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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.)

As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long-term benefits in diabetes will eventually become clear., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aim: To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control., Materials and Methods: In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28., Results: The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was -2.0 ± 0.08% with dulaglutide/glargine and -1.1 ± 0.07% with placebo/glargine (LS mean difference: -1.0%, 95% confidence interval [CI] -1.1 to -0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -1.2 kg, 95% CI -1.8 to - 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: -0.8 mmol/L, 95% CI -1.1 to - 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%)., Conclusions: Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM., (© 2023 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population., Methods: This cross-sectional study enroled patients with T2DM between July and December 2017 from 24 provinces in China. Diabetic peripheral neuropathy and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score (NSS) and neuropathy disability score. The prevalence of DPN and its risk factors were analysed., Results: A total of 14,908 patients with T2DM were enroled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN in females was higher than in males (69.0% vs. 66.6%, P = 0.002). The prevalence of DPN increased with age and course of diabetes and decreased with body mass index (BMI) and education level (all P for trend <0.05). The comorbidities and complications in patients with DPN were higher than in those without DPN, including hypertension, myocardial infarction, diabetic retinopathy, and diabetic nephropathy (all P < 0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated haemoglobin, high-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C-peptide, and uric acid were negatively associated with DPN., Conclusions: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low-income, and undereducated patients., (© 2023 John Wiley & Sons Ltd.)

Aims: It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal-associated invariant T (MAIT) cells, an innate-like T-cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear., Materials and Methods: Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co-cultured with hepatic MAIT cells., Results: Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon-γ (IFN-γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-α (TNF-α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL-17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN-γ + TNF-α + IL-17 +/- producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co-culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN-γ and TNF-α., Conclusions: Our data implicate an increased Th1-like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis., Clinical Trial Registration Number: NCT03296605 (registered at www., Clinicaltrials: gov on 12 October 2018)., (© 2023 John Wiley & Sons Ltd.)

Aim: The study aimed to assess the prevalence and risk factors of painful diabetic peripheral neuropathy (PDPN) in patients with type 2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN) in mainland China., Methods: This nationwide cross-sectional study enrolled T2DM patients with DPN from 25 provinces in China between July 2017 and December 2017. The prevalence, characteristics, and risk factors of PDPN were analyzed., Results: Among 25,710 patients with T2DM and DPN, 14,699 (57.2%) had PDPN. The median age was 63 years old. Age over 40 years old, education level, hypertension, myocardial infarction, duration of diabetes of over five years, diabetic retinopathy and nephropathy, moderate total cholesterol, moderate and higher low-density lipoprotein (LDL) increased uric acid (UA) and decreased estimated glomerular filtration rate (eGFR) were independently associated with PDPN (all P < 0.05). Compared with low levels of C-peptide, moderate levels were independently associated with a higher risk of PDPN, while high levels were associated with a lower risk (all P < 0.001)., Conclusions: In mainland China, more than half of the patients with DPN have neuropathic pain. Patients with older age, lower education level, longer duration of diabetes, lower LDL, increased UA, decreased eGFR, and comorbidities had an increased risk of PDPN., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Up to now, there has not yet been guidance or consensus from Chinese experts in the field of personalized prevention and treatment of type 2 diabetes. In view of the above, the endocrinology diabetes Professional Committee of Chinese Non-government Medical Institutions Association, the integrated endocrinology diabetes Professional Committee of the integrated medicine branch of Chinese Medical Doctor Association, and the diabetes education and microvascular complications group of the diabetes branch of the Chinese Medical Association organized relevant experts to discuss and reach the "Chinese expert consensus on strengthening personalized prevention and treatment of type 2 diabetes" for reference in clinical practice., Competing Interests: Conflict of interest None of the authors has any commercial interest nor do they have conflict of interest, (Copyright © 2023. Published by Elsevier 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.)

Aims/introduction: To explore whether carotid atherosclerosis is an independent risk factor for small fiber nerve dysfunction in type 2 diabetes mellitus patients., Materials and Methods: A total of 247 type 2 diabetes patients from Nanjing Drum Tower Hospital received carotid ultrasonography and quantitative sensory testing, including cold and warm detection thresholds, and some patients received cold and heat pain detection thresholds, respectively. According to the results of quantitative sensory testing, patients were divided into normal small fiber nerve function (NSF) and small fiber nerve dysfunction (SFD) group. Meanwhile, patients were divided into the non-carotid atherosclerosis group, carotid intimal thickening, unilateral carotid atherosclerosis and bilateral carotid atherosclerosis group. The correlation between carotid ultrasonography with quantitative sensory testing parameters was analyzed by SPSS 26.0., Results: First, the incidence rate of SFD increased significantly in patients with carotid atherosclerosis (72.2%, P < 0.001) especially in bilateral carotid atherosclerosis (81.7%, P < 0.001). Second, compared with the NS group, the carotid intima-media thickness in SFD was thicker (P = 0.018) and the size of atherosclerotic plaque was larger (P < 0.001). In addition, the cold detection threshold decreased (P < 0.001), whereas the warm detection threshold (P < 0.001) and heat pain detection threshold (P < 0.001) increased as aggravation of carotid atherosclerosis. In the correlation analysis, the size of atherosclerotic plaque presented a positive correlation with the warm detection threshold (r = 0.476, P < 0.001) and heat pain detection threshold (r = 0.213, P < 0.001), but presented a negative correlation with the cold detection threshold (r = -0.239, P < 0.01). Furthermore, carotid atherosclerosis (odds ratio 2.326, P = 0.017), especially bilateral carotid atherosclerosis (odds ratio 5.042, P = 0.001), was an independent risk factor for SFD (P < 0.05)., Conclusions: Carotid atherosclerosis was significantly associated with quantitative sensory testing and found to be an independent risk factor for small fiber nerve dysfunction in type 2 diabetes patients., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: To investigate whether peripheral neuropathy scale scores are associated with myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: In this cross-sectional study, 32,463 T2DM patients were enroled from 103 tertiary hospitals in 25 Chinese provinces. Based on a history of MI, participants were divided into the MI group (n = 4170) and the non-MI group (n = 28,293). All patients were assessed using four neuropathy scales, namely, Neurological Symptom Score (NSS), Neurological Disability Score (NDS), Toronto Clinical Scoring System (TCSS), and Michigan Neuropathy Screening Instrument (MNSI), and some of the patients underwent evaluation of nerve conduction velocity (NCV) (n = 20,288). The relationship between these scores and myocardial infraction was analysed., Results: The neuropathy scale scores in the MI group were higher than those in the non-MI group (p < 0.001). After dividing patients into four groups based on the grading criteria, our results showed that, in addition to aggravating the degree of neuropathy signs, the incidence of MI increased (p < 0.001). Logistic regression analysis results showed that neuropathy scale scores and NCV were both independent risk factors for MI (p < 0.001). Furthermore, among the scales used, MNSI presented a higher odds ratio and area under the curve (AUC; 0.625, p < 0.001) than the other three scales (AUC NSS  = 0.575, AUC NDS  = 0.606, and AUC TCSS  = 0.602, p < 0.001) for MI., Conclusions: Increased scores on these neuropathy scales (NSS, NDS, TCSS, and MNSI) and NCV were significantly associated with increased risk of MI and were considered independent risk factors., (© 2022 John Wiley & Sons Ltd.)

