Individualized coefficient of variability cut-off values for reducing the risk of hypoglycemia in Chinese type 1 diabetes mellitus(T1DM)patients

To the Editor:Type 1 diabetes mellitus(T1DM)is a progressive disease caused by severe islet b-cell function impairment,resulting in high glucose variability(GV)in patients.[1]While intensive insulin treatment enabled T1DM patients to achieve near-normal glucose,reflected by reduced hemoglobin A1c(HbA1c)levels,stricter HbA1c targets were associated with an increased risk of hypoglycemia,which would compromise patients’quality of life and survival.[2]Recent studies suggest that GV reflects hypoglycemia better than HbA1c alone,and continuous glucose monitoring(CGM)provides a more comprehensive glycemic profile for better glucose indices assessment.[3]Therefore,we aimed to explore the relationship between the coefficient of variability(CV)of blood glucose and hypoglycemia in T1DM patients with different HbA1c levels and to identify the optimal cut-off values of CV for reducing the hypoglycemia risk in Chinese T1DM patients.

Implications of glycemic risk index across different levels of glycated hemoglobin(HbA1c)in type 1 diabetes

To the Editor:Glycemic control in individuals with type 1 diabetes(T1D)is challenging and requires multidimensional evaluation and precise management.Glycated hemoglobin(HbA1c)is currently the gold standard for assessing glucose control and predicting diabetes prognosis.However,it exhibits limitations in terms of accuracy,which is influenced by clinical factors,^([1])and its inability to reflect information about hypoglycemia and glycemic variability.[2]Continuous glucose monitoring(CGM)has revolutionized glycemic profile evaluation by introducing novel glycemic variables that surpass conventional parameters and offer insights into critical areas for improving glycemic control.

Prevalence of maturity-onset diabetes of the young in phenotypic type 2 diabetes in young adults:a nationwide,multi-center,cross-sectional survey in China

Background:Maturity-onset diabetes of the young(MODY)is the most common monogenic diabetes.The aim of this study was to assess the prevalence of MODY in phenotypic type 2 diabetes(T2DM)among Chinese young adults.Methods:From April 2015 to October 2017,this cross-sectional study involved 2429 consecutive patients from 46 hospitals in China,newly diagnosed between 15 years and 45 years,with T2DM phenotype and negative for standardized glutamic acid decarboxylase antibody at the core laboratory.Sequencing using a custom monogenic diabetes gene panel was performed,and variants of 14 MODY genes were interpreted as per current guidelines.Results:The survey determined 18 patients having genetic variants causing MODY(6 HNF1A,5 GCK,3 HNF4A,2 INS,1 PDX1,and 1 PAX4).The prevalence of MODY was 0.74%(95%confidence interval[CI]:0.40-1.08%).The clinical characteristics of MODY patients were not specific,72.2%(13/18)of them were diagnosed after 35 years,47.1%(8/17)had metabolic syndrome,and only 38.9%(7/18)had a family history of diabetes.No significant difference in manifestations except for hemoglobin A1c levels was found between MODY and non-MODY patients.Conclusion:The prevalence of MODY in young adults with phenotypic T2DM was 0.74%,among which HNF1A-,GCK-,and HNF4A-MODY were the most common subtypes.Clinical features played a limited role in the recognition of MODY.

Combination therapy with saxagliptin and vitamin D for the preservation ofβ-cell function in adult-onset type 1 diabetes:a multi-center,randomized,controlled trial

Disease modifying therapies aiming to preserveβ-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking.Here,we conducted a multi-centre,randomized,controlled trial to assess theβ-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes.In this 3-arm trial,301 participants were randomly assigned to a 24-month course of the conventional therapy(metformin with or without insulin)or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy.The primary endpoint was the change from baseline to 24 months in the fasting C-peptide.The secondary endpoints included the area under the concentration-time curve(AUC)for C-peptide level in a 2-h mixed-meal tolerance test,glycemic control,total daily insulin use and safety,respectively.The primary endpoint was not achieved in saxagliptin plus vitamin D group(P=0.18)and saxagliptin group(P=0.26).However,compared with the conventional therapy,2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D(-276 pmol/L vs.-419 pmol/L;P=0.01),and not to the same degree with saxagliptin alone(-314 pmol/L;P=0.14).Notably,for participants with higher glutamic acid decarboxylase antibody(GADA)levels,the decline ofβ-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group(P=0.001).Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control.In conclusion,the combination of saxagliptin and vitamin D preserves pancreaticβ-cell function in adult-onset autoimmune type 1 diabetes,an effect especially efficacious in individuals with higher GADA levels.Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes.(ClinicalTrials.gov identifier:NCT02407899).

