Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo. To improve FGF21's therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo. One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. HEC Pharm R&D Co., Ltd, National natural science fund of China.

The aim of this work was to evaluate the effects of glucagon-like peptide-1 (GLP-1) on high-glucose-induced oxidative stress and investigate the possible mechanisms underlying this process. We measured reactive oxygen species (ROS) production, cell apoptosis, the expression of NOX4 and its subunits, and p47phox translocation in human umbilical vein endothelial cells (HUVECs). An experimental type 2 diabetes model was induced using streptozotocin in male Sprague-Dawley rats. Fasting blood glucose (FBG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TGs), and free fatty acid (FFA) were measured. Histomorphological analysis of the aorta was performed using hematoxylin-eosin staining. NOX4 and VCAM-1 expression in the aorta was measured. We found that high-glucose-induced ROS production and apoptosis were inhibited by GLP-1 treatment. High glucose caused upregulation of NOX4, p47phox, and Rac-1 and translocation of p47phox but had no effect on the cells pretreated with GLP-1. Furthermore, in the diabetic group, FBG, FINS, TG, TC, and FFA were increased, and NOX4 and VCAM-1 levels were also elevated. However, GLP-1 attenuated all these changes. GLP-1 ameliorated high-glucose-induced oxidative stress by inhibiting NOX4, p47phox, and Rac-1 expression and translocation of p47phox, suggesting its clinical usefulness in diabetic vascular complications.

Importance: An intermittent fasting plan consisting of 2 nonconsecutive fasting days and 5 days of habitual intake per week and meal replacement diet (5:2 MR) could provide additional benefits to patients with type 2 diabetes.Objective: To evaluate the effect of the 5:2 MR on glycemic control among patients with early type 2 diabetes compared with metformin and empagliflozin.Design, Setting, and Participants: The EARLY (Exploration of Treatment of Newly Diagnosed Overweight/Obese Type 2 Diabetes Mellitus) study is a randomized, open-label, active parallel-controlled clinical trial conducted between November 13, 2020, and December 29, 2022, in 9 centers across China. A total of 509 eligible patients underwent screening, out of which 405 were randomly assigned to 3 groups and included in the intention-to-treat analysis.Interventions: Patients were randomly allocated in a 1:1:1 ratio to receive either metformin, empagliflozin, or 5:2 MR. The treatment was 16 weeks, with an 8-week follow-up.Main Outcomes and Measures: The primary end point was the change in hemoglobin A_1c (HbA_1c) level from baseline to 16 weeks. Secondary end points included changes in body weight, anthropometric measurements, and biochemical parameters.Results: Of the 405 randomized participants (265 men [65.4%]; mean [SD] age, 45.5 [11.0] years; mean [SD] body mass index, 29.5 [4.1]; and mean [SD] HbA_1c level, 7.9% [0.6%]), 332 completed the 16-week treatment. From baseline to week 16, participants in the 5:2 MR group showed the greatest reduction in HbA_1c (least-squares mean [LSM], −1.9% [SE, 0.2%]), significantly greater than patients receiving metformin (LSM, −1.6% [SE, 0.2%]; adjusted LSM difference, −0.3% [95% CI, −0.4% to −0.1%]) and empagliflozin (LSM, −1.5% [SE, 0.2%]; adjusted LSM difference, −0.4% [95% CI, −0.6% to −0.2%]). At week 16, the mean weight loss in the 5:2 MR group (LSM, −9.7 kg [SE, 2.2 kg]) was greater than that in the metformin group (LSM, −5.5 kg [SE, 2.3 kg]) and empagliflozin group (LSM, −5.8 kg [SE, 2.3 kg]).Conclusions and Relevance: This randomized clinical trial of Chinese adults with overweight or obesity and with early type 2 diabetes found that 5:2 MR could improve glycemic outcomes and weight loss in the short term compared with metformin or empagliflozin, making it a promising initial intervention and early management for type 2 diabetes.Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000040656

