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Aim: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs)., Methods: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed., Results: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported., Conclusions: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Chronic kidney disease (CKD) is a significant long-term complication of diabetes and is a primary contributor to end-stage kidney disease., Objective: This study aimed to report comprehensive nationwide data on the prevalence, screening, and awareness rates of CKD in Chinese patients with type 2 diabetes, along with associated risk factors., Methods: Baseline data analysis of the ongoing prospective, observational IMPROVE study was conducted. The study cohort comprised patients who had been diagnosed with type 2 diabetes more than 12 months prior, received at least 1 hypoglycemic medication, and were aged ≥18 years. The participants completed questionnaires and underwent laboratory assessments, including blood and urine samples. The data encompassed patient demographics, medical history, concurrent medications, and comorbidities. Comprehensive evaluations involved physical examinations, urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA 1c ), fasting blood glucose, 2-hour postprandial blood glucose, fasting blood lipid profile, and urinalysis. Descriptive statistics were applied for data interpretation, and logistic regression analyses were used to identify the CKD-associated risk factors in patients with type 2 diabetes., Results: A national study from December 2021 to September 2022 enlisted 9672 participants with type 2 diabetes from 45 hospitals that had endocrinology departments. The enrollees were from diverse regions in China, as follows: central (n=1221), east (n=3269), south (n=1474), north (n=2219), and west (n=1489). The prevalence, screening, and awareness rates of CKD among patients with type 2 diabetes were 31% (2997/9672), 27% (810/2997), and 54.8% (5295/9672), respectively. Multivariate binary regression analysis revealed that the CKD risk factors were screening, awareness, smoking, age, diabetes duration, concurrent antihypertensive and microcirculation medications, diabetic complications (foot, retinopathy, and neuropathy), hypertension, elevated low-density lipoprotein (LDL) cholesterol, and suboptimal glycemic control. Subgroup analysis highlighted an increased CKD prevalence among older individuals, those with prolonged diabetes durations, and residents of fourth-tier cities. Residents of urban areas that had robust educational and economic development exhibited relatively high awareness and screening rates. Notably, 24.2% (1717/7107) of patients with an eGFR ≥90 mL/min/1.73 m 2 had proteinuria, whereas 3.4% (234/6909) who had a UACR <30 mg/g presented with an eGFR <60 mL/min/1.73 m 2 . Compared with patients who were cognizant of CKD, those who were unaware of CKD had increased rates of HbA 1c ≥7%, total cholesterol >5.18 μmol/L, LDL cholesterol >3.37 μmol/L, BMI ≥30 kg/m 2 , and hypertension., Conclusions: In a Chinese population of adults with type 2 diabetes, the CKD prevalence was notable, at 31%, coupled with low screening and awareness rates. Multiple risk factors for CKD have been identified., Trial Registration: ClinicalTrials.gov NCT05047471; https://clinicaltrials.gov/study/NCT05047471., (©Lixin Shi, Yaoming Xue, Xuefeng Yu, Yangang Wang, Tianpei Hong, Xiaoying Li, Jianhua Ma, Dalong Zhu, Yiming Mu. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 30.08.2024.)

Background: Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations., Methods: We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups., Results: Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease., Conclusion: The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Infusion of mesenchymal stem cells (MSCs) induces polarization of M2 macrophages in adipose tissue of type 2 diabetes (T2D) mice. Studies have shown that M2 macrophages were divided into four sub-phenotypes (M2a, M2b, M2c and M2d) with different functions, and manuscripts have also confirmed that macrophages co-cultured with MSCs were not matched with known four phenotype macrophages. Therefore, our study explored the phenotype and related gene expressions of macrophages in the adipose tissue of T2D mice with/without MSCs infusion., Methods: We induced a T2D mouse model by using high-fat diets and streptozotocin (STZ) injection. The mice were divided into three groups: the control group, the T2D group, and the MSCs group. MSCs were systemically injected once a week for 6 weeks. The phenotype of macrophages in adipose tissue was detected via flow cytometric analysis. We also investigated the gene expression of macrophages in different groups via SMART-RNA-sequencing and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR)., Results: The present study found that the macrophages of adipose tissue in the MSCs group were polarized to the M2 phenotype mixed with four sub-phenotypes. Besides, M2a and M2c held a dominant position, while M2b and M2d (tumor-associated macrophages, TAMs) exhibited a decreasing trend after infusion of MSCs. Moreover, the MSCs group did not appear to express higher levels of tumor-associated, inflammation-associated, or fibrosis-associated genes in comparison to the T2D group., Conclusion: The present results unveiled that the macrophage phenotype was inclined to be present in a hybridity state of four M2 sub-phenotypes and the genes related to tumor-promoting, pro-inflammation and pro-fibrosis were not increased after MSCs injection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint., Methods: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed., Results: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels., Conclusions: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the effect of noiiglutide as an adjunct to lifestyle intervention on the reduction in body weight and tolerability in obese Chinese adults without diabetes., Materials and Methods: In this 24-week, randomized, double-blind, placebo-controlled phase 2 trial, 254 obese adults with a body mass index of 28.0-40.0 kg/m 2 and without diabetes were enrolled. Participants were initially randomized in a 1:1:1 ratio to one of three dose levels: 0.12, 0.24, or 0.36 mg of the study treatment. Within each dose level, participants were further randomized in a 3:1 ratio to receive either subcutaneous injection of noiiglutide or a matching placebo. The primary endpoint was the change in body weight from baseline to week 24., Results: Across all noiiglutide dosage levels, least squares mean reductions in body weight from baseline to week 24 ranged from 8.03 to 8.50 kg, compared with 3.65 kg in the placebo group (all p-values <.0001). In the noiiglutide groups (0.12, 0.24, 0.36 mg/day), a significantly higher proportion of participants achieved a weight loss ≥5% (68.8%, 60.0%, 73.0%) and ≥10% (37.5%, 36.9%, 39.7%), compared with the pooled placebo group (≥5%: 29.0%; ≥10%: 8.1%). Gastrointestinal adverse events, such as nausea, diarrhoea and vomiting, were more common in all noiiglutide groups (15.4%-30.2%, 18.8%-22.2%, 15.6%-18.5%) than in the pooled placebo group (8.1%, 6.5%, 0%)., Conclusions: In obese Chinese adults without diabetes, once-daily subcutaneous noiiglutide significantly reduced body week at week 24 compared with placebo, and had a manageable safety profile, primarily involving gastrointestinal disorders., (© 2023 John Wiley & Sons Ltd.)

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been proved a promising clinical strategy for the treatment of diabetes, and time in range (TIR) has been demonstrated a new metric of glycemic control links to diabetes complications. To further assess the therapeutic effect of UC-MSCs on TIR, a phase II study investigating the efficacy of UC-MSCs in Chinese adults with type 2 diabetes (T2D) assessed by retrospective continuous glucose monitoring (CGM) was conducted. In this randomized and placebo-controlled trial, a total of 73 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 37) or placebo (n = 36) 3 times at 4-week intervals and followed up for 48 weeks. The primary endpoint was the changes in TIR and glycosylated hemoglobin (HbA1c). TIR and HbA1c were both significantly improved in UC-MSCs and placebo groups after 48 weeks of therapy compared with baseline. Compared with placebo group, UC-MSCs group exhibited more pronounced changes at 9 and 48 weeks from baseline in TIR (26.54 vs. 15.84 and 21.36 vs. 6.32) and HbA1c (-1.79 vs. -0.96 and -1.36 vs. -0.51). More patients in UC-MSCs group achieved the glycemic control target of TIR ≥ 70% and HbA1c < 7% at 9 and 48 weeks than in placebo group (59.5% vs. 27.8% and 43.2% vs. 11.1%). The C-peptide area under the curve (AUCC-pep) was an independent risk factor associated with efficacy in T2D undergoing UC-MSCs intervention. These results illustrate that UC-MSCs administration via intravenous infusion is an effective approach for ameliorating TIR., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The hemoglobin glycation index (HGI) was developed to quantify glucose metabolism and individual differences and proved to be a robust measure of individual glycosylated hemoglobin (HbA1c) bias. Here, we aimed to explore the relationship between different HGIs and the risk of 5-year major adverse cardiovascular events (MACEs) by performing a large multicenter cohort study in China., Methods: A total of 9791 subjects from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a Longitudinal Study (the REACTION study) were divided into five subgroups (Q1-Q5) with the HGI quantiles (≤5th, >5th and ≤33.3th, >33.3th and ≤66.7th, >66.7th and ≤95th, and >95th percentile). A multivariate logistic regression model constructed by the restricted cubic spline method was used to evaluate the relationship between the HGI and the 5-year MACE risk. Subgroup analysis between the HGI and covariates were explored to detect differences among the five subgroups., Results: The total 5-year MACE rate in the nationwide cohort was 6.87% (673/9791). Restricted cubic spline analysis suggested a U-shaped correlation between the HGI values and MACE risk after adjustment for cardiovascular risk factors ( χ2 = 29.5, P <0.001). After adjustment for potential confounders, subjects with HGIs ≤-0.75 or >0.82 showed odds ratios (ORs) for MACE of 1.471 (95% confidence interval [CI], 1.027-2.069) and 2.222 (95% CI, 1.641-3.026) compared to subjects with HGIs of >-0.75 and ≤-0.20. In the subgroup with non-coronary heart disease, the risk of MACE was significantly higher in subjects with HGIs ≤-0.75 (OR, 1.540 [1.039-2.234]; P = 0.027) and >0.82 (OR, 2.022 [1.392-2.890]; P <0.001) compared to those with HGIs of ≤-0.75 or >0.82 after adjustment for potential confounders., Conclusions: We found a U-shaped correlation between the HGI values and the risk of 5-year MACE. Both low and high HGIs were associated with an increased risk of MACE. Therefore, the HGI may predict the 5-year MACE risk., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes., Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes., Design, Setting, and Participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol)., Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294)., Main Outcomes and Measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes., Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01)., Conclusions and Relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups., Trial Registration: ClinicalTrials.gov Identifier: NCT04795531.

