Therapeutic Target For Diabetes Research Articles

Abstract 4122717: An Epigenetic Drug, GSK126 Mitigates Endothelial to Mesenchymal Transition Attenuating Atherosclerosis in Diabetes

Background: Endothelial to mesenchymal transition (EndMT) involves transformation of an endothelial to mesenchymal like cellular state. Recent studies implicate EndMT in atherosclerosis development. Diabetes is associated with both EndMT as well as accelerated atherosclerosis. Experimental evidence supports the use of epigenetic drugs that act on relevant epigenetic mechanisms to attenuate atherosclerosis. Recently, inhibition of a histone methyltransferase Enhancer of zest homolog 2 (EZH2) with GSK-126 attenuated atherosclerosis development. However, the role of EZH2 in induction of EndMT in diabetes induced atherosclerosis is not known. Methods: An in-vitro model of EndMT was generated using high glucose (HG) and TNF-α in human aortic endothelial cells (HAECs). EZH2 methyltransferase activity was inhibited using EZH2 specific inhibitor GSK-126. RNA sequencing was performed in this setting. EZH2 genetic knockdown (shRNA) in HAECs was also performed to validate role of EZH2 in EndMT. In addition, EZH2 mediated H3K27me3 and EndMT was assessed in atheroprone diabetic mouse model. Results: In HAECs, morphological changes as well as gene and protein expression confirmed TNF-α+HG induced EndMT, which was blunted by GSK-126. Elevated EZH2 mediated H3K27me3 activity by the TNF-α + HG stimulation was blunted with GSK-126 treatment. Furthermore, RNA sequencing identified several enriched pathways including AGE-RAGE signaling pathway in diabetic complications, focal adhesion, and leukocyte trans-endothelial migration directly relevant to EndMT and commonly deregulated in diabetic complications, which were rescued by EZH2 inhibition. Transcriptomic analysis showed that 242 genes including MMP2, NOS3 linked to EndMT were dysregulated. Interestingly, expression of 76 dysregulated genes in EndMT were rescued by GSK-126. EZH2 knockdown studies in HAECs also validated the role of EZH2 in EndMT. Furthermore, immunofluorescence staining identified elevated levels of H3K27me3 in the aortic endothelial layer of diabetic Apoe -/- mice. Co-localization of EndMT markers was observed in the endothelial layer of aortic sinus of diabetic Apoe -/- mice which was blunted with GSK-126 treatment. Conclusion: The study identified EZH2 inhibition as a novel therapeutic target in diabetes induced EndMT in atherosclerosis. These findings highlighted ongoing efforts to develop targeted therapies for diabetic patients who are at risk to develop cardiovascular disease.

Molecular Mechanisms of Methylglyoxal in Diabetes-related Macrovascular Complications

Diabetes mellitus (DM) is a chronic endocrine and metabolic disease indicated by the presence of hyperglycemia. It has been known that hyperglycemia and oxidative stress are the main culprit of all DM complications, including macrovascular complications. As a byproduct of lipid, protein, and carbohydrate metabolism, methylglyoxal (MGO) is a highly reactive substance which plays a positive signaling role in helping cells regain redox balance under oxidative stress circumstances. DM-related problems lead to an excess of mitochondrial superoxide in the heart and big and small vascular endothelial cells. Elevated intracellular reactive oxygen species induce impaired angiogenesis in reaction to ischemia, trigger several proinflammatory pathways, and result in enduring epigenetic modifications that propel the continuous expression of proinflammatory genes even after glucose levels return to normal. Over time, the significance of the extremely quick advanced glycation end-products (AGE) production caused by the extremely reactive MGO has been clarified. It is now evident that MGO causes vascular tissue to react maladaptively. Glyoxalase 1 (GLO1) is the primary enzyme in an organism's enzymatic glyoxalase defense mechanism, which converts MGO to D-lactate in order to counteract the harmful effects of MGO. Understanding the role of the MGO–GLO1 pathway in the etiology of vascular disease in diabetes has advanced significantly. Therefore, it can be summarized that vascular damage are linked to diabetes. The AGE precursor MGO are important in determining the connection between diabetes and vascular damage. MGO and AGEs play a role in several phases of the development of diabetes complications. MGO and AGEs may be useful therapeutic targets for diabetes's macrovascular problems.KEYWORDS: hyperglycemia, AGE, methylglyoxal, glyoxalase, D-lactate, gluthatione, oxidative stress.

