Rising tide: The global surge of type 2 diabetes in children and adolescents demands action now

Childhood-onset obesity has emerged as a major public healthcare challenge across the globe,fueled by an obesogenic environment and influenced by both genetic and epigenetic predispositions.This has led to an exponential rise in the incidence of type 2 diabetes mellitus in children and adolescents.The looming wave of diabetes-related complications in early adulthood is anticipated to strain the healthcare budgets in most countries.Unless there is a collective global effort to curb the devastation caused by the situation,the impact is poised to be pro-found.A multifaceted research effort,governmental legislation,and effective social action are crucial in attaining this goal.This article delves into the current epidemiological landscape,explores evidence concerning potential risks and consequences,delves into the pathobiology of childhood obesity,and discusses the latest evidence-based management strategies for diabesity.

Management of male obesity-related secondary hypogonadism:A clinical update

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism(MOSH)with emerging evidence on the role of testosterone therapy.We aim to provide an updated and practical approach towards its management.We did a comprehensive literature search across MEDLINE(via PubMed),Scopus,and Google Scholar databases using the keywords“MOSH”OR“Obesity-related hypogonadism”OR“Testosterone replacement therapy”OR“Selective estrogen receptor modulator”OR“SERM”OR“Guidelines on male hypogonadism”as well as a manual search of references within the articles.A narrative review based on available evidence,recommendations and their practical implications was done.Although weight loss is the ideal therapeutic strategy for patients with MOSH,achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice.Therefore,androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity.However,there is conflicting evidence for the appropriate use of testosterone replacement therapy(TRT),and it can also be associated with complications.This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH.Before starting testosterone replacement in functional hypogonadism of obesity,it would be desirable to initiate lifestyle modification to ensure weight reduction.TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients.Balancing the risks and benefits of TRT should be considered in every patient before and during longterm management.

Outcome of COVID-19 infection in patients on antihypertensives:A cross-sectional study

BACKGROUND Patients with coronavirus disease 2019(COVID-19)infection frequently have hypertension as a co-morbidity,which is linked to adverse outcomes.Antihypertensives may affect the outcome of COVID-19 infection.AIM To assess the effects of antihypertensive agents on the outcomes of COVID-19 infection.METHODS A total of 260 patients were included,and their demographic data and clinical profile were documented.The patients were categorized into nonhypertensive,angiotensin-converting enzyme inhibitor/angiotensin receptor blocker(ACEI/ARB),calcium channel blocker(CCB),a combination of ACEI/ARB and CCB,and beta-blocker groups.Biochemical,hematological,and inflammatory markers were measured.The severity of infection,intensive care unit(ICU)intervention,and outcome were recorded.RESULTS The mean age of patients was approximately 60-years-old in all groups,except the nonhypertensive group.Men were predominant in all groups.Fever was the most common presenting symptom.Acute respiratory distress syndrome was the most common complication,and was mostly found in the CCB group.Critical cases,ICU intervention,and mortality were also higher in the CCB group.Multivariable logistic regression analysis revealed that age,duration of antihypertensive therapy,erythrocyte sedimentation rate,high-sensitivity C-reactive protein,and interleukin 6 were significantly associated with mortality.The duration of antihypertensive therapy exhibited a sensitivity of 70.8%and specificity of 55.7%,with a cut-off value of 4.5 years and an area under the curve of 0.670(0.574-0.767;95%confidence interval)for COVID-19 outcome.CONCLUSION The type of antihypertensive medication has no impact on the clinical sequence or mortality of patients with COVID-19 infection.However,the duration of antihypertensive therapy is associated with poor outcomes.

Management of diabesity:Current concepts

The global prevalence of obesity is increasing rapidly with an exponential rise in incidence of type 2 diabetes mellitus in recent years.‘Diabesity’,the term coined to show the strong interlink between obesity and diabetes,is the direct cons-equence of the obesity pandemic,and poses significant challenges in the management of the disease.Without addressing the clinical and mechanistic complications of obesity such as metabolic-associated fatty liver disease and obstructive sleep apnoea,a rational management algorithm for diabesity cannot be developed.Several classes of anti-diabetic medications including insulins,sulphonylureas,thiazolidinediones and meglitinides are associated with the risk of weight gain and may potentially worsen diabesity.Therefore,appropriate selection of antidiabetic drug regimen is crucial in the medical management of diabesity.The role of non-pharmacological measures such as dietary adjustments,exercise interventions and bariatric procedures should also be emphasised.Unfortunately,the importance of appropriate and optimal management of diabesity is often overlooked by medical professionals when achieving adequate glycemic control which results in inappropriate management of the disease and its complications.This review provides a narrative clinical update on the evidence behind the management of diabesity.