Aims: To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short-term intensive insulin therapy (SIIT) during study run-in (prior to randomization) using a basal-first insulin titration method., Materials and Methods: This was exclusively an exploratory analysis of the 7- to 10-day run-in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once-daily insulin glargine and three-times-daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre-meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2-hour postprandial blood glucose (PBG) targets., Results: Overall, 397 entered the run-in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2-hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2-hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2-hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia., Conclusions: Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Islet β-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet β-cell function is beneficial to better management of T2DM. Protecting islet β-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet β-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet β-cell function in type 2 diabetes mellitus." This consensus suggests that β-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet β-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet β-cell function, independent of glycemic control., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: We aimed to examine risks of major cardiovascular events (MACEs), renal outcomes, and all-cause mortality in type 2 diabetes mellitus (T2DM) patients with different diabetic kidney disease (DKD) subtypes., Methods: A total of 36,509 participants with T2DM recruited from 20 community sites across mainland China were followed up during 2011-2016. DKD subtypes were categorized based on albuminuria (urinary albumin-to-creatinine ratio, UACR ≥ 30 mg/g) and reduced estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m 2 ) as Alb - /eGFR - , Alb + /eGFR - , Alb - /eGFR + , and Alb + /eGFR + . Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of developing clinical outcomes in DKD subtypes., Results: More than half (53.5%) of participants with diabetes and reduced eGFR had normal UACR levels (Alb - /eGFR + ), termed as non-albuminuria DKD. These patients had a modest increase in the risks of MACEs (hazard ratio, HR 1.42 [95% CI 1.08;1.88]) and mortality (HR 1.42 [1.04;1.92]) compared with patients without DKD, whereas CKD progression was not significantly increased (HR 0.97 [0.60;1.57]). Participants with albuminuria (Alb + /eGFR - or Alb + /eGFR + ) had higher risks of clinical outcomes. Subgroup analysis revealed that the associations between non-albuminuria DKD and risks of MACEs and mortality were more evident in those aged <65 years., Conclusion: Non-albuminuria DKD accounts for more than half of DKD cases with low eGFR in Chinese diabetes patients. Diabetes patients with albuminuria are at higher risks of developing clinical outcomes and warrant early intervention, as well as patients with non-albuminuria DKD with age < 65 years., Competing Interests: Declaration of Competing Interest The authors declared no conflicts of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: The hemoglobin glycation index (HGI) quantifies the mismatch between glycated hemoglobin A1c and average glycemia among individuals. Currently, it is unknown the potential role of HGI in exhaustively evaluating the progression of glucose metabolism/the risk of developing diabetes mellitus. Therefore, this study aimed to investigate the association between HGI and the risk of incident diabetes., Methods: A total of 7,345 participants aged at least 40 years and without diabetes were divided into three groups according to the tertile of their baseline HGI level and followed for a median of 3.24 years to track new-onset diabetes. Using multivariate Cox regression analyses, we explored the association between the HGI, both categorized and continuous, and incident diabetes., Results: During follow-up, 742 subjects (263 males and 479 females) developed diabetes mellitus. Higher HGI was associated with an increased risk of diabetes, even when adjusted for confounding factors, and every standard deviation increase in HGI was associated with a significant risk increase of 30.6% for diabetes (hazard ratio 1.306, 95% confidence interval 1.232-1.384)., Conclusions: Participants with a higher HGI were at a higher risk of future diabetes, irrespective of their glycemic conditions. Consequently, HGI may be employed to identify individuals at high risk for diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Wang, Jia, Wang, He, Mu and Dou.)