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus

Objective： To evaluate the utility of zinc transporter-8 （ZnT8） in the improvement of type 1 diabetes mellitus （T1DM） diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in TI DM. Data Sources： A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows： ＂ZnTS,＂ ＂type 1 diabetes,＂ ＂latent autoimmune diabetes in adults,＂ ＂type 2 diabetes,＂ ＂islet autoantibodies,＂ ＂zinc supplement,＂ ＂T cells,＂ ＂[3 cell,＂ ＂immune therapy.＂ We also searched the reference lists of selected articles. Study Selection： English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed. Results： The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 （ZnTSA） and ZnTS-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy. Conclusions： ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.

miRNAs： novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

MicroRNAs （miRNAs） are a series of conserved, short, non-coding RNAs that modulate gene expression in a posttranscriptional manner, miRNAs are involved in almost every physiological and pathological process. Type 1 diabetes （TID） is an autoimmune disease that is the result of selective destruction of pancreatic p-cells driven by the immune system, miRNAs are also important participants in TID pathogenesis. Herein, we review the most recent data on the potential involvement of miRNAs in TID. Specifically, we focus on two aspects： the roles of miRNAs in maintaining immune homeostasis and regulating β-cell survival and/or functions in TID. We also discuss circulating miRNAs as potent biomarkers for the diagnosis and prediction of TID and investigate potential therapeutic approaches for this disease.

Diagnostic criteria of latent autoimmune diabetes in adults(LADA):a review and reflection

Diabetes has become a major public health problem in China nowadays.There are almost 97 million diabetic patients nationwide.Latent autoimmune diabetes in adults(LADA)is a subtype of autoimmune diabetes.Although it has been reported for about 20 years,the diagnostic criteria of this disease remain controversial.The discussion mainly focused on serum autoantibodies,period of insulin need and age of diagnosis.Besides,β cell function,metabolic parameters,genetic factors and cell immunity may also contribute to the formulation of the criteria.Here,we aim to review and discuss the diagnostic criteria of latent autoimmune diabetes in adults.

Associations of insulin resistance and beta-cell function with abnormal lipid profile in newly diagnosed diabetes

Background:Abnormal lipids are strong predictors of cardiovascular disease in type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).However,the potential associations of insulin resistance(IR)and beta-cell function(BCF)with abnormal lipids in newly diagnosed T1DM or T2DM patients are not fully understood.Methods:A cross-sectional survey of 15,928 participants was conducted.Homeostasis model assessment and postprandial C-peptide levels were used to estimate IR and BCF.A restricted cubic spline(RCS)nested in binary logistic regression was used to examine the associations of IR and BCF with abnormal lipids.Results:High triglyceride(TG),low high-density lipoprotein cholesterol,and high low-density lipoprotein cholesterol(LDL-C)accounted for 49.7%,47.8%,and 59.2%of the participants,respectively.In multivariable analysis,high IR was associated with an increased risk of high TGs(P for trend<0.001)in T1DM and is associated with an elevated risk of high TG and low HDL-C(all P for trend<0.01)in T2DM.Low BCF was not associated with risks of dyslipidemia in patients with T1DM or T2DM after adjustment for potential confounders.Conclusion:High IR had different associations with the risk of dyslipidemia in newly diagnosed T1DM and T2DM patients,suggesting that early treatment that improves IR may benefit abnormal lipid metabolism.

Identification of monocyte-related transcriptomic signature of peripheral blood mononuclear cells in type 1 diabetes

To the Editor:Type 1 diabetes(T1D)is caused by autoimmunity-mediated destruction of pancreatic islet beta cells,with islet autoimmunity being the essential component in the pathogenesis of T1D.[1]However,studies on human islets are limited due to sampling difficulties.Therefore,immunological changes in peripheral blood mononuclear cells(PBMCs)should be emphasized.In one way,islet-infiltrating immune cells are presumably in equilibrium with circulating pools and changes in PBMCs might partly reflect islet inflammation.On the other,PBMCs represent a useful tool to detect biomarkers for disease.[2]Traditionally,studies on PBMCs in T1D are characterized by the use of limited numbers of cell-surface markers and secreted cytokines measured using flow detection and other antibody-based assays.

Schistosoma japonicum Eggs Exerts Protective Effects in an Experimental Ulcerative Colitis Model

Ulcerative colitis(UC)is a chronic inflammatory disease affecting the colon,with an increasing incidence worldwide.Disease pathogenesis is multifactorial and involves genetic predisposition,epithelial barrier defects,dysregulated immune responses,and environmental factors[1,2].