Artificial intelligence in the diagnosis of thyroid cancer:Recent advances and future directions

The diagnosis and management of thyroid cancer is fraught with challenges despite the advent of innovative diagnostic,surgical,and chemotherapeutic modalities.Challenges like inaccuracy in prognostication,uncertainty in cytopathological diagnosis,trouble in differentiating follicular neoplasms,intra-observer and inter-observer variability on ultrasound imaging preclude personalised treatment in thyroid cancer.Artificial intelligence(AI)is bringing a paradigm shift to the healthcare,powered by quick advancement of the analytic techniques.Several recent studies have shown remarkable progress in thyroid cancer diagnostics based on AI-assisted algorithms.Application of AI techniques in thyroid ultrasonography and cytopathology have shown remarkable improvement in sensitivity and specificity over the traditional diagnostic modalities.AI has also been explored in the development of treatment algorithms for indeterminate nodules and for prognostication in the patients with thyroid cancer.The benefits of high repeatability and straightforward implementation of AI in the management of thyroid cancer suggest that it holds promise for clinical application.Limited clinical experience and lack of prospective validation studies remain the biggest drawbacks.Developing verified and trustworthy algorithms after extensive testing and validation using prospective,multi-centre trials is crucial for the future use of AI in the pipeline of precision medicine in the management of thyroid cancer.

Non-pharmacological interventions for diabetic peripheral neuropathy:Are we winning the battle?

Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy(DPN),such as nerve conduction studies,there is still a knowledge gap about the pathophysiology,and thus limited available in-terventions for symptom control and curtailing disease progression.The pharma-cologic aspect of management is mainly centred on pain control,however,there are several important aspects of DPN such as loss of vibration sense,pressure sense,and proprioception which are associated with risks to lower limb health,which pharmacotherapy does not address.Furthermore,published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy,to reach a desired,however modest effect.Acupuncture is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain syndromes.In their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters,Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment cessation.Although previous studies also support these findings,larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are required.Overall,given the satisfactory safety profile and the positive results found in these studies,it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.

Diabetes and tuberculosis:An emerging dual threat to healthcare

Tuberculosis(TB)remains a huge global healthcare challenge even in the 21^(st) century though the prevalence has dropped in developed countries in recent decades.Diabetes mellitus(DM)is an important risk factor for the development and perpetuation of TB owing to the immune dysfunction in patients with DM.The coexistence of both diseases in the same individual also aggravates disease severity,complications,and chance of treatment failure because of gross immune alterations posed by DM as well as TB.Various complex cellular and humoral immunological factors are involved in the dangerous interaction between TB and DM,some of which remain unknown even today.It is highly important to identify the risk factors for TB in patients with DM,and vice versa,to ensure early diagnosis and management to prevent complications from this ominous coexistence.In their research study published in the recent issue of the World Journal of Diabetes,Shi et al elaborate on the factors associated with the development of TB in a large cohort of DM patients from China.More such research output from different regions of the world is expected to improve our knowledge to fight the health devastation posed by TB in patients with diabetes.

Diabetic cardiomyopathy:Emerging therapeutic options

Diabetic cardiomyopathy(DbCM)is a common but underrecognized complication of patients with diabetes mellitus(DM).Although the pathobiology of other cardiac complications of diabetes such as ischemic heart disease and cardiac autonomic neuropathy are mostly known with reasonable therapeutic options,the mechanisms and management options for DbCM are still not fully understood.In its early stages,DbCM presents with diastolic dysfunction followed by heart failure(HF)with preserved ejection fraction that can progress to systolic dysfunction and HF with reduced ejection fraction in its advanced stages unless appropriately managed.Apart from prompt control of DM with lifestyle changes and antidiabetic medications,disease-modifying therapy for DbCM includes prompt control of hypertension and dyslipidemia inherent to patients with DM as in other forms of heart diseases and the use of treatments with proven efficacy in HF.A basic study by Zhang et al,in a recent issue of the World Journal of Diabetes elaborates the potential pathophysiological alterations and the therapeutic role of teneligliptin in diabetic mouse models with DbCM.Although this preliminary basic study might help to improve our understanding of DbCM and offer a potential new management option for patients with the disease,the positive results from such animal models might not always translate to clinical practice as the pathobiology of DbCM in humans could be different.However,such experimental studies can encourage more scientific efforts to find a better solution to treat patients with this enigmatic disease.

