Journal of Diabetes Investigation最新文献

Aims/introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose-dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon-like peptide-1 (GLP-1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose-lowering and anti-obesity effects of DPP-4 inhibition.

Materials and methods: Male Gipr^+/+ and Gipr^-/- mice were treated with anagliptin or linagliptin under normal diet or high-fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP-1 pathway integrity, dulaglutide was administered to a subset of animals.

Results: DPP-4 inhibition significantly improved glucose tolerance and attenuated body-weight gain in HFD-fed Gipr^+/+ mice, without affecting food intake. These effects were abolished in Gipr^-/- mice, despite similar elevations in circulating biologically intact GIP and GLP-1. Under normal diet, DPP-4 inhibitors enhanced early-phase insulin secretion and lowered glucose levels in Gipr^+/+ mice, but not in Gipr^-/- mice. Importantly, dulaglutide restored glucose-lowering effects in Gipr^-/- mice, confirming preserved GLP-1 receptor function.

Conclusions: Endogenous GIP signaling is essential for both glucose-lowering and anti-obesity actions of DPP-4 inhibitors in mice. GLP-1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP-4 inhibitors, highlighted the physiological importance of GIP, and suggested context-dependent metabolic actions of incretins.

Aims: MicroRNA (miRNA) has been confirmed to be related to gene expression regulation and disease progression. However, the role of miR-155-5p in diabetic retinopathy remains unclear.

Materials and methods: The retinal microvascular endothelial cells (RMECs) were treated with high glucose, and then the changes of miR-155-5p, endothelial cell markers (CD31 and VE-cadherin), mesenchymal cell markers (SM22α and α-SMA), and VEGF were detected by RT-qPCR. The apoptotic markers (Bax, Bcl-2, cleaved caspase-3) were detected by Western blotting. Additionally, miRNA inhibitors or small interfering RNA were used to regulate the levels of miR-155-5p and DDAH1. Subsequently, the changes in endothelial-mesenchymal transition markers, oxidative stress markers, and apoptotic proteins were observed. The regulatory relationship between miR-155-5p and DDAH1 was investigated using dual-luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down assays.

Results: After culturing RMECs with high glucose, the level of miR-155-5p increased. After the miR-155-5p level was reduced, the levels of CD31 and VE-cadherin increased, while the levels of SM22α, α-SMA and VEGF decreased. Additionally, the downregulation of miR-155-5p significantly inhibited the increase in ROS and Malondialdehyde (MDA) levels as well as cell apoptosis. DDAH1 is the downstream target of miR-155-5p. The downregulation of DDAH1 significantly weakened the inhibitory effects of miR-155-5p downregulation on endothelial-mesenchymal transition, oxidative stress, and cell apoptosis.

Conclusions: In diabetic retinopathy, miR-155-5p affects the endothelial-mesenchymal transition process and oxidative stress levels of RMECs through DDAH1 and reduces cell apoptosis induced by high glucose.

Background: Diabetic peripheral neuropathy (DPN), a complication of diabetes, is characterized by complex pathophysiology, high global morbidity, and limited early diagnostic tools. MicroRNAs (miRNAs) have emerged as potential regulators in DPN.

Aims: This study aimed to investigate miR-210-3p as a diagnostic biomarker for DPN and elucidate its molecular mechanisms in disease progression.

Methods: A total of 72 type 2 diabetes patients, 75 DPN patients, and 70 healthy controls were enrolled. Serum miR-210-3p expression was measured by RT-qPCR, and its diagnostic value was evaluated using ROC curve analysis. Multivariate logistic regression identified risk factors for DPN in type 2 diabetes patients. In vitro, a high-glucose (HG) induced RSC96 Schwann cell model was established to explore miR-210-3p function. Dual-luciferase reporter experiments demonstrated that miR-210-3p directly targets BDNF. Additionally, CCK-8 assays measured proliferation, flow cytometry analyzed apoptosis, and transwell chambers quantified cell migration.

Results: Serum levels of miR-210-3p were markedly elevated in DPN patients compared with both type 2 diabetes subjects and healthy controls (P < 0.001). The diagnostic performance was robust, achieving an AUC of 0.830 (sensitivity 72.0%; specificity 80.6%). Multivariate analysis confirmed miR-210-3p, fasting blood glucose, and glycated hemoglobin A1c as independent DPN risk factors. MiR-210-3p negatively regulated BDNF, and the miR-210-3p inhibitor reversed HG-induced Schwann cell dysfunction, while BDNF knockdown abrogated this protective effect.

Conclusions: MiR-210-3p serves as a potential diagnostic biomarker for DPN and regulates Schwann cell function via targeting BDNF, providing novel insights into DPN pathogenesis and therapeutic targets.

Aims/introduction: We aimed to explore the short-term effects of tofogliflozin on the insulin secretory capacity of people with type 2 diabetes.