Unveiling islet heterogeneity using an automated microfluidic imaging system

Islets of Langerhans are a therapeutic target for diabetes and prediabetes. Measurements of therapeutic inhibitory or excitatory concentrations are often performed using large groups of islets, however, the population heterogeneity cannot be observed when examining the ensemble response. Normal islet function and islet response to therapeutic treatment can be affected by islet heterogeneity, influencing the progression of diabetes mellitus. To identify heterogeneity in an islet population, we developed a simple microfluidic device capable of delivering a stimulant to four independent chambers, allowing measurements of individual responses from a population of 20–25 islets. The device enabled accurate delivery of the same stimulant concentration to all four chambers, with an error <1% between chambers. To demonstrate the capability of this system, ensemble and individual EC/IC\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$_{50}$$\\end{document} measurements of glucose and diazoxide were performed on murine islets. Results showed little heterogeneity of glucose EC\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$_{50}$$\\end{document} values with all 21 islets within ± 0.6 mM of the ensemble value of 7.4 mM. In contrast, application of diazoxide to 24 islets in the presence of 20 mM glucose resulted in 37% of islets having an IC\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$_{50}$$\\end{document} greater than 10% from the ensemble value of 10.2 μM. The simple system developed here is amenable to further studies on islet heterogeneity, and is applicable to investigate heterogeneity in other cell types.

A crucial role of adenosine deaminase in regulating gluconeogenesis in mice

Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine to inosine and regulates adenosine concentration. ADA ubiquitously expresses in various tissues to mediate adenosine receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus (T2DM). Here we show that elevated plasma ADA activity is a compensated response to high level of adenosine in T2DM and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA can reduces adenosine levels and decreases hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat-STZ diabetic mice. Mechanistically, ADA catabolizes adenosine and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

Serum Klotho and insulin resistance: Insights from a cross-sectional analysis.

The prevalence of diabetes has surged globally, posing significant health and economic burdens. Insulin resistance underlies the initiation and development of type 2 diabetes. Klotho is a crucial endogenous antiaging factor, associated with atherosclerotic cardiovascular diseases, cancer, neurological disorders, and renal diseases. It additionally has a function in controlling glucose metabolism and holds promise as a new therapeutic target for diabetes. However, its relationship with insulin resistance remains unclear. This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2007 to 2016 data to investigate the relationship between serum Klotho concentrations and insulin resistance. In this observational study, information from the NHANES spanning 2007 to 2016 was employed. The sample consisted of 6371 participants. Weighted linear regression model and chi-square tests were utilized to assess differences in continuous and categorical variables, respectively, among groups categorized by Klotho quartiles. The relationship between Klotho and HOMA-IR (homeostatic model assessment of insulin resistance) was studied using multiple linear regression. Smooth curve fitting was used to analyze nonlinear relationships and the inflection point was determined through a 2-stage linear regression method. After adjusting for multiple confounding factors, serum Klotho levels were found to be positively correlated with insulin resistance [0.90 (0.68, 1.13)]. This correlation is nonlinear and exhibits a saturation effect, with the inflection point identified at 1.24 pg/µL. When Klotho levels are below 1.24 pg/µL, for every unit increase in Klotho, HOMA-IR increases by 1.30 units. Conversely, when Klotho levels exceed 1.24 pg/µL, there is no correlation between HOMA-IR and Klotho. Subgroup analysis reveals that the relationship between HOMA-IR and Klotho varies depending on diabetes and body mass index (BMI). This positive correlation was most prominent in the obese nondiabetic population. There is a positive correlation between serum Klotho and insulin resistance.

LncRNA PVT1 as a Novel Biomarker for Diabetes-related Complications.

Diabetes is now afflicting an expanding population, and it has become a major source of concern for human health. Diabetes affects several organs and causes chronic damage and dysfunction. It is one of the three major diseases that are harmful to human health. Plasmacytoma variant translocation 1 is a member of long non-coding RNA. PVT1 expression profile abnormalities have been reported in diabetes mellitus and its consequences in recent years, suggesting that it may contribute to the disease's progression. Relevant literature from the authoritative database "PubMed" are retrieved and summarized in detail. Mounting evidence reveals that PVT1 has multiple functions. Through sponge miRNA, it can participate in a wide variety of signal pathways and regulate the expression of a target gene. More importantly, PVT1 is crucially implicated in the regulation of apoptosis, inflammation, and so on in different types of diabetes-related complications. PVT1 regulates the occurrence and progression of diabetes-related diseases. Collectively, PVT1 has the potential to be a useful diagnostic and therapeutic target for diabetes and its consequences.

Critical role of FGF21 in diabetic kidney disease: from energy metabolism to innate immunity.

Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease (CKD) on a global scale, with its incidence witnessing a consistent annual rise, thereby imposing a substantial burden on public health. The pathogenesis of DKD is primarily rooted in metabolic disorders and inflammation. Recent years have seen a surge in studies highlighting the regulatory impact of energy metabolism on innate immunity, forging a significant area of research interest. Within this context, fibroblast growth factor 21 (FGF21), recognized as an energy metabolism regulator, assumes a pivotal role. Beyond its role in maintaining glucose and lipid metabolism homeostasis, FGF21 exerts regulatory influence on innate immunity, concurrently inhibiting inflammation and fibrosis. Serving as a nexus between energy metabolism and innate immunity, FGF21 has evolved into a therapeutic target for diabetes, nonalcoholic steatohepatitis, and cardiovascular diseases. While the relationship between FGF21 and DKD has garnered increased attention in recent studies, a comprehensive exploration of this association has yet to be systematically addressed. This paper seeks to fill this gap by summarizing the mechanisms through which FGF21 operates in DKD, encompassing facets of energy metabolism and innate immunity. Additionally, we aim to assess the diagnostic and prognostic value of FGF21 in DKD and explore its potential role as a treatment modality for the condition.

The cGAS-STING pathway: a therapeutic target in diabetes and its complications.

Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is a key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage. However, the contribution of cGAS-STING activation to impaired healing in DWH remains understudied. In this review, we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH. We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing. Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models. We highlight key knowledge gaps regarding cGAS-STING in DWH, including its relationships with endoplasmic reticulum stress and metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH. This review synthesizes current understanding of how cGAS-STING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.

Tetrahydropalmatine from medicinal plants activates human glucokinase to regulate glucose homeostasis.

Many synthetic glucokinase activators (GKAs), modulating glucokinase (GK), an important therapeutic target in diabetes have failed to clear clinical trials. In this study, an in silico structural similarity search with differing scaffolds of reference GKAs have been used to identify derivatives from natural product databases. Ten molecules with good binding score and similar interactions to that in the co-crystallized GK as well good activation against recombinant human GK experimentally were identified. Tetrahydropalmatine, an alkaloid present in formulations and drugs from medicinal plants, has not been explored as an antidiabetic agent and no information regarding its mechanism of action or GK activation exists. Tetrahydropalmatine activates GK with EC50 value of 71.7±17.9μM while lowering the S0.5 (7.1mM) and increasing Vmax (9.22μM/min) as compared to control without activator (S0.5=10.37mM; Vmax=4.8μM/min). Kinetic data (α and β values) suggests it to act as mixed, nonessential type activator. Using microscale thermophoresis, Kd values of 3.8μM suggests a good affinity for GK. In HepG2 cell line, the compound potentiated the uptake of glucose and maintained glucose homeostasis by increasing the expression of GK, glycogen synthase, and insulin receptor genes and lowering the expression of glucokinase regulatory protein (GKRP) and glucagon. Tetrahydropalmatine at low concentrations could elicit a good response by reducing expression of GKRP, increasing expression of GK while also activating it. Thus, it could be used alone or in combination as therapeutic drug as it could effectively modulate GK and alter glucose homeostasis.

Participation of lncRNAs in the development of diabetic complications: Systematic review and meta-analysis. I. Rat.

We evaluated the involvement of lncRNAs in the development of pathologies associated with chronic hyperglycaemia in rat models in a model of type 1, type 2 and gestational diabetes. Reports were searched in Dialnet, Scielo, HINARI, Springer, ClinicalKey, OTseeker, PubMed and different grey literature databases with any restrictions. Bibliography databases will be searched from their inception to December 2022. Thirty-seven studies met our criteria, and they had the following characteristics: original experimental studies on diabetes, the lncRNAs were extracted or measured from tissues of specific areas and the results were expressed in terms of standard measures by RT-PCR. In most studies, both primary and secondary outcomes were mentioned. On the other hand, we found a total of nine diabetic complications, being retinopathy, nephropathy and neuropathy the most representatives. Additionally, it was found that MALAT1, H19, NEAT1 and TUG1 are the most studied lncRNAs about these complications in rats. On the other hand, the lncRNAs with the highest rate of change were MSTRG.1662 (17.85; 13.78, 21.93), ENSRNOT00000093120_Aox3 (7.13; 5.95, 8.31) and NONRATG013497.2 (-5.55; -7.18, -3.93). This review found a significant involvement of lncRNAs in the progression of pathologies associated with chronic hyperglycaemia in rat models, and further studies are needed to establish their potential as biomarkers and therapeutic targets for diabetes.