Aims: To evaluate the immunogenicity of LY2963016 insulin glargine (LY IGlar) versus originator insulin glargine (IGlar [Lantus®]) in Chinese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM)., Materials and Methods: ABES and ABET were prospective, randomized, active control, open-label, phase III studies, which enrolled Chinese patients with T1DM (N = 272) and T2DM (N = 536), respectively. Using data from these trials, immunogenicity of LY IGlar and IGlar was evaluated by comparing the proportion of patients with detectable anti-insulin glargine antibodies and the median antibody levels (percent binding) between the treatment groups. The incidence of anti-insulin antibodies and treatment-emergent antibody response (TEAR) were compared using Fisher's exact test or Pearson's chi-squared test. Levels of anti-insulin antibodies were compared using the Wilcoxon rank-sum test. We also evaluated the relationship between antibody formation or TEAR and clinical outcomes using analysis of covariance, negative binomial regression, or partial correlations., Results: There were no significant treatment differences in the incidence of detectable anti-insulin antibodies, median antibody levels or TEAR, overall or at Week 24 with last observation carried forward, and median antibody levels were low (<5%) after 24 weeks of treatment, in patients with T1DM or T2DM. Levels of anti-insulin antibodies and development of TEAR were not associated with efficacy (glycated haemoglobin, insulin dose [U/kg/d] and hypoglycaemia) or safety outcomes., Conclusions: The immunogenicity profiles of LY IGlar and IGlar are similar, with low levels of anti-insulin antibodies observed for both insulins. No association was observed between antibody levels or TEAR status and clinical outcomes., (© 2022 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: We compared the efficacy and safety of beinaglutide, a glucagon-like peptide-1 (GLP-1) analogue with metformin in lowering the bodyweight of patients who were overweight/obese and non-diabetic., Patients and Methods: Seventy-eight non-diabetic patients were randomly selected and beinaglutide or metformin was administered for 12 weeks. The primary endpoints were changes in body weight and the proportions of patients who lost≥5 and≥10% of their baseline body weights., Results: A total of 64 patients completed the study; patients in the beinaglutide group exhibited more bodyweight loss than those in the metformin group [(9.5±0.8%; 9.1±0.9 kg) and (5.1±0.9%; 4.5±0.8 kg), respectively, corresponding to a difference of approximately 4.5 kg (95% confidence interval, 2.2-6.9 kg; P <0.01)]. In the beinaglutide group, 90.6 and 40.6% of the patients lost≥5 and≥10% of their body weight, respectively, whereas, in the metformin group, these rates were 46.9 and 12.5%, respectively ( P <0.01 and P< 0.05). Weight loss following beinaglutide treatment mainly resulted from the loss of fat mass. Compared to metformin, beinaglutide induced a greater decrease in the body mass index, weight circumference, percent body fat, and body fat mass (total, trunk, limb, android, and gynoid). Additionally, beinaglutide decreased serum insulin levels and ameliorated insulin resistance., Conclusions: Beinaglutide is more efficient than metformin at reducing weight and fat mass in patients who are overweight/obese and non-diabetic. Beinaglutide may be a useful therapeutic option for overweight/obesity control in the Chinese population., Competing Interests: All authors have no conflicts of interest, financial ties, or grant support to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 )., (© 2022. The Author(s).)

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was -1.07% (-1.19%, -0.95%) in the dorzagliatin group and -0.50% (-0.68%, -0.32%) in the placebo group (estimated treatment difference, -0.57%; 95% confidence interval: -0.79%, -0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aim: To investigate the diagnostic utility of corneal confocal microscopy (CCM) for small fiber neuropathy in type 2 diabetes., Materials and Methods: There were 186 participants with type 2 diabetes enrolled in this cross-sectional research. Pure small fiber neuropathy and mixed fiber neuropathy were defined using clinical examination, electromyography, and quantitative sensory testing. Demographics and clinical data, corneal confocal microscopy parameters, and other neuropathy measures were compared among the groups. The diagnostic utility of corneal confocal microscopy for small fiber neuropathy was assessed by the receiver operating curve., Results: Of the 186 patients, 24.7% had a pure small fiber neuropathy and 17.2% of patients were diagnosed with mixed fiber neuropathy. The corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) were significantly lower in subjects with pure small fiber neuropathy compared with those without diabetic peripheral neuropathy (all P < 0.05). The receiver operating curve analysis for corneal confocal microscopy diagnosing small fiber neuropathy demonstrated the area under the curve for CNFD of 0.791, CNFL of 0.778, CNBD of 0.710., Conclusions: Patients with type 2 diabetes with pure small fiber neuropathy showed more corneal nerve loss compared with those without diabetic peripheral neuropathy. It was revealed that corneal confocal microscopy can be a reasonable marker in the diagnosis of small fiber neuropathy in type 2 diabetes., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: Cardiovascular autonomic neuropathy (CAN) is one of the most serious types of diabetic autonomic neuropathy and is a class of small fibre neuropathy. Among many inspection methods, quantitative sensory testing is an effective and convenient method for diagnosing diabetic small fibre neuropathy. This cross-sectional study aimed to identify the correlation between the development of cardiovascular autonomic neuropathy and quantitative sensory testing parameters in patients with type 2 diabetes mellitus., Methods: A total of 266 participants with type 2 diabetes mellitus from Nanjing Drum Tower Hospital were enrolled in this study, and each of them received cardiovascular reflex tests (CARTs) and quantitative sensory testing, including testing of cold, warm, cold pain, and heat pain detection thresholds (CDT, WDT, CPT, and HPT, respectively). The results of CARTs were compared with the thermal detection thresholds in quantitative sensory testing by using SPSS 26.0., Results: A total of 266 participants were divided into the CAN group, early CAN (ECAN) group, and without CAN (NCAN) group. There were significant differences in quantitative sensory testing parameters among three groups, and CARTs presented a positive correlation with the WDT and HPT and a negative correlation with the CDT. Moreover, after adjusting for age, sex, diabetes duration, and other influencing factors, WDT, HPT, and CDT were independent risk factors for cardiovascular autonomic neuropathy., Conclusions: The thermal detection thresholds, including cold, warm, and heat pain detection thresholds, in quantitative sensory testing were found to be significantly related to the results of CARTs. Some thermal detection thresholds were independent risk factors for cardiovascular autonomic neuropathy. Therefore, this study showed that quantitative sensory testing has a reliable predictive ability for the occurrence and development of cardiovascular autonomic neuropathy., (© 2021. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: Glycemic control remains suboptimal in developing countries due to critical system deficiencies. An innovative mobile health (mHealth)-enabled hierarchical diabetes management intervention was introduced and evaluated in China with the purpose of achieving better control of type 2 diabetes in primary care., Methods and Findings: A community-based cluster randomized controlled trial was conducted among registered patients with type 2 diabetes in primary care from June 2017 to July 2019. A total of 19,601 participants were recruited from 864 communities (clusters) across 25 provinces in China, and 19,546 completed baseline assessment. Moreover, 576 communities (13,037 participants) were centrally randomized to the intervention and 288 communities (6,509 participants) to usual care. The intervention was centered on a tiered care team-delivered mHealth-mediated service package, initiated by monthly blood glucose monitoring at each structured clinic visit. Capacity building and quarterly performance review strategies upheld the quality of delivered primary care. The primary outcome was control of glycated hemoglobin (HbA1c; <7.0%), assessed at baseline and 12 months. The secondary outcomes include the individual/combined control rates of blood glucose, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C); changes in levels of HbA1c, BP, LDL-C, fasting blood glucose (FBG), and body weight; and episodes of hypoglycemia. Data were analyzed using intention-to-treat (ITT) generalized estimating equation (GEE) models, accounting for clustering and baseline values of the analyzed outcomes. After 1-year follow-up, 17,554 participants (89.8%) completed the end-of-study (EOS) assessment, with 45.1% of them from economically developed areas, 49.9% from urban areas, 60.5 (standard deviation [SD] 8.4) years of age, 41.2% male, 6.0 years of median diabetes duration, HbA1c level of 7.87% (SD 1.92%), and 37.3% with HbA1c <7.0% at baseline. Compared with usual care, the intervention led to an absolute improvement in the HbA1c control rate of 7.0% (95% confidence interval [CI] 4.0% to 10.0%) and a relative improvement of 18.6% (relative risk [RR] 1.186, 95% CI 1.105 to 1.267) and an absolute improvement in the composite ABC control (HbA1c <7.0%, BP <140/80 mm Hg, and LDL-C <2.6 mmol/L) rate of 1.9% (95% CI 0.5 to 3.5) and a relative improvement of 21.8% (RR 1.218, 95% CI 1.062 to 1.395). No difference was found on hypoglycemia episode and weight gain between groups. Study limitations include noncentralized laboratory tests except for HbA1c, and caution should be exercised when extrapolating the findings to patients not registered in primary care system., Conclusions: The mHealth-enabled hierarchical diabetes management intervention effectively improved diabetes control in primary care and has the potential to be transferred to other chronic conditions management in similar contexts., Trial Registration: Chinese Clinical Trial Registry (ChiCTR) IOC-17011325., Competing Interests: Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WJ is a member of the Editorial Board of PLOS Medicine. The authors declare that no other competing interests exist.