Aim: To compare the efficacy and safety of basal insulin glargine 100 units/ml (Gla) + 2-3 oral antihyperglycaemic drugs (OADs) with twice-daily premixed insulin aspart 70/30 (Asp30) + metformin (MET) after short-term intensive insulin therapy in adults with type 2 diabetes in China., Materials and Methods: This open-label trial enrolled insulin-naïve adults with type 2 diabetes and an HbA1c of 7.5%-11.0% (58-97 mmol/mol) despite treatment with 2-3 OADs. All participants stopped previous OADs except MET, then received short-term intensive insulin therapy during the run-in period, when those with a fasting plasma glucose of less than 7.0 mmol/L and 2-hour postprandial glucose of less than 10.0 mmol/L were randomized to Gla + MET + a dipeptidyl peptidase-4 inhibitor or twice-daily Asp30 + MET. If HbA1c was more than 7.0% (>53 mmol/mol) at week 12, participants in the Gla group were added repaglinide or acarbose, at the physician's discretion, and participants in the Asp30 group continued to titrate insulin dose. The change in HbA1c from baseline to week 24 was assessed in the per protocol (PP) population (primary endpoint)., Results: There were 384 enrollees (192 each to Gla and Asp30); 367 were included in the PP analysis. The threshold for non-inferiority of Gla + OADs versus Asp30 + MET was met, with a least squares mean change from baseline in HbA1c of -1.72% and -1.70% (-42.2 and -42.1 mmol/mol), respectively (estimated difference -0.01%; 95% CI -0.20%, 0.17% [-0.1 mmol/mol; 95% CI -2.2, 1.9]). Achievement of HbA1c less than 7.0% (<53 mmol/mol) was comparable between the groups (60% vs. 57%). The proportion of participants with any (24% vs. 38%; P = .003), symptomatic (19% vs. 31%; P = .007) or confirmed hypoglycaemia (18% vs. 33%; P < .001) was lower in the Gla + OADs group., Conclusions: Compared with Asp30 + MET, Gla + 2-3 OADs showed similar efficacy but a lower hypoglycaemia risk in Chinese individuals with type 2 diabetes who had undergone short-term intensive insulin therapy., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Although previous studies suggest that amino acids (AAs) and microbiota-related metabolites (MRMs) are associated with type 2 diabetes mellitus (T2DM), the results remain unclear among normoglycemic populations. We test 28 serum AAs and 22 MRMs in 3,414 subjects with incident diabetes and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. In fully adjusted logistic regression models, per SD increment of branched-chain AAs, aromatic AAs, asparagine, alanine, glutamic acid, homoserine, 2-aminoadipic acid, histidine, methionine, and proline are positively associated with incident T2DM. In the MRM panel, serum carnitines, N-acetyltryptophan, and uric acid are positively associated with incident T2DM. Causal mediation analyses indicate 34 significant causal mediation linkages, with 88.2% through obesity and lipids. Variances explained in the serum metabolites are modestly limited in the comprehensive catalog of risk factor-metabolite-diabetes associations. These findings reveal that systematic AAs and MRMs change profile before T2DM onset and support a potential role of metabolic alterations in the pathogenesis of diabetes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Advanced glycation end products (AGEs) that abnormally accumulate in diabetic patients have been reported to damage bone health. We aimed to investigate the association between skin autofluorescence (SAF)-AGE age (SAF - AGEs × age/100) and low bone density (LBD)/osteoporosis or major osteoporotic fractures (MOFs) in patients with type 2 diabetes mellitus (T2DM)., Methods: This study was nested in the prospective REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals) study and included 1214 eligible participants. SAF was used to measure skin AGEs (SAF-AGEs). Fracture events were determined by an in-person clinical follow-up. Binary logistic regression analysis, linear regression analysis, and a restricted cubic spline nested in logistic models were used to test outcomes., Results: The overall prevalence of LBD/osteoporosis in middle-aged or elderly T2DM patients was 35.7% (n = 434), and the overall incidence of MOFs was 10.5% (n = 116). Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGE age and the risk of LBD/osteoporosis (odds ratio [OR] 2.02, 95% CI 1.34-3.03; OR 3.63, CI 2.44-5.39; and OR 6.51, CI 4.34-9.78) for the multivariate-adjusted models, respectively. SAF-AGE age was associated with MOFs with a multivariate-adjusted OR of 1.02 (CI 0.52-2.02), 2.42 (CI 1.32-4.46), and 2.70 (CI 1.48-4.91), respectively. Stratified analyses showed that SAF-AGE age was significantly associated with MOFs only in females, nonsmokers, nondrinkers, individuals with lower body mass index, and those without LBD/osteoporosis. Linear regression analyses showed that higher SAF-AGEs were associated with a higher level of serum N-terminal propeptide of type I procollagen (s-PINP) and serum carboxy-terminal cross-linking peptide of type I collagen (s-CTX), with a multivariate-adjusted OR of 1.02 (CI 0.24-1.80) and 6.30 (CI 1.77-10.83), respectively., Conclusions: In conclusion, SAF-AGE age was positively associated with the prevalence of LBD/osteoporosis or MOFs in patients with T2DM. A positive association between SAF-AGEs and the level of s-PINP and s-CTX was found., (© 2022 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Mesenchymal stem cells (MSCs) exert anti-diabetic effects and improve long-term complications via secretory effects that regulate macrophage polarisation and attenuate inflammation. Enhancing the efficacy of MSCs needs to be explored further. The in vitro culture microenvironment influences the secretory profile of MSCs. Therefore, we hypothesised that a diabetic microenvironment would promote the secretion of cytokines responsible for macrophage polarisation, further attenuating systemic inflammation and enhancing the effects of MSCs on type 2 diabetes (T2D) and long-term diabetic complications., Methods: Preconditioned adipose-derived mesenchymal stem cells (pre-ADSCs) were obtained after co-cultivating ADSCs in a diabetic metabolic environment (including high sugar, advanced glycation end-product, and lipopolysaccharides). The regulatory effects of pre-ADSCs on macrophages were observed in vitro. A T2D rat model was induced with a high-fat diet for 32 weeks combined with an intraperitoneal injection of streptozotocin. Sprague-Dawley (SD) rats were divided into four groups: normal group, diabetes without treatment group (PBS), ADSC treatment group, and pre-ADSC treatment group. ADSCs and pre-ADSCs were intravenously administered weekly to SD rats for 6 months, and then glucose homeostasis and long-term diabetic complications were evaluated in each group., Results: The secretion of cytokines related to M2 macrophage polarisation (IL-6, MCP-1, etc.) was increased in the pre-ADSC group in the in vitro model. Pre-ADSC treatment significantly maintained blood glucose homeostasis, reduced insulin resistance, promoted islet regeneration, and ameliorated the complications related to diabetes in rats (chronic kidney disease, non-alcoholic steatohepatitis, lung fibrosis, and cataract) compared to the ADSC group (P < 0.05). Additionally, the number of anti-inflammatory M2 macrophage phenotypes was enhanced in tissues following pre-ADSC injections. Moreover, the expression of pro-inflammatory genes (iNOS, TNF-α, IL-1β) was reduced whereas that of anti-inflammatory genes (Arg1, CD206, and Il-10) was increased after cultivation with pre-ADSCs., Conclusion: Diabetic microenvironment-preconditioned ADSCs effectively strengthen the capacity against inflammation and modulate the progress of long-term T2D complications., (© 2022. The Author(s).)

Aim: To determine the effect of decade-based body weight gain from 20 to 50 years of age on later life diabetes risk., Methods: 35,611 non-diabetic participants aged ≥ 50 years from a well-defined nationwide cohort were followed up for average of 3.6 years, with cardiovascular diseases and cancers at baseline were excluded. Body weight at 20, 30, 40, and 50 years was reported. The overall 30 years and each 10-year weight gain were calculated from the early and middle life. Cox regression models were used to estimate risks of incident diabetes., Results: After 127,745.26 person-years of follow-up, 2,789 incident diabetes were identified (incidence rate, 2.18%) in 25,289 women (mean weight gain 20-50 years, 7.60 kg) and 10,322 men (7.93 kg). Each 10-kg weight gain over the 30 years was significantly associated with a 39.7% increased risk of incident diabetes (95% confidence interval [CI], 1.33-1.47); weight gain from 20-30 years showed a more prominent effect on the risk of developing diabetes before 60 years than that of after 60 years (Hazard ratio, HR = 1.084, 95% CI [1.049-1.121], P < 0.0001 vs. 1.015 [0.975-1.056], P = 0.4643; P Interaction =0.0293). It showed a stable effect of the three 10-year intervals weight gain on risk of diabetes after 60 years (HR=1.055, 1.038, 1.043, respectively, all P < 0.0036)., Conclusions: The early life weight gain showed a more prominent effect on developing diabetes before 60 years than after 60 years; however, each-decade weight gain from 20 to 50 years showed a similar effect on risk developing diabetes after 60 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Qi, Chen, Qin, Wu, Wang, Zhao, Xu, Li, Chen, Chen, Chen, Deng, Gao, Huo, Li, Liu, Luo, Mu, Qin, Shen, Shi, Su, Wan, Wang, Wang, Wang, Hu, Xu, Yan, Yang, Yu, Zhang, Zeng, Tang, Ye, Zhao, Bi, Ning, Lu and Wang.)

Background: Overweight and obesity are well-known risk factors for type 2 diabetes mellitus (T2DM). The effect of the maximum body mass index (BMImax), which indicates the highest body weight before the diagnosis of T2DM, is not fully understood. This study aimed to explore the predictive value of BMImax in the progression of diabetes., Methods: This prospective study recruited 2018 subjects with normal glucose tolerance in Beijing, China. The subjects were followed up for eight years, and the association between BMImax and glucose outcomes was evaluated., Results: Ninety-seven of the 2,018 participants developed diabetes by the end of the study. Compared to individuals with normal glucose tolerance, those who developed diabetes were characterized by higher levels of fasting plasma glucose (FPG), 2 h postload glucose (PBG), glycosylated hemoglobin (HbA 1c ), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-c), a higher prevalence of a familial history of diabetes and a lower level of high-density lipoprotein cholesterol (HDL-c). Multivariate regression analysis of sex-stratified groups suggested that FPG, HbA 1c , SBP and familial history of diabetes were independent risk factors for diabetes, but that BMImax was a unique indicator for female patients., Conclusions: BMImax might be an independent predictor of T2DM in females, but it does not seem to be associated with the risk of diabetes in males. BMImax could be regarded as an indicator in the prevention and management of diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jia, Wang, Yang, Cheng, Wang, Ba, Dou, Mu, Zhao and Lyu.)

