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INTRODUCTION: Irisin is closely related to type 2 diabetes mellitus (T2DM) and other metabolic diseases. It can improve the homeostasis of T2DM. MiR-133a-3p is decreased in the peripheral blood of patients with T2DM. Forkhead box protein O1 (FOXO1) is widely expressed in beta-cells and affects the occurrence of diabetes through transcriptional regulation and signalling pathway regulation. MATERIAL AND METHODS: The miR-133a-3p inhibitor was constructed to verify the effect of irisin on pyroptosis through miR-133a-3p. Next, we predicted the presence of targeted binding sequences between FOXO1 and miR-133a-3p by bioinformatics software, which was then confirmed with a double fluorescence assay. Finally, the FOXO1 overexpression vector was used to further verify the effect of irisin through the miR-133a-3p/FOXO1 axis. RESULTS: We first observed that irisin inhibited the protein levels of N-terminal gasdermin D (GSDMD-N) and cleaved caspase-1 and the secretion of interleukins (IL): IL-1beta and IL-18 in Min6 cells treated with high glucoes (HG). Irisin inhibited pyroptosis of Min6 cells treated with HG by reinforcing miR-133a-3p. Then, FOXO1 was validated to be the target gene of miR-133a. Both miR-133a-3p inhibitor and overexpression of FOXO1 restrained the force of irisin on pyroptosis in HG-induced Min6 cells. CONCLUSION: We explored the protective effect of irisin on HG-induced pyroptosis of islet b-cells in vitro and explained its mechanism of inhibiting pyroptosis through the miR-133a-3p/FOXO1 axis, to provide a theoretical basis for finding new molecular targets to delay beta-cell failure and the treatment of T2DM.

Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.

Traditional Chinese medicine (TCM) formulations have proven to be advantageous in clinical treatment and prevention of disease. LiuWei DiHuang Pill (LWDH Pill) is a TCM that was employed to treat type 2 diabetes mellitus (T2DM). However, a holistic network pharmacology approach to understanding the active ingredients and the therapeutic mechanisms underlying T2DM has not been pursued. A network pharmacology approach including drug-likeness evaluation, oral bioavailability prediction, virtual docking, and network analysis has been used to predict the active ingredients and potential targets of LWDH Pill in the treatment of type 2 diabetes. The comprehensive network pharmacology approach was successfully to identify 45 active ingredients in LWDH Pill. 45 active ingredients hit by 163 potential targets related to T2DM. Ten of the more highly predictive components (such as :quercetin, Kaempferol, Stigmasterol, beta-sitosterol, Kadsurenone, Diosgenin, hancinone C, Hederagenin, Garcinone B, Isofucosterol) are involved in anti-inflammatory, anti-oxidative stress, and the reduction of beta cell damage. LWDH Pill may play a role in the treatment of T2DM and its complications (atherosclerosis and nephropathy) through the AGE-RAGE signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway. Based on a systematic network pharmacology approach, our works successfully predict the active ingredients and potential targets of LWDH Pill for application to T2DM and helps to illustrate mechanism of action on a comprehensive level. This study provides identify key genes and pathway associated with the prognosis and pathogenesis of T2DM from new insights, which also demonstrates a feasible method for the research of chemical basis and pharmacology in LWDH Pill.

Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.

The discovery of functional brown adipose tissue (BAT) in adult humans and the possibility to recruit beige cells with high thermogenic potential within white adipose tissue (WAT) depots opened the field for new strategies to combat obesity and its associated comorbidities. Exercise training as well as cold exposure and dietary components are associated with the enhanced accumulation of metabolically-active beige adipocytes and BAT activation. Both activated beige and brown adipocytes increase their metabolic rate by utilizing lipids to generate heat via non-shivering thermogenesis, which is dependent on uncoupling protein 1 (UCP1) in the inner mitochondrial membrane. Non-shivering thermogenesis elevates energy expenditure and promotes a negative energy balance, which may ameliorate metabolic complications of obesity and Type 2 Diabetes Mellitus (T2DM) such as insulin resistance (IR) in skeletal muscle and adipose tissue. Despite the recent advances in pharmacological approaches to reduce obesity and IR by inducing non-shivering thermogenesis in BAT and WAT, the administered pharmacological compounds are often associated with unwanted side effects. Therefore, lifestyle interventions such as exercise, cold exposure, and/or specified dietary regimens present promising anchor points for future disease prevention and treatment of obesity and T2DM. The exact mechanisms where exercise, cold exposure, dietary interventions, and pharmacological treatments converge or rather diverge in their specific impact on BAT activation or WAT browning are difficult to determine. In the past, many reviews have demonstrated the mechanistic principles of exercise- and/or cold-induced BAT activation and WAT browning. In this review, we aim to summarize not only the current state of knowledge on the various mechanistic principles of diverse external stimuli on BAT activation and WAT browning, but also present their translational potential in future clinical applications.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. Results: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. Conclusions: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.