Chiglitazar (Carfloglitazar) is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes. In this randomized phase 3 trial, we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen. Eligible patients were randomized (1:1:1) to receive chiglitazar 32 mg (n = 245), chiglitazar 48 mg (n = 246), or sitagliptin 100 mg (n = 248) once daily for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin A 1C (HbA 1c ) from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin. Both chiglitazar and sitagliptin significantly reduced HbA 1c at week 24 with values of -1.40%, -1.47%, and -1.39% for chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg, respectively. Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg, with mean differences of -0.04% (95% confidential interval (CI) -0.22 to 0.15) and -0.08% (95% CI -0.27 to 0.10), respectively. Compared with sitagliptin, greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar. Overall adverse event rates were similar between the groups. A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported. The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes., Competing Interests: Conflict of interest This study was sponsored by Chipscreen Biosciences (Shenzhen, China). The sponsor had a role in study design, site monitoring, data analysis, and writing of the report. Zhiqiang Ning, Haixiang Cao, Desi Pan, He Yao, and Xianping Lu are employees of Chipscreen Biosciences. The other authors declare that they have no conflict of interest., (Copyright © 2021 Science China Press. Published by Elsevier B.V. All rights reserved.)

Obesity-induced insulin resistance is the principal cause of type 2 diabetes worldwide. The use of natural products for the treatment of diabetes is increasingly attracting attention. Silymarin (SLM) is a flavonolignan compound that has been shown to have promise for the treatment of diabetes. In the present study, we aimed to investigate the mechanisms underlying its therapeutic effects. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks and then orally administered SLM (30 mg/kg) daily for 1 month. The effects of SLM were also investigated in HepG2 cells that had been rendered insulin resistant by palmitic acid (PA) treatment. SLM ameliorated the dyslipidemia, hepatic steatosis, and insulin resistance of the HFD-fed mice. HFD-feeding and PA treatment reduced the expression of sirtuin-1 (SIRT1) in the livers of the mice and in HepG2 cells, respectively. SLM increased the phosphorylation of AKT and FOXO1, and reduced the level of FOXO1 acetylation in PA-treated cells. However, SIRT1 knockdown by RNA interference reduced these effects of SLM. Moreover, the results of molecular dynamic simulation and in vitro activity assays indicated that SLM may directly bind to SIRT1 and increase its enzymatic activity. These findings suggest that hepatic SIRT1 may be an important pharmacological target of SLM and mediate effects on insulin resistance and gluconeogenesis, which may underlie its anti-diabetic activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: This analysis aims to investigate the efficacy and safety of once-daily lixisenatide add-on treatment to basal insulin in Asian individuals with type 2 diabetes, by baseline body mass index (BMI)., Research Design and Methods: Data from all Asian participants in the placebo-controlled GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C Studies were pooled and categorized according to the following BMI subgroups:<25 kg/m 2 , 25-<30 kg/m 2 and ≥30 kg/m 2 . Efficacy and safety of lixisenatide versus placebo were evaluated among BMI subgroups. Multivariable regression analyses were also conducted to explore the potential influence of BMI on efficacy outcomes after adjusting for baseline characteristics., Results: 555 participants were included (mean age 53.9 years, 52.4% men). No significant differences in treatment effect between the BMI subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose, postprandial glucose (PPG), PPG excursion, body weight, BMI, and basal insulin dose with lixisenatide, as well as the change in basal insulin dose at study endpoint and the proportion of participants achieving an HbA1c <7% at 24 weeks (all p values for interaction >0.15). In the multivariable regression analysis, participants in the lowest BMI group had a smaller reduction in body weight over the 24-week treatment period relative to the highest BMI group (p = 0.023)., Conclusions: This post hoc analysis indicates that lixisenatide improved glycemic control regardless of baseline BMI and was well tolerated in Asian individuals unable to achieve their HbA1c target on basal insulin±oral antidiabetic drugs., Competing Interests: Competing interests: WF, WW, RM and DZ declare no conflict of interest. GW, MZ, XZ and HY are employees of Sanofi China., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) with insulin glargine (Lantus; IGlar) combined with oral antihyperglycaemic medications (OAMs) in insulin-naive Chinese patients with type 2 diabetes (T2D)., Materials and Methods: In this phase III, open-label trial, adult patients with T2D receiving two or more OAMs at stable doses for 12 weeks or longer, with HbA1c of 7.0% or more and 11.0% or less, were randomized (2:1) to receive once-daily LY IGlar or IGlar for 24 weeks. The primary outcome was non-inferiority of LY IGlar to IGlar at a 0.4% margin, and a gated secondary endpoint tested non-inferiority of IGlar to LY IGlar (-0.4% margin), assessed by least squares (LS) mean change in HbA1c from baseline to 24 weeks., Results: Patients assigned to LY IGlar (n = 359) and IGlar (n = 177) achieved similar and significant reductions (p < .001) in HbA1c from baseline. LY IGlar was non-inferior to IGlar for change in HbA1c from baseline to week 24 (-1.27% vs. -1.23%; LS mean difference: -0.05% [95% CI, -0.19% to 0.10%]) and IGlar was non-inferior to LY IGlar. The study therefore showed equivalence of LY IGlar and IGlar for the primary endpoint. At week 24, there were no between-group differences in the proportion of patients achieving an HbA1c of less than 7.0%, seven-point self-measured blood glucose, insulin dose or weight gain. Adverse events, allergic reactions, hypoglycaemia and insulin antibodies were similar in the two groups., Conclusions: Once-daily LY IGlar and IGlar, combined with OAMs, provide effective and similar glycaemic control with comparable safety profiles in insulin-naive Chinese patients with T2D., (© 2021 Lilly Suzhou Pharmaceutical Co., Ltd. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Morphological alterations including adipocyte hypertrophy and fibrosis deposition are important surrogate markers of visceral adipose tissue function, but the relationships between these morphological changes and type 2 diabetes mellitus (T2DM) and impaired insulin sensitivity are poorly defined., Methods: Omental adipose tissue was obtained from 66 individuals with obesity but without T2DM (OB group), 93 individuals with both obesity and T2DM (T2DM group), and 15 individuals with normal BMI and normal glucose tolerance (NGT group). Adipocyte diameter and volume were measured through pathological section analysis. Pericellular and perilobular fibrosis was determined through picrosirius red staining and immunochemistry, while fibrosis-related genes were tested through gene expression and hydroxyproline content., Results: Compared with the NGT and OB groups, individuals from the T2DM group displayed increased adipocyte diameter and volume levels. Increased adipocyte size (diameter and volume) was positively associated with hyperglycemia and insulin resistance and inversely correlated with insulin sensitivity (using the Matsuda whole-body insulin sensitivity index assessment of insulin sensitivity) and β-cell function (disposition index 30 and disposition index 120). The fibrosis levels of the OB group were the highest out of the three groups, whereas the fibrosis levels of T2DM individuals were lower than the OB group but higher than the NGT group. Although fibrosis was negatively correlated with T2DM, fibrosis deposition was not remarkably associated with impaired systemic insulin sensitivity and glucose metabolism., Conclusions: Compared with fibrosis deposition, adipocyte hypertrophy is more closely associated with T2DM and impaired systemic insulin sensitivity., (© 2021 The Obesity Society.)