Breakthrough in microbiome-metabolism disease research: bacterial host isoenzyme DPP4 may become a new therapeutic target for diabetes

Breakthrough in microbiome-metabolism disease research: bacterial host isoenzyme DPP4 may become a new therapeutic target for diabetes

1634-P: Brown Adipose Tissue and Muscle Responses to Tolerable Cold in Black and White Young Lean Men

There has been a renewed interest in brown adipose tissue (BAT) as a therapeutic target for diabetes and obesity treatments due to its ability to consume glucose and expend energy in response to cold temperatures and Beta-adrenergic stimulation. However, comparisons of BAT in different races are limited. To address this knowledge gap, we directly compared healthy, young, lean Black and White men in a controlled inpatient study using a whole-room indirect calorimeter. 12 Black and 12 White men completed a 6-13-day protocol with randomized calorimeter temperatures between 18-31°C for 5 hours. Resting metabolic rate (RMR) was measured under reclined, fasted conditions with standard clothing. Body composition was measured by dual x-ray absorptiometry and BAT and muscle glucose uptake activity was quantified using 18-F Fluorodeoxyglucose (18-F FDG) PET-CT following the last chamber study where each individual's coldest tolerable temperature (Tct) was used. Basal metabolic rate (BMR) was defined as minimum RMR and the cold-induced thermogenesis (CIT) was calculated as the percentage increase of RMR above BMR in the cold. The groups were similar in age (23.8±4.7 yrs) and BMI (23.1±1.5 kg/m2) and their Tct (21.0±1.4°C; p=0.54) and CIT (12.1±8.1 kcal/h; p=0.8) were not different. While White males had significantly higher BAT volume (334 ± 188mL vs 242 ± 89mL; p=0.045), BAT volume was comparable between the groups after normalizing to body volume. BAT activity was similar between the groups. Among all muscle activity measured, the intercostal muscles in the Black males had significantly higher activity (p=0.002) and activity was present in all 12 Black participants but only 4 of 12 White males. Individual BAT or muscle activity did not correlate with each other nor with Tct or CIT. Our data suggest that the cold-induced BAT activity was comparable in Black and White young, lean men. The surprising difference in intercostal muscle activity warrants further investigation. Disclosure R.J.Thomas: None. R.Brychta: None. A.B.Courville: None. S.Mcgehee: None. A.M.Cypess: None. K.Y.Chen: None.

Pax4 in Health and Diabetes

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of β cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote β cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional β-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of β cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic β cells and its potential as a therapeutic target for diabetes.

Association between soluble neprilysin and diabetes: Findings from a prospective longitudinal study.

The potential role of neprilysin (NEP) in glucose metabolism has been found by basic studies but lacks population evidence. The objective of this study was to examine the association between serum NEP and diabetes in Chinese adults. In a prospective longitudinal cohort study - the Gusu cohort (n=2,286, mean age: 52 years, 61.5% females), the cross-sectional, longitudinal, and prospective associations between serum NEP and diabetes were systemically examined by logistic regression adjusting for conventional risk factors. Serum NEP was measured at baseline using commercial ELISA assays. Fasting glucose was repeatedly measured 4 years apart. The cross-sectional analysis found a positive association between serum NEP and fasting glucose at baseline (β=0.08, P=0.004 for log-transformed NEP). This association persisted after controlling for the dynamic risk profiles during follow-up (β=0.10, P=0.023 for log-transformed NEP). The prospective analysis found that a higher level of serum NEP at baseline was associated with a higher risk of diabetes during follow-up (OR=1.79, P=0.039 for log-transformed NEP). Serum NEP was not only associated with prevalent diabetes but also predicted the future risk of diabetes development in Chinese adults, independent of many behavioral and metabolic factors. Serum NEP may be a predictor and even a new therapeutic target for diabetes. However, the casualty and mechanisms of NEP in the development of diabetes require further investigation.

Ferroptosis as a potential new therapeutic target for diabetes and its complications.

Diabetes is a complex metabolic disease. In recent years, diabetes and its chronic complications have become a health hotspot of global concern. It is very important to find promising therapeutic targets and directions. Ferroptosis is a new type of programmed cell death that is different from cell necrosis, apoptosis, and autophagy. Ferroptosis is mainly characterized by iron-dependent lipid peroxidation. With the reduction of the anti-oxidative capacity of cells, the accumulated reactive lipid oxygen species will cause oxidative cell death and lead to ferroptosis at lethal levels. Recent studies have shown that ferroptosis plays an important regulatory role in the initiation and development of diabetes, as well as various complications of diabetes. In this review, we will summarize new findings related to ferroptosis and diabetic complications and propose ferroptosis as a potential target for treating diabetic complications.