Materials and methods: We performed a multicenter, prospective, randomized, active-controlled, open-label, parallel-group comparison study of people with type 2 diabetes aged 20-89 years, with hemoglobin A1c (HbA1c) 6.5%-9.0%, not previously treated with antihyperglycemic agents. The participants were randomly assigned to a group that received 20 mg tofogliflozin per day or a group that received 500 mg metformin per day for 4 weeks. Fasting blood samples were obtained and oral glucose tolerance testing was performed before and after treatment. The changes from baseline to week 4 in glucose tolerance and insulin secretory capacity were compared.

Results: Thirty participants in the metformin group and 35 in the tofogliflozin group completed the study. After 4 weeks, the HbA1c, glycated albumin, and fasting plasma glucose concentrations had significantly decreased in both groups, with no significant differences between the two groups. The fatty liver index improved significantly more in the tofogliflozin group. The disposition index (DI) did not significantly increase in either group, and there was no difference between the groups. However, in the tofogliflozin group, the DI improved in participants with poorer glucose tolerance at baseline or larger improvements after treatment, but not in the metformin group.

Conclusion: Short-term tofogliflozin therapy did not improve the insulin secretory capacity of treatment-naïve people with type 2 diabetes. However, tofogliflozin may facilitate the early recovery of insulin secretory capacity in individuals with poor glucose tolerance.

Aims/introduction: Diabetic retinopathy (DR) is a prevalent chronic complication of type 2 diabetes mellitus (T2DM), contributing significantly to vision impairment. Circular RNAs (circRNAs) have emerged as key regulators in the pathogenesis of DR. This study aimed to investigate the differential expression profiles and potential functions of circRNAs in patients with DR compared to those without DR.

Materials and methods: In this single-center, prospective study, serum samples from 20 T2DM patients with DR and 20 without DR were analyzed using the Arraystar Human circRNA Expression Profile V2.0 microarray. An additional cohort of 40 patients (20 DR and 20 without DR) was used to validate selected circRNAs via quantitative reverse transcription PCR (qRT-PCR). Enriched signaling pathways were identified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. CircRNA-miRNA-mRNA interaction networks were constructed using bioinformatics tools.

Results: A total of 376 circRNAs were differentially expressed, including 169 upregulated and 207 downregulated circRNAs. qRT-PCR validation confirmed five downregulated circRNAs and three upregulated circRNAs, which were selected for competing endogenous RNA analysis. The circRNA-miRNA-mRNA network analysis revealed that hsa_circRNA_407262 (also known as circRNA LOC389906) may act as a miRNA sponge regulating key signaling pathways, including wingless/integrated, gonadotropin-releasing hormone, tumor necrosis factor, and rat sarcoma pathways.

Conclusions: This study identified five downregulated and three upregulated circRNAs associated with DR. Among them, hsa_circRNA_407262 may play a crucial role in the pathological process of DR and holds potential as a candidate biomarker for early diagnosis.

Introduction: Type 2 diabetes mellitus (T2DM) is a common public health problem in the world. Patients with T2DM patients are accompanied with the risk of cardiovascular disease. Clarification of the potential molecular mechanism underlying vascular complications in diabetes mellitus (DM) is crucial for avoiding cardiovascular disease. Fibroblast growth factor 11 (FGF11) is a member of FGF family which, as reported before, can play a causative role in vascular dysfunction in T2DM.

Materials & methods: Human microvascular endothelial cells (HMVECs) were treated with high glucose (HG) to simulate T2DM model. Functional assays were carried out to disclose the cell proliferation, apoptosis, migration and angiogenesis of HG-treated HMVECs. Several mechanical experiments including RNA pull down, luciferase reporter and RNA immunoprecipitation (RIP) determined the regulatory mechanism of FGF11 in HG-treated HMVECs.

Results: FGF11 displayed a low expression in HG-treated HMVECs. FGF11 overexpression inhibited proliferation, migration and angiogenesis of HMVECs while facilitated the cell apoptosis in under HG condition. Moreover, FGF11 was targeted by miR-520a-5p and miR-432-5p, and CTBP1-AS2 acted as a competing endogenous RNA to modulate FGF11 expression via sponging miR-520a-5p and miR-432-5p.

Conclusion: The axis of CTBP1-AS2/miR-520a-5p/miR-432-5p/FGF11 might be a potential target for T2DM treatment.

The goal of diabetes management is to achieve longevity and quality of life equivalent to those of people without diabetes, and for that, it is now deemed important to pay close attention not only to diabetic vascular complications but also to diabetic comorbidities, as is recommended by the Japan Diabetes Society. In this editorial, we focus on sarcopenia as an important diabetic comorbidity which is an aging-related phenomenon in skeletal muscle. Taking our recent report on a sarcopenia mouse model and other accumulated evidence into account, we propose the existence of a skeletal muscle-centered inter-tissue network that regulates frailty and systemic aging. Sarcopenia is deemed to be a state in which skeletal muscle serving as a protective mighty armor against frailty and systemic aging is lost, and it is vitally important to establish how to recover it and keep it in good shape, so that the goal of diabetes management can be achieved.