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.)

Aims: Epidemiological data on diabetic retinopathy (DR) in Chinese population is still rather scarce, and risk factors for diabetic retinopathy are inconsistent because of study designs, grading standards, and population samples., Materials and Methods: This hospital-based retrospective study included 1052 type 2 diabetes patients. Diabetic retinopathy was diagnosed by nonmydriatic fundus photography and/or fundus examination apparatus. Logistic regression analysis was performed to evaluate the risk of diabetic retinopathy., Results: A total of 352 (33.5% prevalence) subjects were diagnosed with diabetic retinopathy based on our population. The patients in the DR group not only had significantly higher hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), urinary microalbumin-creatinine ratio (ACR), and systolic blood pressure but also had higher follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG) levels compared to those in the non-DR group. Moreover, we confirmed that diabetes duration and HbA1c are strongly associated with DR risk. We also found that serum LH was an independent risk factor in male diabetic retinopathy patients (OR = 1.086, 95% CI 1.024-1.152), and the levels of LH were significantly associated with diabetic retinopathy prevalence ( P = 0.018)., Conclusions: Our study strengthens the argument that diabetes duration and HbA1c are risk factors for patients with DR. Additionally; we firstly confirmed that serum LH was an independent risk factor in male diabetic retinopathy patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Qingmin Sun et al.)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China., Research Design and Methods: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD., Results: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group., Conclusions: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Diabetes management in primary care remains suboptimal in China, despite its inclusion in the essential public health service (EPHS). We aimed to evaluate the effectiveness of a mobile health (mHealth) based and three-tiered diabetes management system in diverse Chinese contexts., Methods and Analysis: This is a cluster randomised controlled trial, named road to hierarchical diabetes management at primary care (ROADMAP). 19 008 patients with type 2 diabetes (T2D) were recruited from primary care clinics in 864 communities across 144 counties/districts of 24 provinces. Eligible participants were adult patients diagnosed with T2D and registered for diabetes management in communities. Patients within the same communities (clusters) were randomly allocated into the intervention or control arm for 1 year in a 2:1 ratio. The control arm patients received usual care as EPHS packaged: at least four blood glucose (BG) and blood pressure (BP) tests, and lifestyle and medication instruction, yearly, from primary care providers. The intervention arm patients received at least two BG and one BP tests, monthly, and lifestyle and treatment instruction from a three-tiered contracted team. A mHealth platform, Graded ROADMAP, enabled test results uploading and sharing, and patient referral within the team. The intervention participants will be further divided into basic or intensive intervention group according to whether they were actively using the Your Doctor App. The primary outcome is the BG control rate with glycated haemoglobin (HbA1c)<7.0%. Secondary outcomes include control rates and changes of ABC (HbA1c, BP and low-density lipoprotein cholesterol) and fasting BG, hypoglycaemia episodes and health-related quality of life (EuroQol (EQ-5D))., Ethics and Dissemination: The trial has been approved by the Institutional Review Board at Shanghai Sixth People's Hospital. Findings on the intervention effectiveness will be disseminated through peer-reviewed journals, conference presentations and other relevant mechanisms., Trial Registration Number: ChiCTR-IOC-17011325., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Because there has been no quality improvement initiatives targeting patients with type 2 diabetes (T2D) receiving basal insulin therapy, this study evaluated the effectiveness of physician-targeted education for optimizing glycemic management in these patients in China., Methods: This multicenter open-label observational study conducted across China had a baseline sample survey, followed by a 6-month education program, and ended with a post-education sample survey. Education based on T2D treatment guidelines was given at Months 1 and 3, and was reinforced by self-audit every month. Each hospital enrolled 100 patients with T2D receiving basal insulin at both the baseline and post-education survey. The primary outcome was the proportion of hospitals meeting individual improvement goals. The goal setting was based on the proportion of patients achieving HbA1c <7.0% in each hospital at the time of the baseline survey., Results: Overall, the individual improvement goal was achieved by 35 centers (49%). Hospitals with poor glycemic management at the baseline survey had higher possibility to improve at post-education survey. Two large sample surveys at baseline and post-education showed improved glucose management among these hospitals. A higher proportion of patients achieved HbA1c <7.0% in the post-education survey (27.2% vs 36.5%; P < 0.001) with reduced HbA1c levels (8.10% vs 7.72%; P < 0.001). Questionnaires from 723 physicians showed that confidence and practice of basal insulin use were significantly improved., Conclusions: Physician-targeted education improved glycemic management of patients with T2D in 71 hospitals in China, and was more effective at hospitals with poor glycemic management at the baseline survey., (© 2019 Sanofi (Beijing) Pharmaceuticals Co., Ltd. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.)

Aims: Diminished energy turnover of skeletal muscle is involved in the development of type 2 diabetes. Intensive insulin therapy has been reported to maintain glycaemic control in newly diagnosed type 2 diabetes, while the underlying mechanism remains unclear. Herein, we aimed to characterize the contribution of muscular mitochondrial oxidative phosphorylation (OxPhos) activity to insulin-induced glycaemic control., Materials and Methods: There were 21 drug naïve patients with type 2 diabetes receiving continuous subcutaneous insulin infusion for 7 days. Nine nondiabetics matched for age, body mass index, and physical activity were recruited as controls. We applied 31 P magnetic resonance spectroscopy to record in vivo muscular phosphocreatine (PCr) flux in controls and diabetics before and after insulin therapy. The mitochondrial OxPhos rate was calculated as ΔPCr / Δtime during the first 50 seconds after cessation of exercise., Results: In drug naïve type 2 diabetes, muscular mitochondrial OxPhos rate was restored after insulin therapy. Notably, this alteration was positively associated with the improvements of 1,5-anhydroglucitol, a serum marker for glucose control over the last 1 week, as well as homeostasis model assessment of β cell function and C-peptide/glucose ratio t 0 , two indices for basal insulin secretion. Furthermore, patients with diabetes family history and more severe glucotoxicity tend to achieve greater improvement in mitochondrial function by insulin., Conclusions: This study provides evidence that intensive insulin therapy facilitates muscular energy metabolism in drug naïve type 2 diabetes. It correlates to the recovery of β cell function, contributing to insulin-induced glucose control., (© 2019 John Wiley & Sons, Ltd.)