Background: Albuminuria has been widely considered a risk factor for cardiovascular diseases (CVDs), which is associated with hypertension (HTN), type 2 diabetes mellitus (T2DM), HTN with T2DM, and dyslipidemia. However, the associations between albuminuria and HTN, T2DM, HTN with T2DM, dyslipidemia, and CVDs are still unclear. Thus, this study aimed to explore the association of albuminuria thoroughly, especially within the normal range, with the abovementioned diseases in the Chinese population., Methods: This study included 40,188 participants aged over 40 years from seven centers across China. Urinary albumin-creatinine ratio (UACR) was firstly divided into the ≥30-mg/g group, indicating kidney damage, and <30-mg/g group. Furthermore, UACR was divided into five groups: the <20%, 20%-39%, 40%-59%, 60%-79%, and ≥80% groups, according to the quintile division of participants within the normal range. Propensity score matching was used to reduce bias, and multiple logistic regression models were conducted to examine the association between UACR and HTN, T2DM, HTN with T2DM, dyslipidemia, and CVDs., Results: Multivariable regression analysis revealed that UACR, even within the normal range, is significantly associated with HTN, T2DM, HTN with T2DM, dyslipidemia, and CVDs, and the association between UACR and HTN with T2DM was the most significant in model 3 even after adjusting for confounding factors (HTN: OR = 1.56 (95% CI = 1.45-1.68), p < 0.0001; T2DM: OR = 1.78 (95% CI = 1.60-1.97), p < 0.0001; HTN with T2DM: OR = 1.76 (95% CI = 1.59-1.95), p < 0.0001; dyslipidemia: OR = 1.08 (95% CI = 1.01-1.14), p = 0.0146; CVDs: OR = 1.12 (95% CI = 1.00-1.25), p = 0.0475). In the stratified analysis, high normal UACR was significantly associated with HTN, T2DM, HTN with T2DM, and dyslipidemia in subgroups., Conclusions: In summary, we observe a higher prevalence of HTN, T2DM, HTN with T2DM, dyslipidemia, and CVDs in abnormal UACR and reveal a significant association of UACR, even within the normal range, with HTN, T2DM, HTN with T2DM, dyslipidemia, and CVDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Li, Hu, Jin, Wang, Gao, Tang, Yan, Wan, Luo, Qin, Chen, Gu, Lyv and Mu.)

Background: To determine the efficacy and safety of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in Chinese adults with type 2 diabetes mellitus (T2DM)., Methods: In this single-center, double-blinded, randomized, placebo-controlled phase II trial, 91 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 45) or placebo (n = 46) three times with 4-week intervals and followed up for 48 weeks from October 2015 to December 2018. The primary endpoint was the percentage of patients with glycated hemoglobin (HbA1c) levels of < 7.0% and daily insulin reduction of ≥ 50% at 48 weeks. Additional endpoints were changes of metabolic control, islet β-cell function, insulin resistance, and safety., Results: At 48 weeks, 20% of the patients in the UC-MSCs group and 4.55% in the placebo group reached the primary endpoint (p < 0.05, 95% confidence interval (CI) 2.25-28.66%). The percentage of insulin reduction of the UC-MSCs group was significantly higher than that of the placebo group (27.78% versus 15.62%, p < 0.05). The levels of HbA1c decreased 1.31% (9.02 ± 1.27% to 7.52 ± 1.07%, p < 0.01) in the UC-MSCs group, and only 0.63% in the placebo group (8.89 ± 1.11% to 8.19 ± 1.02%, p˃0.05; p = 0.0081 between both groups). The glucose infusion rate (GIR) increased significantly in the UC-MSCs group (from 3.12 to 4.76 mg/min/kg, p < 0.01), whereas no significant change was observed in the placebo group (from 3.26 to 3.60 mg/min/kg, p ˃ 0.05; p < 0.01 between both groups). There was no improvement in islet β-cell function in both groups. No major UC-MSCs transplantation-related adverse events occurred., Conclusions: UC-MSCs transplantation could be a potential therapeutic approach for Chinese adults with T2DM. Trial registration This study was registered on ClinicalTrials.gov (identifier: NCT02302599)., (© 2022. The Author(s).)

Hundreds of research and review articles concerning genome-wide association study (GWAS) in diabetes have been published in the last two decades. We aimed to evaluate the hotspots and future trends in GWAS in diabetes research through bibliometric analysis. Accordingly, 567 research and review articles published between 2001 and 2021 were included. A rising trend was noted in the annual number of publications and citations on GWAS in diabetes during this period. Harvard University and Harvard Medical School have played leading roles in genome research. Hotspot analyses indicated that DNA methylation and genetic variation, especially in type 2 diabetes mellitus, are likely to remain the research hotspots. Moreover, the identification of genetic phenotypes associated with adiposity, metabolic memory, pancreatic islet, and inflammation is the leading trend in this research field. Through this review, we provide predictions on the main research trends in the future so as to shed light on new directions and ideas for further investigations on the genetic etiology of diabetes for its prevention and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Wang, Qin, Jin, Jin, Gu and Mu.)