Celastrol targets the ChREBP-TXNIP axis to ameliorates type 2 diabetes mellitus

BackgroundsThioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose homeostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications. PurposeThis study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent. Methodsdb/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immunosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohistological staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss- and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM. ResultsCelastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose homeostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its proteasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression. ConclusionCelastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP.

Comparative G-Protein-Coupled Estrogen Receptor (GPER) Systems in Diabetic and Cancer Conditions: A Review.

For many patients, diabetes Mellitus and Malignancy are frequently encountered comorbidities. Diabetes affects approximately 10.5% of the global population, while malignancy accounts for 29.4 million cases each year. These troubling statistics indicate that current treatment approaches for these diseases are insufficient. Alternative therapeutic strategies that consider unique signaling pathways in diabetic and malignancy patients could provide improved therapeutic outcomes. The G-protein-coupled estrogen receptor (GPER) is receiving attention for its role in disease pathogenesis and treatment outcomes. This review aims to critically examine GPER' s comparative role in diabetes mellitus and malignancy, identify research gaps that need to be filled, and highlight GPER's potential as a therapeutic target for diabetes and malignancy management. There is a scarcity of data on GPER expression patterns in diabetic models; however, for diabetes mellitus, altered expression of transport and signaling proteins has been linked to GPER signaling. In contrast, GPER expression in various malignancy types appears to be complex and debatable at the moment. Current data show inconclusive patterns of GPER expression in various malignancies, with some indicating upregulation and others demonstrating downregulation. Further research should be conducted to investigate GPER expression patterns and their relationship with signaling pathways in diabetes mellitus and various malignancies. We conclude that GPER has therapeutic potential for chronic diseases such as diabetes mellitus and malignancy.

Post-transcriptional control by RNA-binding proteins in diabetes and its related complications.

Diabetes mellitus (DM) is a fast-growing chronic metabolic disorder that leads to significant health, social, and economic problems worldwide. Chronic hyperglycemia caused by DM leads to multiple devastating complications, including macrovascular complications and microvascular complications, such as diabetic cardiovascular disease, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. Numerous studies provide growing evidence that aberrant expression of and mutations in RNA-binding proteins (RBPs) genes are linked to the pathogenesis of diabetes and associated complications. RBPs are involved in RNA processing and metabolism by directing a variety of post-transcriptional events, such as alternative splicing, stability, localization, and translation, all of which have a significant impact on RNA fate, altering their function. Here, we purposed to summarize the current progression and underlying regulatory mechanisms of RBPs in the progression of diabetes and its complications. We expected that this review will open the door for RBPs and their RNA networks as novel therapeutic targets for diabetes and its related complications.

Induced Human Regulatory T Cells Express the Glucagon-like Peptide-1 Receptor.

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

In silico ADME-T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy

Context: Tithonia diversifolia (Hemsl.) A. Grayhas been known for treatment of diabetes mellitus, yet its mechanism as anti-diabetic has not been defined. There are various therapeutic targets for diabetes and its complication such as diabetic nephropathy. Aims: To investigate the mechanism of phytoconstituents in Tithonia diversifolia to various targets of diabetic nephropathy and predict the pharmacokinetic profile such as absorption, distribution, metabolism, elimination, and toxicity (ADME-T). Methods: Eighteen phytoconstituents in Tithonia diversifolia were analyzed for drug-likeness. The molecular docking of molecules was performed to protein targets, then its molecular interaction was determined. ADME-T properties were predicted using three different web servers. Results: Drug-likeness analysis showed that all the phytoconstituents were within the range set by Lipinski’s rule of five. This study showed that Tithonia diversifolia have potential as a candidate for diabetic nephropathy therapy agent with various mechanisms by inhibiting α-glucosidase, ACE, ALR, DPP-4, LMW-PTP, RAGE, SGLT2, SUR1, and an analog of PPAR-γ. 5-Caffeoylquinic acid, catechin, diversifolin, hispidulin, tagitinin A, tagitinin C, tagitinin F, tithonine, and tirotundin were phytoconstituents with a high binding affinity to several proteins. β-gurjunene, tagitinin A,tagitinin C, tagitinin F, and tirotundin were predicted to have a better ADME-T properties than other compounds. In summary, tagitinin A, tagitinin C, tagitinin F, and tirotundin were showed the high binding affinity to various diabetes-related proteins and have a good ADME-T profile. Conclusions: This study suggests that Tithonia diversifolia constituents have potential properties as an anti-diabetic nephropathy agent, and further studies to analyze its potency are required.