Background: Cardiovascular autonomic neuropathy (CAN) is a risk factor for arrhythmias and adverse cardiovascular events, but the relationship between CAN severity and nocturnal arrhythmias needs to be clarified. This study evaluated the association between nocturnal arrhythmias and CAN severity in patients with type 2 diabetes (T2D)., Methods: In all, 219 T2D patients were recruited from January 2017 to May 2018. Subjects were classified into no CAN (NCAN), early CAN (ECAN), definite CAN (DCAN), or advanced CAN (ACAN) based on cardiovascular autonomic reflex tests (CARTs). A 24-hour electrocardiogram was recorded and daytime (0700-2300 hours) and night-time (2300-0700 hours) heartbeats were analyzed separately., Results: After adjusting for age, the incidence of ventricular arrhythmias increased with CAN severity at night-time (18.6%, 29.9%, 36.2%, and 60.0% in the NCAN, ECAN, DCAN, and ACAN groups, respectively; P trend  = 0.034). Patients with nocturnal ventricular arrhythmias (NVAs) had higher CART scores (2.0 ± 1.0 vs 1.5 ± 0.9; P < 0.001) and lower heart rate variability (HRV) during deep breathing (9.5 ± 5.7 vs 11.6 ± 6.6 b. p. m; P = 0.021), HRV during the Valsalva maneuver (1.2 ± 0.1 vs 1.2 ± 0.2; P = 0.006), and postural blood pressure change (-8.8 ± 15.5 vs -4.1 ± 11.2 mmHg; P = 0.023). Multivariate regression analysis revealed that CAN stage (odds ratio 1.765; 95% confidence interval 1.184-2.632; P = 0.005) was independently associated with NVAs., Conclusions: In T2D, CAN stage was independently associated with the presence of NVAs. Early detection, diagnosis, and treatment of CAN may help predict and prevent adverse cardiovascular events and cardiovascular mortality in diabetes., (© 2019 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

The prevalence of diabetes in China has increased rapidly from 0.67% in 1980 to 10.4% in 2013, with the aging of the population and westernization of lifestyle. Since its foundation in 1991, the Chinese Diabetes Society (CDS) has been dedicated to improving academic exchange and the academic level of diabetes research in China. From 2003 to 2014, four versions of Chinese diabetes care guidelines have been published. The guidelines have played an important role in standardizing clinical practice and improving the status quo of diabetes prevention and control in China. Since September 2016, the CDS has invited experts in cardiovascular diseases, psychiatric diseases, nutrition, and traditional Chinese medicine to work with endocrinologists from the CDS to review the new clinical research evidence related to diabetes over the previous 4 years. Over a year of careful revision, this has resulted in the present, new version of guidelines for prevention and care of type 2 diabetes in China. The main contents include epidemiology of type 2 diabetes in China; diagnosis and classification of diabetes; primary, secondary, and tertiary diabetes prevention; diabetes education and management support; blood glucose monitoring; integrated control targets for type 2 diabetes and treatments for hyperglycaemia; medical nutrition therapy; exercise therapy for type 2 diabetes; smoking cessation; pharmacologic therapy for hyperglycaemia; metabolic surgery for type 2 diabetes; prevention and treatment of cardiovascular and cerebrovascular diseases in patients with type 2 diabetes; hypoglycaemia; chronic diabetic complications; special types of diabetes; metabolic syndrome; and diabetes and traditional Chinese medicine., (© 2019 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.)

Blood glucose monitoring is an important part of diabetes management. Continuous glucose monitoring (CGM) technology has become an effective complement to conventional blood glucose monitoring methods and has been widely applied in clinical practice. The indications for its use, the accuracy of the generated data, the interpretation of the CGM results, and the application of the results must be standardized. In December 2009, the Chinese Diabetes Society (CDS) drafted and published the first Chinese Clinical Guideline for Continuous Glucose Monitoring (2009 edition), providing a basis for the standardization of CGM in clinical application. Based on the updates of international guidelines and the increasing evidence of domestic studies, it is necessary to revise the latest CGM guidelines in China so that the recent clinical evidence can be effectively translated into clinical benefit for diabetic patients. To this end, the CDS revised the Chinese Clinical Guideline for Continuous Glucose Monitoring (2012 Edition) based on the most recent evidence from international and domestic studies., (© 2019 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons, Ltd.)

In this post hoc analysis of the randomized controlled LixiLan-O trial in insulin-naive patients with type 2 diabetes mellitus (T2DM) not controlled with metformin, with or without a second oral antihyperglycaemic drug (OAD), the efficacy and safety of the fixed-ratio combination, iGlarLixi (insulin glargine 100 U [iGlar] and lixisenatide [Lixi]), compared to its individual components was assessed in two patient subgroups: group 1) baseline HbA1c ≥9% (n = 134); group 2) inadequate control (HbA1c ≥7.0% and ≤9.0%) despite administration of two OADs at screening (n = 725). Treatment with iGlarLixi resulted in significantly greater reduction in least squares mean HbA1c compared to treatment with iGlar or Lixi alone in both subgroups (group 1: 2.9%, 2.5%, 1.7% and group 2: 1.5%, 1.2%, 0.7%, respectively). Target HbA1c less than 7% was achieved in more than 70% of patients using iGlarLixi in both subgroups, while mitigating the weight gain observed with use of iGlar alone. Rates of hypoglycaemic events were low overall. These results suggest that treatment with iGlarLixi achieves superior glycaemic control compared to treatment with iGlar or Lixi alone in T2DM patients with HbA1c ≥9% or in those inadequately controlled with two OADs., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Group 1 innate lymphoid cells (ILC1s) are effectors of innate immunity and enriched in inflamed tissues. Here we show that the number of adipose ILC1s increases in obese T2D patients and correlates with glycemic parameters and with the number of ILC1s in the blood; circulating ILC1 numbers decrease as a result of metabolic improvements after bariatric surgery. In vitro co-culture experiments show that human adipose ILC1s promote adipose fibrogenesis and CD11c + macrophage activation. Reconstruction of the adipose ILC1 population in Prkdc -/- IL2rg -/- mice by adoptive transfer drives adipose fibrogenesis through activation of TGFβ1 signaling; however, transfer of Ifng -/- ILC1s has no effect on adipose fibrogenesis. Furthermore, inhibiting adipose accumulation of ILC1s using IL-12 neutralizing antibodies attenuates adipose tissue fibrosis and improves glycemic tolerance. Our data present insights into the mechanisms of local immune disturbances in obesity-related T2D.

Objective: Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks., Research Design and Methods: Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes., Results: Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation., Conclusions: Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients., (© 2019 by the American Diabetes Association.)