Interferon (IFN) is a broad-spectrum antiviral agent that activates cell surface receptors and causes cells to produce antiviral proteins, inhibiting viral replication. Interferon use has long been associated with diabetes. The PubMed database was searched for articles related to diabetes and interferon from March 30, 2020. Patients were divided into type 1 diabetes group and type 2 diabetes group. We reviewed the relevant literature to compare interferon-associated T1D and interferon-associated T2D differences. Interferon treatment shortened the incubation period of T2D and changed the original T2D to T1D. The onset of interferon-associated T1D required longer periods of IFN treatment than interferon-associated T2D, and the interferon-associated T1D group had higher GADA positive rates, lower BMI, lower fasting blood glucose, and greater insulin dependence (p<0.05). More patients in the T1D group were positive for HLA-DRB1*04, DRB1*03, DRB1*09, DRB1*14, HLA-DQB1*04, HLA-DQB1*02, HLA-DQB1*03, and HLA-DQB1*05. The combined detection of GAD antibodies and HLA alleles may be an effective method to predict the incidence of T1D after IFN treatment., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Patients with normoalbuminuria and a reduced estimated glomerular filtration rate (eGFR) account for a considerable proportion of type 2 diabetes patients. The aim of this research was to investigate the epidemiological and clinical characteristics of normoalbuminuric kidney disease in a Chinese population., Methods: We included 8131 diabetic patients from a multicenter prospective study in China. Based on eGFR and urinary albumin-to-creatinine ratio (UACR), participants were stratified into four groups-normal albuminuria, albuminuria, normoalbuminuria with eGFR < 60 mL/min/1.73 m 2 , and albuminuria with eGFR < 60 mL/min/1.73 m 2 . Clinical parameters and characteristics of patients with normoalbuminuria and eGFR < 60 mL/min/1.73 m 2 were retrospectively analyzed., Results: A total of 1060 out of 8131 individuals with diabetes had decreased eGFR (<60 mL/min/1.73 m 2 ). Normoalbuminuria accounted for 63.3% of participants with eGFR < 60 mL/min/1.73 m 2 , and microalbuminuria and macroalbuminuria accounted for 30.1% and 6.3%, respectively. Patients with normoalbuminuria and reduced eGFR were more frequently male, older, and had higher levels of triglycerides than patients with normal albuminuria and eGFR. We also detected a correlation between lower extremity arterial disease, newly diagnosed diabetes, and normoalbuminuria-reduced eGFR. Compared with participants with both albuminuria and eGFR decline, those with normoalbuminuria had better metabolic indicators, including systolic blood pressure and glycosylated hemoglobin, and shorter diabetes duration. Even in the normal range, UACR has a significant correlation with the risk of eGFR insufficiency., Conclusions: Normoalbuminuric renal insufficiency, characterized by male sex, older age, a higher level of triglyceride levels, and a higher risk of lower extremity arterial disease, accounted for a dominant proportion of diabetic patients with eGFR decline., (© 2021 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aim: To assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin., Materials and Methods: In DUAL II China, a randomized, double-blinded, multicentre, treat-to-target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)-confirmed hypoglycaemic episodes (confirmatory secondary endpoints)., Results: Overall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (-1.9% vs. -1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: -0.92% [-1.09; -0.75], P < .0001), body weight change (-0.7 vs. +0.4 kg, respectively, ETD [95% CI]: -1.08 kg [-1.63; -0.52], P = .0002) and severe or BG-confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed., Conclusions: IDegLira may be an efficacious and well-tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Type 2 diabetes is increasingly diagnosed at a younger age worldwide and in China. Limited data are available regarding the association between age at diabetes diagnosis and risks of albuminuria. This study sought to examine the independent effect of age at diagnosis of type 2 diabetes on the risk of albuminuria., Methods: We used data from a nationwide multicenter study with 207 961 participants in mainland China. Age, sex, and study site were matched for 31 366 screen-detected type 2 diabetes cases and 31 366 normal controls. Age, sex, study site, and diabetes duration were matched for 7490 self-reported type 2 diabetes cases and 7490 normal controls. Risks of having albuminuria in matched type 2 diabetes vs controls were examined using multivariable logistic regression analysis in strata of age at diabetes diagnosis., Results: Although the absolute rate of albuminuria is higher in older adults, the odds ratio of albuminuria in type 2 diabetes vs matched controls decreased with increasing age at diagnosis. For participants with diabetes diagnosed at an age of <50, 50 to 59, 60 to 69, or ≥70 years, the multivariable adjusted risk of albuminuria increased by 81%, 60%, 45%, and 33% for screen-detected diabetes, and 135%, 121%, 90%, and 58% for self-reported diabetes compared with their normal controls, respectively., Conclusions: A younger age at diagnosis of type 2 diabetes is associated with a more significantly elevated risk of albuminuria than an older age at diagnosis in Chinese adults., (© 2021 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Parity, pregnancy loss, and breastfeeding duration were found to be associated with diabetes. However, the results are inconsistent. Also, no epidemiological studies have examined the association of these reproductive factors with diabetes in the same large population. We aim to investigate the associations between parity, pregnancy loss, breastfeeding duration, and the risk of maternal diabetes in middle-aged and elderly Chinese females., Methods: We included 131 174 females aged ≥40 years from the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study). Multivariable linear regression and logistic regression were used to assess the association between parity, pregnancy loss, and breastfeeding duration and type 2 diabetes., Results: The number of parities and breastfeeding duration were positively related to fasting plasma glucose, 2-hour postload glucose, glycosylated hemoglobin, and homeostatic model assessment of insulin resistance. Compared with those with one birth, nulliparous women or women with 2 or ≥3 births had a significantly increased risk of diabetes. The odds ratios (OR) and 95% confidence intervals (CI) were 1.27 (1.10-1.48), 1.17 (1.12-1.22), and 1.28 (1.21-1.35), respectively. Compared with women without pregnancy loss, those who underwent 2 (OR 1.09; 95% CI, 1.04-1.14) or ≥3 pregnancy losses (OR 1.11; 95% CI, 1.04-1.18) had an increased risk of diabetes. Moreover, women with a breastfeeding duration ≥0 to 6 months (OR 0.82; 95% CI, 0.75-0.90) and ≥6 to 12 months (OR 0.94; 95% CI, 0.89-0.99) had a significantly lower risk of diabetes., Conclusions: Nulliparous women or women with multiparity or more than one pregnancy loss have an increased risk of diabetes in later life, while women who breastfeed more than 0 to 12 months have a lower risk of diabetes., (© 2021 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aims: The aims of this study were to evaluate the associations of metabolic abnormalities with incident diabetic kidney disease (DKD) and to explore whether dyslipidaemia, particularly high fasting triglyceride (TG), was associated with the development of DKD., Methods: In total, 11 142 patients with new-onset type 2 diabetes with baseline estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73 m 2 were followed up during 2011-2016. Incident DKD was defined as eGFR <60 mL/min/1.73 m 2 at follow-up. Multiple logistic regression analysis was conducted to explore the relationship of metabolic abnormalities at baseline and at follow-up with risks of DKD. High TG was defined by TG ≥1.70 mmol/L. Low high-density lipoprotein cholesterol (HDL-c) was defined by HDL-c <1.0 mmol/L for men or <1.3 mmol/L for women., Results: Participants who developed DKD had higher levels of waist circumference and systolic blood pressure, and lower levels of HDL-c at both baseline and follow-up visits. The DKD group also had higher levels of post-load plasma glucose and TG at follow-up. Multivariate logistic regression analysis revealed that both high TG at baseline [odds ratio (OR) = 1.37, p = .012) and high TG at follow-up (OR = 1.71, p < .001) were significantly associated with increased risks of DKD. Patients with high TG levels at both baseline and follow-up had higher risk of DKD compared with constantly normal TG (OR = 1.65, p < .001) after adjustment for covariates., Conclusions: In a large population of patients with new-onset type 2 diabetes, a high TG level was an independent risk factor for the development of DKD. Tight TG control might delay the occurrence of DKD., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: We aimed to evaluate the effect of NAFLD on the risk of incident cardiovascular disease (CVD) and estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD), and further test the joint effects and interactions between NAFLD status and individual metabolic element, as well as the total 'ABCs' metabolic goal achievement, on the CVD and CKD risk among 101,296 patients with prediabetes or diabetes from a prospective cohort study., Methods: We conducted the study based on the China Cardiometabolic Disease and Cancer Cohort (4C) study, a large-scale, population-based prospective cohort. After excluding alcohol abuse and other cause of hepatic diseases, we used fatty liver index (FLI) ≥ 60 as a proxy of NAFLD and stratified the probability of fibrosis by aspartate transaminase/alanine transaminase ratio (AAR) with cut-offs of 0.8 and 1.4. 'ABCs' metabolic goal was defined as subjects who had HbA1c < 6.5% (A), SBP/DBP < 130/80 mmHg (B), and LDL-C < 100 mg/dL (C). During 3.8 years follow-up, we validated 2340 CVD events based on medical records and identified 1943 participants developed CKD based on centrally tested eGFR., Results: The multivariable adjusted hazard ratios (HRs) were 1.15 (95% confidence interval (CI), 1.05-1.27) for CVD events and 1.33 (95% CI, 1.20-1.48) for CKD among NAFLD patients, compared with participants without NAFLD. Of NAFLD patients, relative to individuals with low AAR (<0.8), those with high AAR (≥1.4) were more likely to experience CVD events [1.62 (1.21-2.18)] and CKD [1.63 (1.17-2.28)]. Participants with NAFLD and comorbid poorly controlled metabolic risk factors had higher risk of CVD events or CKD than having either alone, with a significant interaction between poor glycemic control and NAFLD on the risk of vascular complications., Conclusions: NAFLD was associated with incident CVD and CKD among patients with prediabetes or diabetes. Such associations were substantially modified by the comprehensive achievement of metabolic goal., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Nationwide studies focusing on the impact of early-onset type 2 diabetes and obesity on the development of cardiovascular diseases (CVD) are limited in China. We aimed to investigate the association between age at diagnosis of type 2 diabetes and the risk of CVD, and to further examine the modifying effect of obesity on this association among Chinese adults., Methods: This study included 23,961 participants with previously diagnosed diabetes from a large nationwide population-based cohort study across mainland China. With an interviewer-assisted questionnaire, we collected detailed information on CVDs. Logistic regression analysis was used to evaluate the risk of CVDs associated with age at diagnosis of diabetes., Results: Compared with patients with late-onset diabetes (≥60 years), those with earlier-onset diabetes had increased risks for CVD, with adjusted ORs (95% CIs) of 1.72 (1.36-2.17), 1.52 (1.31-1.75) and 1.33 (1.19-1.48) for patients diagnosed aged <40, 40-49 and 50-59 years, respectively. Each 5-year earlier age at diagnosis of type 2 diabetes was significantly associated with 14% increased risk of CVD (OR, 1.14; 95%CI, 1.11-1.18). This association was more prominent for patients with obesity than those with normal body mass index (BMI). Significant interaction was detected between age at diagnosis and BMI categories on CVD risk ( P for interaction=0.0457)., Conclusion: Early-onset type 2 diabetes was significantly associated with higher risk of CVD, and this association was more prominent among patients with obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Lin, Zhu, Zhang, Wang, Zhang, Qi, Li, Zhu, Huo, Wan, Qin, Hu, Shi, Su, Yu, Yan, Qin, Tang, Chen, Xu, Xu, Wang, Zhao, Gao, Wang, Shen, Luo, Chen, Li, Ye, Zhang, Liu, Wang, Yang, Deng, Chen, Zeng, Li, Zhao, Mu, Bi, Wang, Ning, Wu, Chen and Lu.)