The role of artificial intelligence technology in the care of diabetic foot ulcers: the past, the present, and the future

Foot ulcers are common complications of diabetes mellitus and substantially increase the morbidity and mortality due to this disease.Wound care by regular monitoring of the progress of healing with clinical review of the ulcers,dressing changes,appropriate antibiotic therapy for infection and proper offloading of the ulcer are the cornerstones of the management of foot ulcers.Assessing the progress of foot ulcers can be a challenge for the clinician and patient due to logistic issues such as regular attendance in the clinic.Foot clinics are often busy and because of manpower issues,ulcer reviews can be delayed with detrimental effects on the healing as a result of a lack of appropriate and timely changes in management.Wound photographs have been historically useful to assess the progress of diabetic foot ulcers over the past few decades.Mobile phones with digital cameras have recently revolutionized the capture of foot ulcer images.Patients can send ulcer photographs to diabetes care professionals electronically for remote monitoring,largely avoiding the logistics of patient transport to clinics with a reduction on clinic pressures.Artificial intelligence-based technologies have been developed in recent years to improve this remote monitoring of diabetic foot ulcers with the use of mobile apps.This is expected to make a huge impact on diabetic foot ulcer care with further research and development of more accurate and scientific technologies in future.This clinical update review aims to compile evidence on this hot topic to empower clinicians with the latest developments in the field.

Dehydroepiandrosterone sulfate supplementation in health and diseases

Dehydroepiandrosterone sulfate(DHEAS)is a hormone produced by the zona reticularis of the adrenal gland and the ovaries.Initially considered as an inert compound merely serving as an intermediate in the conversion of cholesterol to androgens,interest in DHEA began to grow in the 1960s when it was found that DHEAS is the most abundant steroid hormone in human plasma and that its levels decline with age.In many countries,DHEA is considered a nutritional supplement.It has been used for a multitude of conditions which include sexual dysfunction,infertility,genitourinary syndrome of menopause,musculoskeletal disorders,cardiovascular diseases,ageing,neurological diseases,autoimmune conditions,adrenal insufficiency,and anorexia nervosa.We describe an overview of the historical evolution of DHEA,its physiology,and the disease states where it has been evaluated as a supplement.

Simultaneous pancreas-kidney transplantation for end-stage renal failure in type 1 diabetes mellitus: Current perspectives

Type 1 diabetes mellitus(T1DM)is one of the important causes of chronic kidney disease(CKD)and end-stage renal failure(ESRF).Even with the best available treatment options,management of T1DM poses significant challenges for clinicians across the world,especially when associated with CKD and ESRF.Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM.Simultaneous pancreas-kidney transplant(SPK)is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications.However,limited availability of the organs for transplantation,the need for long-term immunosuppression to prevent rejection,peri-and post-operative complications of SPK,lack of resources and the expertise for the procedure in many centers,and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe.This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.

CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome

Genetic manipulation of mitochondrial DNA(mtDNA)could be harnessed for deciphering the gene function of mitochondria;it also acts as a promising approach for the therapeutic correction of pathogenic mutation in mtDNA.However,there is still a lack of direct evidence showing the edited mutagenesis within human mtDNA by clustered regularly interspaced short palindromic repeats-associated protein 9(CRISPR/Cas9).Here,using engineered CRISPR/Cas9,we observed numerous insertion/deletion(InDel)events at several mtDNA microhomologous regions,which were triggered specifically by double-strand break(DSB)lesions within mtDNA.InDel mutagenesis was significantly improved by sgRNA multiplexing and a DSB repair inhibitor,iniparib,demonstrating the evidence of rewiring DSB repair status to manipulate mtDNA using CRISPR/Cas9.These findings would provide novel insights into mtDNA mutagenesis and mitochondrial gene therapy for diseases involving pathogenic mtDNA.

A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling

Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases(CKD).Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease;but their exact roles in this disease and renal fibrosis have not been explored.Here,we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model.In the obstructed kidneys,Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling.Instead,decreased levels of TGF-β1 and TGF-βreceptors(TβRs)were detected in Lrp5 knockout kidneys,followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules,suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling.In consistent with this hypothesis,LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells.Furthermore,LRP5 was co-immunoprecipitated with TβRI and TβRII,and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity.In addition to stabilizing TβRs,LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors.Notably,TGF-β1 also induced LRP5 internalization.These findings indicate that LRP5 promotes tubulointerstitial fibrosis,at least partially,via direct modulation of TGF-β/Smad signaling,a novel,Wnt-independent function.