Aim: To assess metabolic effects and safety of Roux-en-Y gastric bypass (RYGB) versus conventional medication (CM) in obese Chinese patients with type 2 diabetes (T2DM)., Methods: This retrospective cohort study included 40 patients who underwent RYGB (mean age 44.1 years, body mass index [BMI] 33.3 kg/m 2 ) and 36 patients administered CM (mean age 49.4 years, BMI 32.1 kg/m 2 ). The primary endpoint was achievement of the triple endpoint (haemoglobin A1C [HbA1c] < 7.0%, low-density lipoprotein cholesterol < 2.6 mmol/L, and systolic blood pressure < 130 mmHg). Changes in weight, BMI, medication usage, complications, and adverse events were assessed., Results: After 1-year follow-up, 35% of RYGB patients and 8% of CM patients achieved the triple endpoint (P = 0.005). More patients in the RYGB group achieved complete (48% vs 3%, P < 0.001) and partial (23% vs 0%, P = 0.007) remission of diabetes, and complete remission of hypertension (58% vs 24%, P = 0.019). Patients in the RYGB group had greater weight loss and decrease in BMI, waist circumference, fasting and postprandial of blood glucose and insulin levels, HbA1c, blood pressure, triglycerides, and increased high-density cholesterol (P < 0.001- < 0.05). A lower proportion of the RYGB group received antidiabetics, antihypertensives, or antilipemic treatments, and had non-alcoholic fatty liver disease (NAFLD) than the CM group during follow-up. More patients had nutrient deficiency-related diseases in the RYGB group over 1-year follow-up., Conclusions: For obese Chinese patients with T2DM, RYGB resulted in better metabolic control, greater weight loss, and lower medication usage and NAFLD, but more frequently resulted in diseases related to nutrient deficiency., (© 2019 John Wiley & Sons, Ltd.)

Aims: To compare the efficacy and safety of saxagliptin and glimepiride in type 2 diabetes (T2D) patients who are inadequately controlled with metformin monotherapy., Materials and Methods: In this 48-week, multi-centre, open-label, randomized, parallel trial (NCT02280486, clinicaltrials.gov), a total of 388 T2D patients were randomized 1:1 to saxagliptin or glimepiride groups. The primary endpoint was achievement of HbA1c <7.0%, without hypoglycaemia, defined as blood glucose <3.9 mmol/L and weight gain <3.0% after 48 weeks of treatment., Results: Over 48 weeks, a greater proportion of patients achieved the primary endpoint with saxagliptin compared with glimepiride (43.3% vs 31.3%; odds ratio, 1.38, 95% CI, 1.05-1.82; P = 0.019), especially among patients with baseline HbA1c <8.0%, duration <5 years or baseline BMI ≥25 kg/m 2 . Mean reduction in HbA1c was similar in the two treatment groups at Week 48 (-0.94% with saxagliptin vs -0.98% with glimepiride; P = 0.439). Bodyweight decreased with saxagliptin, but increased with glimepiride over the treatment period, and the treatment difference was -1.6 kg (P < 0.001) at Week 48. The proportion of patients experiencing hypoglycaemia was much lower with saxagliptin vs glimepiride (3.1% vs 12.8%; P < 0.001)., Conclusions: This study provides evidence that, compared to glimepiride, saxagliptin more effectively achieves a composite endpoint of adequate glycaemic control without hypoglycaemia and without weight gain in T2D patients who are inadequately controlled with metformin monotherapy, especially in overweight patients with moderate hyperglycaemia and a relatively short duration of diabetes., (© 2018 John Wiley & Sons Ltd.)

Aims: To investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies in people with phenotype of type 2 diabetes (T2D)., Materials and Methods: We included a nationally representative sample of 46 239 adults aged ≥20 years from 14 provinces, of whom 4671 had diabetes, plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GAD), islet antigen 2 (IA2) and zinc transporter isoform-8 (Znt8) and were defined as having ADM where positive for these antibodies. We then assayed thyroid peroxidase (TPO), tissue transglutaminase (tTG) and 21-hydroxylase (21-OH) autoantibodies in randomly selected participants with ADM and in age-matched, sex-matched and non-ADM controls with T2D plus controls with NGT., Results: Post-normalization, the standardized prevalence rate of ADM was 6.0% (95% confidence interval [CI] 5.3-6.8) in initially non-insulin-requiring participants with ADM, corresponding to six million adults in China, in whom adjusted antibody positivity was: TPO autoantibodies 16.3% (95% CI 10.8-21.8), tTG autoantibodies 2.1% (95% CI 0.0-4.2), and 21-OH autoantibodies 1.8% (95% CI -0.2 to 3.8). Those participants with ADM who were GAD autoantibody-positive had high risk of TPO autoantibody positivity (odds ratio [OR] 2.39, P = 0.0031) and tTG autoantibody positivity (OR 6.98, P = 0.027), while those positive for IA2 autoantibodies had a high risk of tTG autoantibody positivity (OR 19.05, P = 0.001)., Conclusions: A proportion of people with phenotype of T2D in China have ADM, with diabetes-associated autoantibodies, and may be at risk of developing other organ-specific autoimmune diseases; therefore, it may be clinically relevant to consider screening such Chinese populations., (© 2018 John Wiley & Sons Ltd.)

Aims/introduction: To investigate the direct medical costs for patients with type 2 diabetes in China and to examine the influencing factors., Materials and Methods: In the present multicenter study, 1,070 patients with type 2 diabetes from 16 tertiary hospitals in 14 major cities of China were enrolled. Patient data and direct medical costs were collected during a follow-up period of 6 months at intervals of 1 month. The log-transformed direct medical costs were fitted by a generalized estimation equation to indicator variables for demographics, metabolic control, treatments, complications and comorbidities., Results: Data of 871 participants were included in the analysis. The mean annual total direct medical costs and outpatient medical costs were $1,990.20 and $1,687.20 respectively. The average costs per inpatient per admission were $2,127.10. The share of out-of-pocket for total medical costs, outpatient costs and cost per inpatient per admission were 45.4, 46.3 and 26.0% respectively. Independent determinants of total medical costs were diabetes duration, dyslipidemia and diabetic complications, such as neuropathy and nephropathy, as well as diabetes treatment, such as the use of glucagon-like peptide-1 receptor agonists. Costs showed prominent variation across centers., Conclusions: Diabetes is imposing a growing economic burden in patients with type 2 diabetes in China. Diabetes-related complications and comorbidities have a great impact on the medical costs. As different health policies, economic development and regional health inequalities also have an important influence on the direct medical cost, healthcare reform needs to optimize resource allocation in health service delivery systems, and provide more equitable and affordable healthcare., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Efficacy trials showed that glucagon-like peptide-1 receptor (GLP1R) agonists reduced metabolic risk factors in addition to glucose lowering, but the cardiovascular and microvascular efficacy of this drug class remains to be determined. We aimed to evaluate the overall cardiovascular and microvascular efficacy of GLP1R agonists by performing a meta-analysis with trial sequential analysis., Methods: Randomized controlled, cardiovascular outcomes trials including at least 2000 patient-years' follow-up and 100 composite cardiovascular events were included. Trial sequential analysis (TSA) was performed and the quality of evidence was graded., Results: Thirty-three thousand four hundred fifty-seven patients and 4105 cardiovascular events from 4 large trials were included. GLP1R agonists were associated with a statistically significant reduction in risks for all-cause mortality (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.95; number needed to treat [NNT]: 286 person-years), cardiovascular mortality (HR: 0.87, 95% CI: 0.79 to 0.96; NNT: 412 person-years), stroke (HR: 0.87, 95% CI: 0.76 to 0.98; NNT: 209 person-years) and the composite adverse cardiovascular outcome (MACE; HR: 0.91, 95% CI: 0.85 to 0.96; NNT: 241 person-years). The magnitude of benefit on MACE was attenuated in patients with a history of congestive heart failure (HR: 0.96, 95% CI: 0.85 to 1.08 with; HR: 0.87, 95% CI: 0.77 to 1.00 without). The risks for hospitalization for heart failure and myocardial infarction were not significantly different. The quality of the evidence was deemed as moderate to high based on GRADE approach. TSA provided firm evidence for a 10% reduction in all-cause mortality, a 15% reduction in MACE, and lack of a 15% reduction in hospitalization for heart failure, but evidence remains inconclusive for cardiovascular mortality and myocardial infarction. GLP1R agonists numerically reduced the rates for nephropathy but the risk for retinopathy was similar., Conclusions: Meta-analysis with trial sequential analysis suggested that GLP1R agonists significantly reduced the risk for all-cause mortality and composite cardiovascular outcomes, but the reduction of cardiovascular mortality remains to be confirmed.

