in INS-1 832/13 cells and conversely caused the increase in expression of insulin receptor, insulin receptor substrate, and phosphoinositide-3-kinase regulatory subunit 1. Thus, these results reveal a novel mechanism whereby GAS5 is involved in maintaining insulin secretion and may represent a novel therapeutic target for T2DM.

RETRACTED: miR-363 Alleviates Detrusor Fibrosis via the TGF-β1/Smad Signaling Pathway by Targeting Col1a2 in Rat Models of STZ-Induced T2DM

Dysregulated expression of microRNAs (miRNAs or miRs) has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). However, their underlying role in the complication of detrusor fibrosis remains poorly understood. Therefore, this study aimed to examine the potential functional relevance of miR-363 in detrusor fibrosis of rats with streptozotocin (STZ)-induced T2DM through the predicted target gene collagen type I alpha 2 (Col1a2). Immunohistochemical analysis found an increase in the positive expression of collagen type III alpha 1 (Col3a1) and Col1a2 in detrusor tissues, where miR-363 expression was decreased. Next, gain- and loss-of-function experiments were performed to clarify the effects of miR-363 and Col1a2 on the activities of bladder detrusor cells. Of note, binding affinity between miR-363 and Col1a2 was verified by a dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. Upregulated miR-363 inhibited Col1a2 expression, which led to increased expression of B-cell lymphoma 2 (Bcl-2) and Smad7 and accelerated cell viability, along with decreases in cell apoptosis and Col3a1, Bcl-2-associated X protein (Bax), transforming growth factor (TGF)-β1, and Smad4 expressions. In conclusion, miR-363 upregulation reduces detrusor fibrosis in rats with STZ-induced T2DM through suppression of the TGF-β1/Smad signaling pathway by targeting Col1a2. Therefore, our study provided further insights for the development of new therapeutic targets for T2DM.

TRPV1 Antagonists as Novel Anti-Diabetic Agents: Regulation of Oral Glucose Tolerance and Insulin Secretion Through Reduction of Low-Grade Inflammation?

With a global prevalence among adults over 18 years of age approaching 9%, Type 2 diabetes mellitus (T2DM) has reached pandemic proportions and represents a major unmet medical need. To date, no disease modifying treatment is available for T2DM patients. Accumulating evidence suggest that the sensory nervous system is involved in the progression of T2DM by maintaining low-grade inflammation via the vanilloid (capsaicin) receptor, Transient Receptor Potential Vanilloid-1 (TRPV1). In this study, we tested the hypothesis that TRPV1 is directly involved in glucose homeostasis in rodents. TRPV1 receptor knockout mice (Trpv1−/−) and their wild-type littermates were kept on high-fat diet for 15 weeks. Moreover, Zucker obese rats were given the small molecule TRPV1 antagonist, N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), per os twice-a-day or vehicle for eight days. Oral glucose tolerance and glucose-stimulated insulin secretion was improved by both genetic inactivation (Trpv1−/− mice) and pharmacological blockade (BCTC) of TRPV1. In the obese rat, the improved glucose tolerance was accompanied by a reduction in inflammatory markers in the mesenteric fat, suggesting that blockade of low-grade inflammation contributes to the positive effect of TRPV1 antagonism on glucose metabolism. We propose that TRPV1 could be a promising therapeutic target in T2DM by improving glucose intolerance and correcting dysfunctional insulin secretion.

Association of vaspin rs2236242 gene variants with type 2 diabetes and obesity in a Chinese population: A prospective, single-center study.

Vaspin is an adipokine separated from visceral fat tissues of obese diabetic rats. This study was to investigate the association between vaspin rs2236242 gene polymorphism and type 2 diabetes mellitus (T2DM) or obesity in a Chinese population. T2DM patients and nondiabetic controls were recruited from Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University (Shanghai, China) from May 1, 2015 to June 30, 2017. Clinicopathologic characteristics were recorded and their blood samples were collected. Serum vaspin levels were detected by enzyme-linked immunosorbent assay and vaspin rs2236242 genotypes by tetra-amplification refractory mutation system-polymerase chain reaction. Two hundred and ninety-nine patients with T2DM and 311 controls were recruited at last. The vaspin genotypes of diabetic patients were distinct from nondiabetic controls (χ 2 = 54.611, p < 0.0001). Genotyping revealed that T2DM patients have a greater prevalence of A allele compared with controls (61.9% vs. 42.1%, p < 0.0001). A allele was associated with an increased risk of T2DM (odds ratio = 2.23, 95% confidence interval = 1.773-2.804, p < 0.0001) compared with T allele. The genotype distribution did not differ among nondiabetic subjects with or without obesity. The serum vaspin levels were higher in T2DM patients and obese controls than the nonobese controls, however, the rs2236242 was not found to be significantly related to serum vaspin levels. Our findings showed the association between vaspin rs2236242 gene variants with obesity and T2DM in a Chinese population. People with rs2236242 A allele had a 2.23-fold increased risk of T2DM. These findings suggest that vaspin rs2236242 may serve as a potential diagnostic and/or therapeutic targets for T2DM.

Novel protective effect of O-1602 and abnormal cannabidiol, GPR55 agonists, on ER stress-induced apoptosis in pancreatic β-cells

Insulin resistance and β-cell dysfunction are the main defects in Type 2 Diabetes Mellitus (T2DM), and β-cell dysfunction and apoptosis is the critical determinant in the progression of T2DM. G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by endocannabinoids and lipid transmitters. Recently, GPR55 was shown to regulate glucose and energy homeostasis, however its role in β-cell apoptosis was not studied. Therefore, in this study, we investigated the novel effect of GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on endoplasmic reticulum (ER) stress-induced apoptosis in mouse pancreatic β-cell lines, MIN6 and Beta-TC-6, and its underlying mechanisms. Our results showed that O-1602 and Abn-CBD reduced ER stress-induced apoptosis in MIN6 and Beta-TC-6 cells. This was through the phosphorylation of 3′-5′-cyclic adenosine monophosphate response element-binding protein (CREB) in β-cells, hence activating CREB downstream anti-apoptotic genes, Bcl-2 and Bcl-xL. Moreover, O-1602 and Abn-CBD directly activated kinases, CaMKIV, Erk1/2 and PKA, to induce CREB phosphorylation. Therefore, our results indicated that GPR55 agonists protected from β-cell apoptosis through CREB activation, thus up-regulating anti-apoptotic genes. In conclusion, our study provided a novel protective effect of GPR55 agonists on ER stress-induced apoptosis in β-cells and its underlying mechanisms mediating this protection, therefore we suggested that GPR55 might be a therapeutic target for T2DM.