With the deepening of aging in China, the prevalence of diabetes in older people has increased noticeably, and standardized diabetes management is critical for improving clinical outcomes of diabetes in older people. In 2021, the National Center of Gerontology, Chinese Society of Geriatrics, and Diabetes Professional Committee of Chinese Aging Well Association organized experts to write the first guideline for diabetes diagnosis and treatment in older people in China, the Guideline for the Management of Diabetes Mellitus in the Elderly in China (2021 Edition). The guideline emphasizes that older patients with diabetes are a highly heterogeneous group requiring comprehensive assessment and stratified and individualized management strategies. The guideline proposes simple treatments and de‐intensified treatment strategies for older patients with diabetes. This edition of the guideline provides clinicians with practical and operable clinical guidance, thus greatly contributing to the comprehensive and full‐cycle standardized management of older patients with diabetes in China and promoting the extensive development of clinical and basic research on diabetes in older people and related fields. In the past 3 years, evidence‐based medicine for older patients with diabetes and related fields has further advanced, and new treatment concepts, drugs, and technologies have been developed. The guideline editorial committee promptly updated the first edition of the guideline and compiled the Guideline for the Management of Diabetes Mellitus in the Elderly in China (2024 Edition). More precise management paths for older patients with diabetes are proposed, for achieving continued standardization of the management of older Chinese patients with diabetes and improving their clinical outcomes.

Objective: This systematic review and meta-analysis aimed to evaluate the effects of SGLT-2 inhibitors (SGLT-2i) on endothelial function and arteriosclerosis in diabetic patients.Methods: Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science databases to evaluate the effects of SGLT-2i on endothelial function and atherosclerosis in type 2 diabetic patients.Results: We selected 9 RCTs and 2 cohort studys involving 868 patients. Of these, six studies provided flow-mediated dilation (FMD) levels before and after the intervention. The pooled analysis showed that SGLT-2i could significantly improve the FMD compared to the control group (SMD: 0.18, 95% CI: 0.02 ~ 0.34, P = 0.03). Three studies provided the change in FMD before and after the intervention. Pooled analysis showed no significant differences in FMD change between the SGLT-2i group and the control group. (MD: 2.1, 95%-CI: -0.11~4.31, P = 0.06). Five studies showed pulse wave velocity (PWV) results. Pooled analysis showed no significant differences in the change in PWV between the SGLT-2i group and the control group (SMD: 0.11, 95%-CI: − 0.15 ~ 0.37, P = 0.4).Conclusions: The ability of SGLT-2 inhibitors to improve FMD was significant, but there was no significant effect on PWV levels. SGLT-2i was superior to other antidiabetic agents in improving arterial endothelial function.

Summary: Data on the prevalence of obstructive sleep apnea in subjects with type 2 diabetes mellitus in China is scarce. We conducted a multi‐centre, cross‐sectional study involving 12 hospitals from six regional cities to investigate the prevalence of obstructive sleep apnea in hospitalized patients with type 2 diabetes mellitus and to explore the association between obstructive sleep apnea and related risk factors, diabetic complications and comorbidities in China. Each hospital recruited at least 70 consecutive patients with type 2 diabetes mellitus who were admitted to the endocrinology ward. A total of 880 participants were enrolled and administered overnight sleep monitoring with a portable monitor (ApneaLink^™, ResMed, San Diego, CA, USA); other information was collected from medical charts and a standardized questionnaire. In this study, 60.0% (95% confidence interval: 56.8%, 63.2%) of hospitalized patients in China with type 2 diabetes mellitus had comorbid obstructive sleep apnea (apnea–hypopnea index ≥ 5). Only 1.5% (eight of 528) of the patients with both conditions had been diagnosed previously with obstructive sleep apnea. The prevalence of moderate–severe (apnea–hypopnea index ≥ 15) and severe obstructive sleep apnea (apnea–hypopnea index ≥ 30) was estimated to be 25.6% (22.7, 28.5%) and 10.3% (8.3, 12.4%), respectively. Age, sex, body mass index, snoring, reported breath‐holding in sleep or gasping or choking arousal, sleepiness, diabetes duration, hypertension, diabetic nephropathy and cardiovascular diseases history were correlated significantly with the severity of obstructive sleep apnea. In China, the prevalence of obstructive sleep apnea in hospitalized patients with type 2 diabetes mellitus is high. Routine screening for and treatment of obstructive sleep apnea is an important, but often neglected, part of the management of diabetes.