Purpose: Diabetic peripheral neuropathies are the common chronic complications of diabetes, but the diagnosis is insensitive by physical examination in busy outpatients. Here we evaluated the performance of SUDOSCAN in screening diabetic peripheral neuropathies in Chinese type 2 diabetic patients., Methods: The study enrolled 180 patients for annually screening. All patients underwent neurological symptoms assessment, clinical examination, nerve conduction studies and cardiovascular autonomic reflex tests. SUDOSCAN was tested and evaluated with electrochemical skin conductance in hands and feet, asymmetry ratio in hands and feet and predicted cardiac neuropathy., Results: Patients enrolled had an average age of 56.1 years, 9.8 years of diabetic duration. Patients with diabetic sensorimotor polyneuropathy showed significantly lower electrochemical skin conductance in feet and higher asymmetry ratio in feet compared with those without. Sensitivity and specificity of asymmetry ratio in feet for diagnosing diabetic sensorimotor polyneuropathy were 88.2% and 46.9% and area under ROC curve was 0.713. Patients with cardiovascular autonomic neuropathy showed significantly lower electrochemical skin conductance in hands and feet, and higher asymmetry ratio in feet and predicted cardiac neuropathy compared with those without. Sensitivity and specificity of electrochemical skin conductance in feet in diagnosing cardiovascular autonomic neuropathy were 85.6% and 76.1% with an area under ROC curve of 0.859., Conclusions: SUDOSCAN is a sensitive test to detect diabetic peripheral neuropathy in China and could be an effective screening tool in in busy outpatients and primary health care., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Glucokinase acts as a glucose sensor in the pancreas and a glucose processor in the liver, and has a central role in glucose homoeostasis. Dorzagliatin is a new, dual-acting, allosteric glucokinase activator that targets both pancreatic and hepatic glucokinases. Dorzagliatin has good pharmacokinetic and pharmacodynamic properties in humans, and provides effective 24-h glycaemic control and improves glucose sensitivity in patients with type 2 diabetes. We aimed to assess the efficacy and safety of dorzagliatin monotherapy at different doses in Chinese patients with type 2 diabetes., Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 study, we randomly assigned (1:1:1:1:1) patients to receive oral placebo or one of four doses of oral dorzagliatin (75 mg once a day, 100 mg once a day, 50 mg twice a day, or 75 mg twice a day) using permuted-block randomisation, with a block size of ten and without stratification. Eligible patients were men or non-fertile women (aged 40-75 years) with type 2 diabetes who had a BMI of 19·0-30·0 kg/m 2 , were on a diet and exercise regimen, and were previously untreated or treated with metformin or α-glucosidase inhibitor monotherapy. The study started with a 4-week placebo run-in period followed by a 12-week treatment period. The primary endpoint was the change in HbA 1c from baseline to week 12, which was assessed in all patients who received at least one dose of study drug and had both baseline and at least one post-baseline HbA 1c value. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02561338., Findings: Between Sept 29, 2015, and Aug 17, 2016, we randomly assigned 258 patients to one of the five study groups. At the end of 12 weeks, the least squares mean change in HbA 1c from baseline was -0·35% (95% CI -0·60 to -0·10) in the placebo group, -0·39% (-0·64 to -0·14) in the 75 mg once daily group, -0·65% (-0·92 to -0·38) in the 100 mg once daily group, -0·79% (-1·06 to -0·52) in the 50 mg twice daily group, and -1·12% (-1·39 to -0·86) in the 75 mg twice daily group. Compared with the placebo group, the change in HbA 1c between baseline and 12 weeks was significant in the 50 mg twice daily (p=0·0104) and the 75 mg twice daily (p<0·0001) groups. The number of adverse events was similar between the treatment groups and the placebo group. There were no reports of drug-related serious adverse events or severe hypoglycaemia., Interpretation: Dorzagliatin had a beneficial effect on glycaemic control and was safe and well tolerated over 12 weeks in Chinese patients with type 2 diabetes., Funding: Hua Medicine, National Major Scientific and Technological Special Project for Significant New Drugs Development, Shanghai Science and Technology Innovation Action Project, Shanghai Pudong District Science and Technology Innovation Action Project, and Shanghai Municipal Commission of Economy and Informatisation Innovation Action Project., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes., (© 2018 by the American Diabetes Association.)

Aims: Metformin treatment for type 2 diabetes mellitus (T2DM) can be limited by gastrointestinal (GI) adverse events (AEs), resulting in treatment discontinuation. We investigated whether once-daily metformin extended release (XR) is superior in terms of GI tolerability, with non-inferior efficacy, compared with thrice-daily metformin immediate release (IR) in treatment-naïve Chinese patients with T2DM., Materials and Methods: This prospective, open-label, randomized, multicentre, phase IV interventional study enrolled Chinese T2DM patients to receive either metformin XR or metformin IR with a 2-week screening period, a 16-week treatment period and a 2-week follow-up period without treatment. Co-primary endpoints were a non-inferiority assessment of metformin XR vs metformin IR in glycated haemoglobin (HbA1c) least squares mean (LSM) change from baseline to week 16 and the superiority of GI tolerability for metformin XR vs metformin IR., Results: Overall, 532 patients were randomized to metformin IR (n = 267) or metformin XR (n = 265). The HbA1c LSM change was -1.61% and -1.58% in each group, respectively (LSM difference, 0.03; 95% confidence interval [CI], -0.10, 0.17). Incidences of drug-related AEs were 26.5% (n = 66) in the metformin IR-only group and 32.2% (n = 85) in the metformin XR-only group, and GI AEs were 23.8% and 22.3% in each group, respectively (difference, -1.52; 95% CI, -8.60, 5.56). The treatment difference met the predefined non-inferiority upper CI margin of 0.4% in HbA1c., Conclusions: Metformin XR was non-inferior to metformin IR for the LSM change in HbA1c from baseline to week 16 and not superior to metformin IR for overall GI AE incidence during treatment of Chinese T2DM patients., (© 2017 John Wiley & Sons Ltd.)