Aims: This study aimed to assess the effects of the hemoglobin glycation index (HGI) on hyperglycemia diagnosis and summarize the general characteristics of patients with a high-HGI phenotype., Methods: The fasting plasma glucose and glycated hemoglobin (HbA1c) levels of participants (n = 47,648) were used to estimate a linear regression equation and determine the baseline HGI. Overall, 42,317 participants without a history of diabetes were included in the final analysis. The participants were divided into three groups according to the tertiles (low, moderate, and high) of baseline HGI. Proportions and variables were compared among the three HGI groups. A multivariate ordered logistic regression model was used to explore associations between related variables and the high-HGI phenotype., Results: Regression analysis indicated that the high-HGI phenotype was positively associated with female sex, advanced age, obesity, increased low-density lipoprotein and triglyceride levels, decreased high-density lipoprotein cholesterol, and postprandial glycemic excursion levels (all P < 0.05). The prevalence of hyperglycemia increased from the low- to the high-HGI groups when using HbA1c for diagnosis., Conclusions: Individuals with high HGI have similar clinical characteristics. Measuring HbA1c alone for diagnosis could lead to inappropriate diabetes management decisions in people with low or high HGI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians., Methods: In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all-cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category., Results: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m 2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all-cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m 2 or higher., Conclusion: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Age at menarche was reported to be associated with the risk of diabetes. However, the impact of ideal cardiovascular health metrics (ICVHMs) on the association between age at menarche and adulthood diabetes risk was unclear., Methods: We included 121 431 women from the nationwide, population-based cohort of the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals: a Longitudinal Study). The diagnosis of diabetes was based on the oral glucose tolerance test (OGTT) and glycosylated hemoglobin (HbA1c) measurement. Logistic regression and multiplicative interaction analysis were conducted to investigate the potential interaction effect between age at menarche and ICVHMs on the development of diabetes., Results: The multivariable-adjusted odds ratios of diabetes across categories of age at menarche (<14, 14-17, and > 17 years) were 1.22 (95% confidence interval [CI]: 1.17, 1.28), 1.00 (reference), and 0.89 (95% CI: 0.85, 0.93), respectively. In subgroup analysis, significant interactions were detected between total cholesterol/blood pressure levels and age at menarche regarding the risk of diabetes (P for interaction = .0091 and .0019, respectively). The increased risk associated with age at menarche <14 years was observed in participants with three or fewer ICVHMs, but not in women with four or more ICVHMs (P for interaction = .0001)., Conclusions: Age at menarche was inversely associated with the risk of diabetes in adulthood in Chinese women, and it appeared to be modified by the presence of ICVHMs. Further studies are needed to clarify the precise interrelationship and the generalizability of our results., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background Aims: The authors aimed to observe β-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage β-cell dedifferentiation., Methods: In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of β-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of β-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of β-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of β-cell dedifferentiation markers were examined., Results: In HFD/STZ-induced T2DM mice, the proportion of β-cell dedifferentiation was much greater than that of apoptosis, demonstrating that β-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed β-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on β-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders., Conclusions: UC-MSC therapy is a promising strategy for reversing β-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of β-cell dedifferentiation., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with type 2 diabetes mellitus (T2DM) are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD), which are important causes of disabling and death in patients with T2DM. For the prevention and management of ASCVD or CKD, cardiovascular risk factors should be systematically evaluated, and ASCVD and CKD should be screened in patients with T2DM. In this consensus, we recommended that metformin should be used as the first-line therapy for patients with T2DM and ASCVD or very high cardiovascular risk, heart failure (HF) or CKD, and should be retained in the treatment regimen unless contraindicated or not tolerated. In patients with T2DM and established ASCVD or very high cardiovascular risk, addition of a glucagon-like peptide 1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter type 2 (SGLT2) inhibitor with proven cardiovascular benefits should be considered independent of individualised glycated haemoglobin (HbA 1C ) targets. In patients with T2DM and HF, an SGLT2 inhibitor should be preferably added regardless of HbA 1C levels. In patients with T2DM and CKD, SGLT2 inhibitors should be preferred for the combination therapy independent of individualised HbA 1C targets, and GLP-1RAs with proven renal benefits would be alternative if SGLT2 inhibitors are contraindicated. Moreover, the prevention of hypoglycaemia and management of multiple risk factors by comprehensive regimen, including lifestyle intervention, antihypertensive therapies, lipid-lowering treatment and antiplatelet therapies, should be kept in mind in treating patients with T2DM and ASCVD, HF or CKD., (© 2020 John Wiley & Sons Ltd.)

Background: Previous studies have shown that the ratio of triglyceride to high-density lipoprotein cholesterol level (TG/HDL-C) is a risk factor for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the nonlinear relationship between TG/HDL-C and the incidence of T2DM in a Chinese population., Methods: We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the incidence of T2DM among 7,791 participants from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) cohort study at baseline., Results: After adjusting for age, sex, body mass index, smoking status, alcohol intake, low-density lipoprotein cholesterol level, strenuous activity, education level, family histories of T2DM and tumors, and the presence of hypertension, tumor, stroke, and coronary heart disease, we showed that TG/HDL-C was positively associated with the incidence of T2DM at the 4-year follow-up (OR = 1.49, 95%CI = 1.26-1.78). TG/HDL-C and incidence of T2DM showed a nonlinear relationship; the inflection point of TG/HDL-C was 1.50. The ORs (95% CI) on the left and right sides of the inflection point were 2.50 (1.70-3.67) and 0.96 (0.67-1.37), respectively. After adjusting for age, sex, and body mass index (BMI) in the linear relationship, the OR of the incidence of T2DM was 1.60 (95%CI = 1.37-1.87). When the TG/HDL-C was less than 1.50 or greater than 1.76, the ORs (95% CI) were 2.41 (1.82-3.18) or 0.81 (0.53-1.25), respectively. Subgroup analysis showed no relationships of T2DM incidence with sex, BMI, family history of T2DM, or TG/HDL-C., Conclusion: TG/HDL-C is positively associated with diabetes risk. In our study, with each increasing quintile, the risk of T2DM after 4 years was 1.60 or 1.49 depending on the variables adjusted. In addition, our cohort study showed a nonlinear relationship between TG/HDL-C and T2DM incidence, with an inflection point of 1.76 or 1.50, depending on the variables adjusted. When the TG/HDL was less than 1.50, the ORs (95% CI) were 2.41 (1.82-3.18) and 2.50 (1.70-3.67). When the TG/HDL-C was greater than 1.76 or 1.50, there was no significant difference in the change in OR., Competing Interests: All authors declare that there is no conflict of interest associated with this research., (Copyright © 2021 Hongzhou Liu et al.)

Objective: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults., Research Design and Methods: We tested 23 serum BA species in subjects with incident diabetes ( n = 1,707) and control subjects ( n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression., Results: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid ( P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset., Conclusions: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes., (© 2020 by the American Diabetes Association.)