Structured nutrition and advanced carbohydrate counting questionnaire for adult type 1 diabetes

To the Editor:Advanced carbohydrate counting(CC)is a recommended dietary strategy and necessary nutritional knowledge for individuals with type 1 diabetes mellitus(T1DM).^([1])Evidence supports the positive effects of advanced CC on glucose control,quality of life,and food flexibility.^([2])However,the education and awareness of advanced CC are far from ideal for T1DM patients and even healthcare professionals.^([3])Accordingly,a measure for T1DM patients that quantifies their understanding of such nutrition knowledge would be essential for tailored care.

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy(STRATEGY):a multicenter,randomized,controlled,non-inferiority clinical trial

Despite the current guideline's recommendation of a timely stepwise intensification therapy,the "clinical inertia",termed as the delayed treatment intensification,commonly exists in the real world,which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy.In this clinical trial performed in 237 centers in China,5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks.The patients who did not reach the glycated hemoglobin A1c(HbA1c) goal were then further randomized into glimepiride,gliclazide,repaglinide,or acarbose group for an additional 24-week triple therapy.A mean HbAlc reduction of 0.85%was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks.Further HbAlc reductions in the 24-week triple therapy stage were 0.65%in glimepiride group,0.70%in gliclazide group,0.61%in repaglinide group,and 0.45%in acarbose group.The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide,but not for acarbose,compared with glimepiride,when added to metformin/sitagliptin dual therapy.The incidences of adverse events(AEs) were 29.2%in the dual therapy stage and30.3%in the triple therapy stage.Metformin/sitagliptin as baseline therapy,with the addition of a third oral antihyperglycemic agent,including glimepiride,gliclazide,repaglinide,or acarbose,was effective,safe and well-tolerated for achieving an HbAlc<7.0%goal in type 2 diabetic patients inadequately controlled with previous therapies.The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Latent autoimmune diabetes in adults： evidences for diabetes spectrum？

In 1936, Himworth first investigated insulin resistance and non-insulin resistance in diabetes. Then the terminology ＂type 1 diabetes （T1D）＂ and ＂type 2 diabetes （T2D）＂ were first used in 1951. In 1999, the World Health Organization （WHO） announced the classification of diabetes： as we all known, T1D and T2D.1 This classification is widely accepted and used. However, in clinical practice, it is quite often to find some patients cannot be simply diagnosed as T1D or T2D.

Gene expression changes in patients with fulminant type 1 diabetes

Background Fulminant type 1 diabetes （F1D） is a complex disease. Microarray analysis was used to identify gene expression changes and obtain understanding of the underlying mechanisms. Methods Microarray analysis was performed on peripheral blood mononuclear cells from six F1D patients and six matched healthy subjects. Real-time polymerase chain reaction was used to verify the differentially expressed genes. NK cell activity was detected by methyl thiazoleterazolium assay. Results Microarray analysis identified 759 genes differing in expression between F1D patients and controls at a false discovery rate of 0.05. Expression of TLR9, ELF4 and ILIRAP were verified and consistent with changes in microarray results. NK cell activity was decreased in FID. With use of a knowledge base, differentially expressed genes could be placed within different pathways with predicted functions including interleukin-1, and tumor necrosis factor-a signaling. Conclusions These results identify several genes indicating possible mechanisms in FID. NK cell dysfunction resulting from changes in expression of TLR9, ELF4 and IL1RAP, and pathways of interleukin-1 and tumor necrosis factor-a sianalino miaht be involved in F1D throuoh inducino B-cell dysfunction.

Rheb promotes brown fat thermogenesis by Notch-dependent activation of the PKA signaling pathway

Increasing brown and beige fat thermogenesis have an anti-obesity effect and thus great metabolic benefits.However,the molecular mechanisms regulating brown and beige fat thermogenesis remain to be further elucidated.We recently found that fat-specific knockout of Rheb promoted beige fat thermogenesis.In the current study,we show that Rheb has distinct effects on thermogenic gene expression in brown and beige fat.Fat-specific knockout of Rheb decreased protein kinase A(PKA)activity and thermogenic gene expression in brown adipose tissue of high-fat diet-fed mice.On the other hand,overexpression of Rheb activated PKA and increased uncoupling protein 1 expression in brown adipocytes.Mechanistically,Rheb overexpression in brown adipocytes increased Notch expression,leading to disassociation of the regulatory subunit from the catalytic subunit of PKA and subsequent PKA activation.Our study demonstrates that Rheb,by selectively modulating thermogenic gene expression in brown and beige adipose tissues,plays an important role in regulating energy homeostasis.

Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function

Innate immunity mediated by Toll-like receptors(TLRs),which can recognize pathogen molecular patterns,plays a critical role in type 1 diabetes development.TLR7 is a pattern recognition receptor that senses single-stranded RNAs from viruses and host tissue cells;however,its role in type 1 diabetes development remains unclear.In our study,we discovered that Tlr7-deficient(Tlr7^(−/−))nonobese diabetic(NOD)mice,a model of human type 1 diabetes,exhibited a significantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7-sufficient(Tlr7^(+/+))NOD mice.Mechanistic investigations showed that Tlr7 deficiency significantly altered B-cell differentiation and immunoglobulin production.Moreover,Tlr7^(−/−)NOD B cells were found to suppress diabetogenic CD4^(+)T-cell responses and protect immunodeficient NOD mice from developing diabetes induced by diabetogenic T cells.In addition,we found that Tlr7 deficiency suppressed the antigen-presenting functions of B cells and inhibited cytotoxic CD8^(+)T-cell activation by downregulating the expression of both nonclassical and classical MHC class I(MHC-I)molecules on B cells.Our data suggest that TLR7 contributes to type 1 diabetes development by regulating B-cell functions and subsequent interactions with T cells.Therefore,therapeutically targeting TLR7 may prove beneficial for disease protection.

A long and winding road to understand latent autoimmune diabetes in adults

Latent autoimmune diabetes in adults(LADA)describes a subgroup of patients who develop phenotypic type 2 diabetes(T2D)but with markers of islet autoimmunity.It is under debate whether LADA is a subtype of type 1 diabetes(T1D)or a unique disease.LADA comprises about 1.5%to 14.2%in phenotypic T2D depending on ethnicity.It is the most common form of autoimmune diabetes diagnosed in adults,with 3.3-to 12.2-fold higher prevalence than that of adult-onset T1D.

Serum fibroblast growth factor 19 (FGF19) levels are associated with atherogenic dyslipidemia in patients with type 2 diabetes

To the Editor:Type 2 diabetes(T2D)is a metabolic disease characterized by hyperglycemia caused by multiple etiologies.[1]Long-term hyperglycemia causes microvascular and macrovascular damage and lipid metabolism disorders in T2D patients,which can lead to atherosclerosis.[1]About two-thirds of patients with T2D die of cardiovascular complications,mainly atherosclerotic cardiovascular disease.[2]The overall prevalence of macrovascular complications in T2D is approximately 32%.[3]There are no clinical indicators that can accurately predict the cardiovascular complications of T2D.The early detection of biomarkers for atherogenic dyslipidemia in patients with T2D can realize the early identification of diabetic macrovascular disease,which is of great significance for early intervention,improvement of clinical prognosis,and reduction of disability mortality and economic burden.Fibroblast growth factor 19(FGF19)is a hormone secreted by the distal small intestine which regulates lipid and glucose metabolism.However,it is unclear whether FGF19 functions in the progression of T2D to atherogenic dyslipidemia.In humans,some studies have investigated the relationship between circulating FGF19 and the presence of coronary artery disease(CAD),and have also proved the association between FGF19 and the development of major cardiovascular adverse events in stable CAD.[4,5]Our previous studies also showed that FGF19 could predict the progression of subclinical atherosclerosis in men with T2D.[6]In this study,we aimed to investigate the relationship between FGF19 and the risk of atherogenic dyslipidemia in patients with T2D and to explore whether FGF19 can be a biomarker for early diagnosis of atherogenic dyslipidemia in patients with T2D.

The composition,function,and regulation of adipose stem and progenitor cells

White adipose tissue(WAT)is a highly plastic organ that plays a central role in regulating whole-body energy metabolism.Adipose stem and progenitor cells(ASPCs)are essential components of the stromal vascular fraction(SVF)of adipose tissue.They give rise to mature adipocytes and play a critical role in maintaining adipose tissue function.However,the molecular heterogeneity and functional diversity of ASPCs are still poorly understood.Recently,single-cell RNA sequencing(scRNA-seq)analysis has identified distinct subtypes of ASPCs in murine and human adipose tissues,providing new insights into the cellular complexity of ASPCs among multiple fat depots.This review summarizes the current knowledge on ASPC populations,including their markers,functions,and regulatory mechanisms.Targeting one or several of these cell populations may ameliorate metabolic disorders by promoting adaptive hyperplastic adipose growth.

Chemokine CCL1 as a therapeutic target for pulmonary fibrosis: comments on ‘The chemokine CCL1 triggers an AMFR‒SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis’

Pulmonary fibrosis(PF)is a type of chronic and progressive respiratory diseases characterized by excessive extracellular matrix(ECM)deposition,interstitial fibrotic lesions,and architectural distortion.Patients with PF suffer from pulmonary function decline and progressive worsening of dyspnea with poor prognosis(Wilson and Wynn,2009).Although recent progress provides mechanistic insights into the pathogenesis of PF,no effective treatment against PF is available other than lung transplantation.Therefore,a better understanding of the molecular and cellular mechanisms of PF is crucial for the discovery of new therapeutic targets for safe and effective anti-PF drugs.