Modulatory effect on dyslipidemia and anti-atherosclerotic function of Xuezhikang in newly diagnosed type 2 diabetes patients

The modulatory effect of Xuezhikang on dysli-pidemia and the preventive effect on atherosclerosis in newly diagnosed type 2 diabetic patients were studied.A prospective clinical trial was conducted to test the effec-tiveness of Xuezhikang in selected 201 newly diagnosed type 2 diabetic patients.All patients were randomly divided into two groups:108 with Xuezhikang therapy and 93 without Xuezhikang therapy.The mean follow-up period was 22 months.The blood glucose and blood pressure of all patients were under control.Serum levels of total cholesterol(TC),triglyceride(TG),and low density lipoprotein cholesterol(LDL-C)were significantly low-ered and their decreased percentages were significantly higher in Xuezhikang therapy group(P<0.05).The num-ber of patients with arteria iliaca intima thickening was significantly lower in group of Xuezhikang therapy(P=0.024).With stepwise multivariate logistic regression analysis,the decreased percentage of TG was significantly and independently related with the decreased number of patients with arteria iliaca intima thickening(P=0.005).The study demonstrates that Xuezhikang therapy is effec-tive on modulating dyslipidemia in newly diagnosed type 2 diabetes patients,and may be related with the improve-ment of early atherosclerosis.

The first E59Q mutation identified in the NEUROD1 gene in a Chinese family with maturity-onset diabetes of the young: an observational study

Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity,therefore causing the MODY6 subtype with defective insulin secretion.

Interaction between neutrophil extracellular traps and cardiomyocytes contributes to atrial fibrillation progression

Atrial fibrillation(AF)is a frequent arrhythmia associated with cardiovascular morbidity and mortality.Neutrophil extracellular traps(NETs)are DNA fragments with cytoplasm proteins released from neutrophils,which are involved in various cardiovascular diseases.To elucidate the role of NETs in AF,we investigated the effect of NETs on AF progression and the secretion of NETs in AF.Results showed that:NETs induced the autophagic apoptosis of cardiomyocytes,and NETs also led to mitochondrial injury by promoting mitochondrial depolarization and ROS production.Ongoing tachy-pacing led to the structural loss of cardiomyocytes and provided potent stimuli to induce NETs secretion from neutrophils.In the meanwhile,increased Ang II in AF facilitated NETs formation through the upregulation of AKT phosphorylation,while it could not directly initiate NETosis as the autophagy was not induced.In vivo,DNase I was administrated to abrogate NETs formation,and AF-related fibrosis was ameliorated as expected.Correspondingly,the duration of the induced AF was reduced.Our study addresses the formation mechanism of NETs in AF and demonstrates the lethal effects of NETs on cardiomyocytes through the induction of mitochondrial injury and autophagic cell death,which comprehensively describes the positive feedback comprised of NETs and stimuli secreted by cardiomyocytes that sustains the progression of AF and AF related fibrosis.

SBC(Sanhuang Xiexin Tang combined with Baihu Tang plus Cangzhu)alleviates NAFLD by enhancing mitochondrial biogenesis and ameliorating inflammation in obese patients and mice

In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis—a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.

Human umbilical cord-derived mesenchymal stem cells alleviate oxidative stress-induced islet impairment via the Nrf2/HO-1 axis

Hyperglycaemia-induced oxidative stress may disrupt insulin secretion andβ-cell survival in diabetes mellitus by overproducing reactive oxygen species.Human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)exhibit antioxidant properties.However,the mechanisms by which hUC-MSCs protectβ-cells from high glucose-induced oxidative stress remain underexplored.In this study,we showed that intravenously injected hUC-MSCs engrafted into the injured pancreas and promoted pancreaticβ-cell function in a mouse model of type 1 diabetes mellitus.The in vitro study revealed that hUC-MSCs attenuated high glucoseinduced oxidative stress and preventedβ-cell impairment via the Nrf2/HO-1 signalling pathway.Nrf2 knockdown partially blocked the anti-oxidative effect of hUC-MSCs,resulting inβ-cell decompensation in a high-glucose environment.Overall,these findings provide novel insights into how hUC-MSCs protectβ-cells from high glucose-induced oxidative stress.

Clinical evidence and treatment requirements related to heart failure in type 2 diabetes mellitus

Heart failure(HF),which is a common and serious complication of diabetes,has received more attention in recent years.One reason for this focus on HF is that,with a large reduction in atherothrombotic events after acute myocardial infarction,HF is a relatively more frequently encountered cardiac outcome in patients with type 2 diabetes(T2DM).Another reason is the unexpected reduction in hospitalization for HF observed in cardiovascular outcome trials with sodium-glucose co-transporter-2 inhibitors(SGLT2is).[1-3]These findings led to speculation by clinicians and researchers on whether more effort should be made to differentiate patients with diabetes at a high risk of developing HF.

Bacteroides ovatus-mediated CD27^(−)MAIT cell activation is associated with obesity-related T2D progression

Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.