Aims/introduction: This secondary analysis of the 24-week SMART study examined the efficacy of add-on saxagliptin or acarbose to metformin across different patient subgroups with type 2 diabetes mellitus, based on baseline characteristics., Materials and Methods: Randomized patients (n = 481) were classified into subgroups based on their baseline age (<65, ≥65 years), body mass index (BMI; <24, 24-<28, ≥28 kg/m 2 ), glycated hemoglobin (HbA1c; <8%, 8-<9%, 9-<10%, ≥10%) and renal function (creatinine clearance 50-<80, ≥80 mL/min). Treatment effects on primary outcome (HbA1c) and key secondary outcomes of fasting plasma glucose (FPG), 2-h postprandial glucose and homeostatic model assessment of β-cell function were assessed across patient subgroups., Results: For saxagliptin, reductions in HbA1c from baseline to week 24 were consistent across different subgroups regardless of baseline age, body mass index, HbA1c and renal function (range -0.66 to -1.16%). Saxagliptin was associated with consistent reductions in FPG (-0.60 to -1.33 mmol/L) and 2-h postprandial glucose (-0.48 to -1.95 mmol/L) across the majority of subgroups studied. The efficacy of acarbose on FPG attenuated progressively with increasing baseline HbA1c (+0.86 to -1.43 mmol/L); an increase from baseline FPG was observed in patients with HbA1c >9%. The effect of acarbose on postprandial glucose was also variable (+0.23 to -3.38 mmol/L)., Conclusions: As add-on to metformin, both saxagliptin and acarbose reduced HbA1c regardless of baseline HbA1c, age, body mass index and renal function; however, only saxagliptin was effective at a stable glycemic control (FPG and PPG). The efficacy of acarbose on FPG and PPG was significantly attenuated in patients with higher baseline HbA1c (≥8%)., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: The relationship between albuminuria and insulin resistance (IR) has not been clarified in previous studies. This study was conducted to examine whether IR is associated with albuminuria in subjects with diverse blood pressure and glycometabolism statuses., Methods: This study included 34 136 participants whose data were drawn from a cross-sectional survey named the 2011 REACTION study. The participants were divided into six groups. The urinary albumin-creatinine ratio (UACR) and glomerular filtration rate (GFR) were used as markers of chronic kidney disease (CKD). Variance tests and logistic regression models were performed for homeostatic model assessment of insulin resistance (HOMA-IR) in relation to UACR and eGFR., Results: First, UACR levels and HOMA-IR exhibited a positive correlation among participants (P < 0.05), and a negative correlation existed between GFR and HOMA-IR (P < 0.05). Second, in the hypertension with diabetes group, in individuals whose body mass index (BMI) was 18.5-24.0 kg/m 2 , age was 50-60 years old, low density lipoprotein cholesterol (LDL-C) was 2.6-3.4 mmol/L or high density lipoprotein cholesterol (HDL-C) was 0.9-1.55 mmol/L, HOMA-IR was positively associated with UACR (P < 0.05). However, there was a negative correlation between GFR and HOMA-IR in the hypertension with diabetes group in individuals whose BMI was 18.5-24.0 kg/m 2 or whose age was over 65 years old (P < 0.05)., Conclusions: In the context of different blood pressure and glycometabolism statuses, the positive correlation between UACR levels and HOMA-IR was affected by BMI, age, LDL-C, HDL-C, and GFR. In patients with hypertension and diabetes, the early detection and intervention of IR and related risk factors in patients with normal BMI may reduce the occurrence of microalbuminuria and delay the progression of CKD., (© 2019 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Introduction: Many Chinese patients who are uncontrolled by oral antidiabetic drugs (OADs) receive short-term intensive insulin therapy (IIT) in hospital to rapidly relieve glucose-associated toxicity and to preserve/improve β-cell function. However, evidence for optimizing insulin algorithms for maintenance treatment after IIT is lacking. This study will compare the efficacy and safety of basal insulin-based treatment versus twice-daily premixed insulin in type 2 diabetes mellitus (T2DM) patients after short-term in-hospital IIT., Methods: This 26-week randomized, multicenter, positive-controlled, open-label, parallel-group study will enroll approximately 400 male and female patients aged 18-70 years with poorly-controlled T2DM (HbA1c > 7.5%) despite treatment with metformin plus at least one other OAD for 8 or more weeks. During a run-in period of 7-10 days, patients will be treated in-hospital with IIT comprising insulin glargine (Lantus ® ) once daily and insulin glulisine (Apidra ® ) three times daily; both regimens will be titrated daily to achieve the glycemic goal. Eligible patients will then be randomized in a 1:1 ratio to insulin glargine plus OADs or twice-daily premixed insulin (NovoLog ® Mix 70/30) for 24 weeks, with metformin maintained throughout the study in both treatment groups. The primary endpoint is HbA1c change from baseline to week 24. Secondary endpoints include assessment of fasting plasma glucose, total daily insulin dose, hypoglycemia incidence, body weight change, adverse events, and patient satisfaction., Discussion: Given the current lack of clinical data, this study will provide evidence supporting safe and effective glycemic control using basal insulin glargine-based therapy plus OADs compared with twice-daily premixed insulin in Chinese patients with T2DM after short-term IIT. This will assist physicians by providing a wider choice of treatments., Trial Registration: ClinicalTrials.gov identifier, NCT03359837 (registered on 2 December 2017).

Aims: To investigate the effect of preoperative HbA1c levels on the postoperative outcomes of coronary artery disease surgery in diabetic and nondiabetic patients., Methods and Results: The MEDLINE (via PubMed), Cochrane Library, Web of Science, Embase, Wanfang Data, China National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) databases were used to search the effects of different preoperative HbA1c levels on the postoperative outcomes of coronary artery disease surgical treatment in diabetic and nondiabetic patients from inception to December 2018. Two review authors worked in an independent and duplicate manner to select eligible studies, extract data, and assess the risk of bias of the included studies. We used a meta-analysis to synthesize data and analyze subgroups, sensitivity, and publication bias as well as the GRADE methodology if appropriate. The literature search retrieved 886 records initially, and 23 cohort studies were included in the meta-analysis. In this meta-analysis, we found that there was a reduced incidence of surgical site infections (OR = 2.94, 95% CI 2.18-3.98), renal failure events (OR = 1.63, 95% CI 1.13-2.33), and myocardial infarction events (OR = 1.69, 95% CI 1.16-2.47), as well as a shortened hospital stay (MD = 1.08, 95% CI 0.46-1.71), in diabetic patients after coronary artery disease surgical treatment with lower preoperative HbA1c levels. For nondiabetic patients, a higher preoperative HbA1c level resulted in an increase in the incidence of mortality (OR = 2.23, 95% CI 1.01-4.90) and renal failure (OR = 2.33, 95% CI 1.32-4.12). No significant difference was found between higher and lower preoperative HbA1c levels in the incidence of mortality (OR = 1.06, 95% CI 0.88-1.26), stroke (OR = 1.49, 95% CI 0.94-2.37), or atrial fibrillation (OR = 0.94, 95% CI 0.67-1.33); the length of ICU stay (MD = 0.20, 95% CI -0.14-0.55); or sepsis incidence (OR = 2.49, 95% CI 0.99-6.25) for diabetic patients or for myocardial infarction events (OR = 1.32, 95% CI 0.27-6.31) or atrial fibrillation events (OR = 0.99, 95% CI 0.74-1.33) for nondiabetic patients. The certainty of evidence was judged to be moderate or low., Conclusion: This meta-analysis showed that higher preoperative HbA1c levels may potentially increase the risk of surgical site infections, renal failure, and myocardial infarction and reduce the length of hospital stay in diabetic subjects after coronary artery disease surgical treatment and increase the risk of mortality and renal failure in nondiabetic patients. However, there was great inconsistency in defining higher preoperative HbA1c levels in the studies included; we still need high-quality RCTs with a sufficiently large sample size to further investigate this issue in the future. This trial is registered with CRD42019121531., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Jinjing Wang et al.)

Background: National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes., Methods: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011-12 (baseline) and invited participants to attend follow-up visits in 2014-16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and β-cell dysfunction (HOMA of β-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations., Findings: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08-7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10-2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72-4·48; per unit decrease in Z score: 1·92, 1·85-2·00). Approximately 24·4% (95% CI 23·6-25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2-13·7) could be attributed to β-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72-1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86-2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93-2·11) and 1·88 (1·79-1·98) among participants with obesity (p interaction =0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes., Interpretation: Insulin resistance shows a stronger association with incident diabetes than does β-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and β-cell dysfunction, these findings should be interpreted with caution., Funding: National Natural Science Foundation of China., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This study investigated the association between birth weight and diabetes in a Chinese population, and the effects of body mass index (BMI) and lifestyle factors in later life on this association., Methods: Data from 49 118 participants aged ≥40 years with recalled birth weight from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study, a nationwide population-based cohort, were used. Diabetes diagnosis was based on oral glucose tolerance tests and HbA1c measurements. Logistic regression models were used to evaluate the association of birth weight and risk of diabetes in later life., Results: Increased risk of diabetes was associated with lower or higher birth weight. Compared with individuals with a birth weight of 2500 to 3499 g, the odds ratios (ORs) and 95% confidence intervals (CIs) of diabetes for individuals with a birth weight of <2500, between 3500 and 3999, and ≥4000 g were 1.28 (1.11-1.47), 1.11 (1.04-1.19), and 1.20 (1.07-1.34), respectively. Significant associations were prominent in participants with a current BMI ≥24 kg/m 2 , but not detected in those with a normal BMI (OR 1.20 [95% CI 0.96-1.49], 1.11 [95% CI 0.98-1.25], and 1.10 [95% CI 0.89-1.37], respectively). Moreover, there was no increased risk of diabetes in individuals with a low birth weight but with healthy dietary habits (OR 0.94; 95% CI 0.68-1.29) or ideal physical activity (OR 1.41; 95% CI 0.97-2.04)., Conclusions: A U-shaped association was observed between birth weight and the risk of diabetes. Healthy lifestyles (healthy dietary habits or ideal physical activity) may eliminate the negative effects of low birth weight in the development of diabetes, but not the effect of high birth weight., (© 2019 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Long-term diabetes-associated complications are the major causes of morbidity and mortality in individuals with diabetes. These diabetic complications are closely linked to immune system activation along with chronic, non-resolving inflammation, but therapies to directly reverse these complications are still not available. Our previous study demonstrated that mesenchymal stem cells (MSCs) attenuated chronic inflammation in type 2 diabetes mellitus (T2DM), resulting in improved insulin sensitivity and islet function. Therefore, we speculated that MSCs might exert anti-inflammatory effects and promote the reversal of diabetes-induced kidney, liver, lung, heart, and lens diseases in T2DM rats., Methods: We induced a long-term T2DM complication rat model by using a combination of a low dose of streptozotocin (STZ) with a high-fat diet (HFD) for 32 weeks. Adipose-derived mesenchymal stem cells (ADSCs) were systemically administered once a week for 24 weeks. Then, we investigated the role of ADSCs in modulating the progress of long-term diabetic complications., Results: Multiple infusions of ADSCs attenuated chronic kidney disease (CKD), nonalcoholic steatohepatitis (NASH), lung fibrosis, and cataracts; improved cardiac function; and lowered serum lipid levels in T2DM rats. Moreover, the levels of inflammatory cytokines in the serum of each animal group revealed that ADSC infusions were able to not only inhibit pro-inflammatory cytokines IL-6, IL-1β, and TNF-α expression but also increase anti-inflammatory cytokine IL-10 systematically. Additionally, MSCs reduced the number of iNOS(+) M1 macrophages and restored the number of CD163(+) M2 macrophages., Conclusions: Multiple intravenous infusions of ADSCs produced significant protective effects against long-term T2DM complications by alleviating inflammation and promoting tissue repair. The present study suggests ADSCs may be a novel, alternative cell therapy for long-term diabetic complications.