Aims: To assess the effects on glycaemic control of lixisenatide vs placebo as add-on treatment to basal insulin (BI) ± metformin and effects on glycated haemoglobin (HbA1c) reduction in patients with insufficiently controlled type 2 diabetes (T2D)., Methods: Patients (n = 448) with inadequately controlled T2D were randomized (1:1) to lixisenatide or placebo as add-on to BI ± metformin for 24 weeks after an 8-week run-in phase, during which BI was titrated to a target self-monitored plasma glucose (SMPG; 4.4-5.6 mmol/L). The primary endpoint was absolute change in HbA1c from baseline to week 24. Secondary efficacy endpoints included: percentage of responders; changes in 2-hour postprandial plasma glucose (PPG); 7-point SMPG (daily average); body weight (BW); total daily BI dose; fasting plasma glucose; and safety assessments., Results: Baseline demographics were similar in the two treatment groups. After insulin optimization during run-in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation {s.d.}, 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error {s.e.}] change -0.62% [0.09] vs -0.11% [0.09]; P < .0001, respectively) and higher proportions of patients achieved HbA1c targets. Two-hour PPG, daily mean SMPG and mean BW were reduced further and daily BI dose was lower with lixisenatide than placebo (-1.12 kg vs 0.04 kg [P < .0001]; -3.0 U vs -1.9 U [P = .0033], respectively). Treatment-emergent adverse events were greater with lixisenatide than placebo (63.8% vs 40.8%, respectively). The incidence of symptomatic hypoglycaemia was similar (lixisenatide 15.6% vs placebo 13.5%)., Conclusions: In Asian patients insufficiently controlled on BI ± metformin, lixisenatide was superior to placebo in glycaemic control, with a tolerability profile in line with other glucagon-like peptide-1 receptor agonists., Clinical Trial Number: NCT01632163 (clinicaltrials.gov)., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

An early insulin regimen ameliorates glucotoxicity but also lipotoxicity in type 2 diabetes; however, the underlying mechanism remains elusive. In the present study, we investigated the role of mitochondria in lipid regulation following early insulin administration in insulin-resistant skeletal muscle cells. Male C57BL/6 mice, fed a high-fat diet (HFD) for 8 weeks, were treated with insulin for 3 weeks, and L6 myotubes cultured with palmitate (PA) for 24 h were incubated with insulin for another 12 h. The results showed that insulin facilitated systemic glucose disposal and attenuated muscular triglyceride accumulation in vivo. Recovery of AMP-activated protein kinase (AMPK) phosphorylation, inhibition of sterol-regulated element binding protein-1c (SREBP-1c) and increased carnitine palmitoyltransferase‑1B (CPT1B) expression were observed after insulin administration. Moreover, increased ATP concentration and cellular energy charge elicited by over-nutrition were suppressed by insulin. Despite maintaining respiratory complex activities, insulin restored muscular uncoupling protein 3 (UCP3) protein expression in vitro and in vivo. By contrast, knockdown of UCP3 abrogated insulin-induced restoration of AMPK phosphorylation in vitro. Importantly, the PA-induced decrease in UCP3 was blocked by the proteasome inhibitor MG132, and insulin reduced UCP3 ubiquitination, thereby prohibiting its degradation. Our findings, focusing on energy balance, provide a mechanistic understanding of the promising effect of early insulin initiation on lipotoxicity. Insulin, by recovering UCP3 activity, alleviated energy surfeit and potentiated AMPK-mediated lipid homeostasis in skeletal muscle cells following exposure to PA and in gastrocnemius of mice fed HFD.

Objective: To investigate exenatide, a GLP-1 analogue, compared with acarbose, for intra-abdominal fat reduction in patients with obesity and type-2 diabetes., Methods: This randomized controlled trial included 36 patients with obesity and type-2 diabetes, who were metformin-unresponsive, receiving metformin/exenatide (GLP-1 group) or metformin/acarbose (control group) for 3 months. Primary end-point: intra-abdominal fat content from baseline to 3 months; Secondary end-points: changes in fasting blood glucose, glycated haemoglobin (HbAlc), fasting insulin, blood lipids, weight, body mass index, and inflammatory cytokines from baseline to 3 months., Results: Intra-abdominal fat content decreased in the GLP-1 group from baseline to 3 months (17,947±5804; 13,717±3628mm 2 , P=0.001, respectively), but was not significantly reduced in the control group (P=0.197) and at 3 months post-treatment, it was significantly lower in the GLP-1 group than control group (P=0.043). Glucose control, measured by HbA1c (GLP-1: 9.72±1.38; 7.09±0.60%, P<0.001, 9.46±1.25; 7.42±0.84%, P<0.001, respectively) and insulin resistance index LN(HOMA-IR) (GLP-1: 1.58±0.40; 1.01±0.33, P<0.001, Control: 1.53±0.57; 1.10±0.33, P=0.003, respectively) significantly improved in both groups with no significant difference between them. TNF-α, IL-6, and leptin were lower and adiponectin levels higher in the GLP-1 group at 3 months compared with baseline (all P<0.05), but not significantly changed in the control group. TNF-α, IL-6 and leptin levels were similar between groups. Adiponectin level was higher in the GLP-1 group than the control group at 3 months (P=0.025)., Conclusion: Combined exenatide/metformin reduced intra-abdominal fat content, and enhanced insulin resistance and inflammatory status in patients with obesity and type-2 diabetes, representing a novel treatment regimen., (Copyright © 2017 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of the present study was to compare the effects of gliclazide, liraglutide, and metformin in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Eighty-seven subjects were randomized to receive liraglutide, metformin, or gliclazide for 24 weeks. Primary outcomes included HbA1c levels, intrahepatic fat (IHF) content, and liver function., Results: Both HbA1c levels and IHF content were reduced after treatment in all three groups. However, HbA1c levels were lower in the liraglutide- and metformin-treated groups than in the gliclazide-treated group, and reductions in IHF content were greater with liraglutide than with gliclazide. Liraglutide and metformin treatments reduced weight and improved liver function. Changes in IHF content were positively correlated with reductions in serum alanine aminotransferase and triglyceride levels, as well as weight. At 24 weeks, reductions in IHF content were greater in subjects with weight loss ≥5%, changes in waistline ≤0 cm (including decreases in waistline), HbA1c reductions ≥2.5%, and HbA1c levels <6.5%., Conclusions: In T2DM patients with NAFLD, compared with liraglutide and metformin, gliclazide resulted in less improvement in liver function, reductions in IHF content and HbA1c levels, and less weight loss; in addition, slightly better improvements were achieved with liraglutide than with metformin., (© 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background and Objective: Pharmacokinetic/pharmacodynamic modeling and simulation can aid clinical drug development by dynamically integrating key system- and drug-specific information into predictive profiles. In this study, we propose a methodology to predict pharmacokinetic/pharmacodynamic profiles of sinogliatin (HMS-5552, RO-5305552), a novel glucokinase activator to treat diabetes mellitus, for first-in-patient (FIP) studies., Methods and Results: Initially, pharmacokinetic/pharmacodynamic profiles of sinogliatin and another glucokinase activator (US2) previously acquired from healthy subjects were fitted using Model A incorporating an indirect response mechanism. The pharmacokinetic/pharmacodynamic profiles of US2 in patients with type 2 diabetes mellitus (T2DM) were then fitted using Model B incorporating circadian rhythm and food effects after thoughtful research on the difference between healthy subjects and T2DM patients. The differences in results between the two US2 modeling populations were used to scale the values of the pharmacodynamic parameters and refine the pharmacodynamic model of sinogliatin, which was then utilized to project pharmacokinetic/pharmacodynamic profiles of sinogliatin in T2DM patients after an 8-day simulated treatment. Results showed that the projected pharmacokinetic/pharmacodynamic values of five parameters were within 70-130% of values fitted from observed clinical data while the other two remaining projected parameters were within a twofold error. Population pharmacokinetic/pharmacodynamic analysis conducted for sinogliatin also suggested that age and sex were significantly correlated to pharmacokinetic/pharmacodynamic characteristics. Additionally, Model B was combined with a glycosylated hemoglobin (HbA 1c ) compartment to form Model C, which was then used to project serum HbA 1c levels in patients after a 1-month simulated treatment of sinogliatin. The predicted HbA 1c changes were nearly identical to observed clinical values (0.82 vs. 0.78%)., Conclusions: Model-based drug development methods utilizing a learn-research-confirm cycle may accurately project pharmacokinetic/pharmacodynamic profiles of new drugs in FIP studies.