BackgroundWith the rising incidence of Type 2 Diabetes Mellitus (T2DM) and the number of undiagnosed cases, there is an urgent need for innovative strategies for early identification of individuals at higher risk. To address this, we explore the utility of deep learning applied to 12-lead electrocardiograms (ECGs) for predicting the risk of incident T2DM in non-diabetic individuals, offering a novel approach for early detection and risk stratification.MethodsThe AI-ECG model, developed on the Beth Israel Deaconess Medical Center (BIDMC) dataset of 1.1 million ECGs and externally validated in the UK Biobank (UKB, N = 65,606), employs a residual neural network architecture tailored for a discrete-time survival model. Model performance was evaluated using the concordance index (C-index), and its enhancement of traditional risk factors was assessed via likelihood ratio tests (LRT) and net reclassification index (NRI). We also explored associations with clinical and echocardiographic features through a phenome-wide association study (PheWAS), and with genetic loci through a genome-wide association study (GWAS).ResultsThe model predicted future T2DM in non-diabetic outpatient individuals with a C-index of 0.666 (0.658–0.675) in BIDMC and 0.689 (0.663–0.715) in UKB. The model showed consistent performance in both sexes, across ethnic groups, and BMI categories, except for patients aged ≥ 65. An improved performance was noted in individuals aged < 65, with a C-index of 0.691 (0.681, 0.701) and 0.765 (0.730, 0.797) in UKB. Adding the AI-ECG model to age, sex, BMI, and ECG parameters significantly enhanced predictive accuracy in the BIDMC cohort (p < 0.0001). Similarly, adding the model to the American Diabetes Association (ADA) risk score in the UKB substantially improved predictive accuracy (p < 0.0001). The continuous Net Reclassification Improvement (NRI) was 0.30 (0.22–0.40) for the BIDMC and 0.35 (0.21–0.47) for the UKB.The PheWAS and echocardiographic analyses identified significant associations between model predictions and a range of cardiac and non-cardiac phenotypes, including lipid profiles, glycaemic control, blood pressure, as well as echocardiographic measures of cardiac structure and function. This was substantiated by the GWAS study, highlighting genes associated with left ventricular structure, left atrial function, myocardial mass, blood pressure, T2DM, and HbA1C.ConclusionWe have developed an AI-ECG model capable of predicting the risk of future T2DM in non-diabetic outpatient populations, validated in both primary and secondary care cohorts. The model enhances T2DM risk prediction and stratification when integrated with traditional risk factors and scores. Its application in primary care settings holds promise for the early identification of individuals at higher risk of T2DM, enabling timely interventions and personalised management.Conflict of InterestNone

The epidemic of the century, Diabetes Mellitus (DM) is continuously rising. Intensive research is urgently needed whereby experimental models represent an essential tool to optimise the diagnostic strategy and to improve therapy. In this review, we describe the central principles of the metabolic tests available in order to study glucose and insulin homeostasis in mice, focusing on the most widely used - the glucose and insulin tolerance tests. We provide detailed experimental procedures as well as the practical implementation of these methods and discuss the main factors that should be taken into account when using this methodology.

Background Diabetic kidney disease (DKD) is a globally prominent microvascular sequela of Type 2 Diabetes Mellitus (T2DM), making effective early prevention paramount. The well-established cardiorenal benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) are largely derived from studies on patients with T2DM. Clear evidence is lacking to support the use of SGLT2i as a first-line monotherapy in newly diagnosed T2DM patients who have not yet initiated other glucose-lowering or protective agents. This study aimed to fill this knowledge gap by assessing the acute impact of Dapagliflozin on reducing albuminuria and correcting metabolic derangements during this critical early disease window to halt disease progression at its onset. Methods This quasi-experimental study conducted over a 3-month intervention period, included 133 newly diagnosed T2DM patients (76 males, 57 females) with evidence of micro- or macro-albuminuria. All patients were treated with Dapagliflozin 10 mg/day, primary and secondary endpoints were assessed by cardiorenal markers (albumin-to creatinine ratio (ACR) and calculated glomerular filtration rate (GFR)), metabolic marker (HbA1c), Anthropometric parameters (BMI and blood pressure), were measured at baseline and follow-up, Paired t-tests were used for pre- and post-intervention analysis. Results Dapagliflozin significantly improved both metabolic and renal markers within the short follow-up period. The primary outcome, ACR, declined markedly from 108.44 mg/g to 65.79 mg/g ( P  < 0.001), representing a mean relative reduction of approximately 40%. Glycemic control was rapidly achieved, with a mean HbA1c drop from 9.04% to 7.31% ( P  < 0.001). While calculated GFR remained stable overall, a significant reduction in systolic blood pressure was also observed ( P  < 0.001). Conclusion Dapagliflozin demonstrates a rapid and multi-organ protective effect when introduced early in T2DM, achieving potent reduction in albuminuria and excellent glycemic control while preserving kidney function stability. These findings strongly support the integration of SGLT2i as a first-line therapy to mitigate cardiorenal risk from the earliest stages of T2DM.