Background: In patients with type 2 diabetes mellitus (T2DM) and poor glycemic control receiving metformin (MET), glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended as the adjunctive therapy. However, there are only a few studies involving the comparative effects of exenatide twice a day (EXBID) and exenatide once weekly (EXQW) on HOMA- β . This meta assessed the comparative effects of EXQW and EXBID on HOMA- β among T2DM patients., Materials and Methods: PubMed, Cochrane Library, and Embase databases were searched to collect randomized controlled trials (RCTs). Network meta-analysis was performed, and network diagrams were constructed to evaluate the effects. The primary outcome is HOMA- β , and the secondary outcomes are fasting blood glycose (FBG), glycated hemoglobin (HbA1c), and weight loss., Results: A total of 8 studies with 3506 subjects were included. Compared with other antidiabetic agents, EXQW has a greater improvement in HOMA- β than EXBID (weight mean difference (WMD) = -0.46, 95% confidence interval (CI) [-0.64, -0.28], P = 0.001). The effect of EXQW on HbA1c is superior to that of sitagliptin (SITA) (WMD = 0.51, 95% CI [0.03, 0.99], P = 0.037). The significant reduction of weight was detected for EXBID in comparison with EXQW (WMD = -0.73, 95% CI [-1.13, -0.33], P = 0.001), and no significant difference was found between EXQW and MET., Conclusions: EXQW shows a greater improvement in HOMA- β than EXBID. Moreover, the efficacy of EXQW on glycemic control is similar to other antidiabetic agents including EXBID. It is an advisable treatment for diabetic patients to improve HOMA- β and has an advantage of fewer number of injections compared with EXBID, to increase patients' adherence and quality of life., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Jie Wang et al.)

Objective: The aim of this study was to systematically evaluate the quality of the clinical practice guidelines (CPGs) for diabetes mellitus published in China over the period of January 2007 to April 2017., Methods: We searched the China National Knowledge Infrastructure, Chinese Biomedical Literature database, VIP database and WanFang databases and guideline websites for CPGs for diabetes mellitus published between January 2007 and April 2017 in China. Two reviewers independently screened the literature according to the inclusion and exclusion criteria and extracted data. We used the the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool (Canadian Institutes of Health Research, Ottawa, Canada) to evaluate the quality of the included guidelines, calculated the scores of each domain and evaluated the consistency among the assessors via use of the intragroup correlation coefficient. And then we compared the results with Chinese CPGs and international CPGs. We conducted a subgroup analysis based on different classification criteria and compared scores of each domain subgroup analyses., Results: A total of 98 guidelines were identified. The correlation coefficient within the group was 0.93, suggesting that the consistency between the evaluators was good. The scores of the six domains of AGREE II were described in median (IQR) as follows: scope and purpose 53.7 (50.0-59.7), stakeholder involvement 31.5 (27.3-37.0), rigour of development 19.1 (15.3-22.2), clarity of presentation 59.3 (50.0-64.8), applicability 18.1 (13.9-25.7) and editorial independence 0.0 (0.0-0.0). The mean score in each domain of quality of Chinese diabetes CPGs was lower than that of CPGs published worldwide but higher than the mean score of Chinese guidelines of all topics. A funding source, the updated version, organisation and publishers of the guidelines and target fields are all the factors influencing the quality of CPGs to a certain degree., Conclusions: A large number of Chinese diabetes CPGs have been produced. Their quality remain unsatisfactorily low compared with CPGs worldwide, there is still room for improvement. Chinese guideline developers should pay more attention to the transparency of methodology, and use the AGREE II instrument to develop and report guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mesenchymal stem cells (MSCs) have emerged as a promising therapy for type 2 diabetes (T2D). Mechanistic researches demonstrate that the anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels. In this study, we used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice., Methods: High-fat diet (HFD) and streptozocin (STZ) were given to induce T2D mouse model. Successfully induced T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC + DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated during the entire analysis period. Epididymal fat was extracted for analysis of macrophage phenotype and inflammation in adipose tissue. In vitro, we examined the effect of MSC + DAC on macrophage polarization in bone marrow-derived macrophages (BMDMs) and explore the possible mechanism., Results: MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week, whereas combination therapy of MSCs + DAC extended the anti-diabetic effects of MSCs from 1 to 4 weeks (the end of the observation). Correspondingly, more M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period. In vitro, compared with the MSC group, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. Further analysis showed that the effect of MSC + DAC on macrophage polarization was largely abrogated by the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662., Conclusions: Our data suggest that MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong and enhance the anti-diabetic effect of MSCs in T2D mice in part by prompting M2 polarization in a PPARγ-dependent manner. Thus, decitabine may be an applicable addition to MSCs for diabetes therapy. UC-MSCs combined with decitabine activate the IL4R/STAT6/STAT3/PPARγ axis to further promote M2 macrophage polarization in adipose tissue, reduce inflammation, improve insulin sensitivity, and lead to better glucose metabolism and long-term hypoglycemic effects.

Objective: The relationship between age at natural menopause and type 2 diabetes mellitus (T2DM) has yielded conflicting results, particularly when confounded by the presence of obesity. We therefore aimed to examine the association between age at natural menopause and development of T2DM and the influence of postmenopausal obesity status on this association., Design: The data for this study was derived from one center (Beijing) of the REACTION study. After screening through our inclusion and exclusion criteria, 2689 postmenopausal women who completed a 3-year follow-up were included. Logistic regression analysis was conducted to clarify the association of the age at natural menopause with the development of T2DM., Results: After adjustment for potential confounders, there was no significant association between the age at natural menopause and development of T2DM for all subjects. However, when subjects were stratified along the postmenopausal obesity status at baseline, in the presence or absence of obesity, we found a surprising contradictory association in two subgroups: late menopause (age >50 years) was associated with an increased risk (OR, 1.45; 95% CI, 1.02 to 2.05) of developing T2DM in the postmenopausal group without obesity, whereas we found a reduced risk (OR, 0.43; 95% CI, 0.27 to 0.71) in the postmenopausal group with obesity. Moreover, we found that early menopausal women (age ≤45 years) with postmenopausal obesity had the highest risk (OR, 2.10; 95% CI, 1.11 to 4.00) of developing T2DM compared with all other postmenopausal women., Conclusions: Postmenopausal obesity status may influence the association of age at natural menopause and the development of T2DM., (Copyright © 2019 Endocrine Society.)