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Background: Diabetic retinopathy (DR) is one of the most common complications of diabetes worldwide. The aim of this study was to assess the prevalence of DR in hospitalized patients with type 2 diabetes (T2DM) in Tibet and to identify risk factors that may influence the occurrence of DR., Methods: This was a cross-sectional study conducted in a third-class hospital in the Tibet Autonomous Region. The prevalence of DR in hospitalized patients with T2DM was measured. Univariate and multivariate logistic regression, restricted cubic spline (RCS) analysis and receiver-operating characteristic curve analysis were used to investigate the risk factors for DR., Results: The prevalence of DR was 29.3%. The duration of diabetes; concentrations of 25-OH-VitD3, hemoglobin, fasting insulin, alanine aminotransferase, total bilirubin, and creatinine; and HOMA-IR were significantly different between DR patients and non-DR patients (all P < 0.05). Univariate and multivariate logistic regression revealed that a longer duration of diabetes and lower 25-OH-VitD3 levels were associated with increased DR risk. RCS analysis suggested overall positive associations of the duration of diabetes and 25-OH-VitD3 concentrations with DR risk (P nonlinearity < 0.05). The turning points for the duration of diabetes and 25-OH-VitD3 concentrations were 5.1 years and 10.6 ng/mL, respectively. The sensitivity, specificity, and area under the receiver-operating characteristic curve for the combination of the duration of diabetes and 25-OH-VitD3 levels were 79.4%, 69.4% and 0.764, respectively., Conclusions: Given the high prevalence of DR in hospitalized patients with T2DM in Tibet, vitamin D supplementation seems to be important in the prevention of DR to some degree., (© 2024. The Author(s).)

Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP-D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by pathogenetic variants in FBN1. Here, we report a patient with type 2 diabetes mellitus, AVP-D, and Marfan syndrome. Although the coexistence of type 2 diabetes mellitus and AVP-D is rare, for those patients with type 2 diabetes mellitus, the existence of AVP-D should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: Sodium-glucose co-transporter 2 inhibitors, including dapagliflozin, improve ß cell function in type 2 diabetic individuals. Whether dapagliflozin can protect islet microvascular endothelial cells (IMECs) and thus contribute to the improvement of ß cell function remains unknown., Materials and Methods: The db/db mice were treated with dapagliflozin or vehicle for 6 weeks. ß cell function, islet capillaries and the levels of inflammatory chemokines in IMECs were detected. The mouse IMEC cell line MS-1 cells were incubated with palmitate and/or dapagliflozin for 24 h. Angiogenesis and inflammatory chemokine levels were evaluated, and the involved signalling pathways were analysed. The mouse ß cell line MIN6 cells, in the presence or absence of co-culture with MS-1 cells, were treated with palmitate and/or dapagliflozin for 24 h. The expression of ß cell specific markers and insulin secretion in MIN6 cells were determined., Results: Dapagliflozin significantly improved ß cell function, increased islet capillaries and decreased the levels of inflammatory chemokines of IMECs in db/db mice. In the palmitate-treated MS-1 cells, angiogenesis was enhanced and the levels of inflammatory chemokines were downregulated by dapagliflozin. Either a PI3K inhibitor or mTOR inhibitor eliminated the dapagliflozin-mediated effects. Importantly, dapagliflozin attenuated the palmitate-induced downregulation of ß cell function-related gene expression and insulin secretion in MIN6 cells co-cultured with MS-1 cells but not in those on mono-culture., Conclusions: Dapagliflozin restores islet vascularisation and attenuates the inflammation of IMECs in type 2 diabetic mice. The dapagliflozin-induced improvement of ß cell function is at least partially accounted for by its beneficial effects on IMECs in a PI3K/Akt-mTOR-dependent manner., (© 2022 John Wiley & Sons Ltd.)

Aims: We aimed to investigate whether treatment with exenatide could ameliorate endothelial injury in patients with type 2 diabetes mellitus (T2DM), and to identify biomarkers for predicting amelioration of the endothelial injury induced by the treatment., Methods: Ninety-three patients with T2DM were recruited and treated with exenatide for 16 weeks. Enzyme-linked immunosorbent assays were performed at baseline and after the treatment to measure serum levels of endothelial injury markers, including soluble thrombomodulin (sTM). Patients were categorized as responders (n = 47) or non-responders (n = 46) based on median changes in their sTM levels. Serum levels of metabolites at baseline were measured with non-targeted liquid chromatography-mass spectrometry. The results obtained were evaluated with multivariate analysis., Results: Treatment with exenatide for 16 weeks resulted in reduced body weight and improved levels of fasting plasma glucose, 2-hour postprandial plasma glucose, and HbA1c in patients with T2DM (all P < 0.05). Compared with baseline, serum levels of endothelial injury markers including sTM were significantly lowered after the treatment. Metabolites presented at significantly different levels in responders versus non-responders were considered as biomarkers for a therapeutic response of sTM to the exenatide treatment. Among those identified, 4-hydroxyproline and 12-oxo-9(Z)-dodecenoic acid were found to correlate most closely with the exenatide-induced endothelial protection response. The specificity and sensitivity of the multi-metabolite signature model contained higher 4-hydroxyproline and lower 12-oxo-9(Z)-dodecenoic acid were 53.3% and 92.3%, respectively, and the area under receiver operating characteristic curve was 69.2% (P < 0.001)., Conclusions: Treatment with exenatide for 16 weeks ameliorates endothelial injury in patients with T2DM. Endothelial protection benefit from exenatide treatment was effectively predicted by the specific metabolomic combination of higher 4-hydroxyproline and lower 12-oxo-9(Z)-dodecenoic acid., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Clinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells., Methods: Two diabetic mouse models, db/db mice and pancreatic alpha cell lineage-tracing (glucagon-β-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25-25 μmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined., Results: Treatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels in db/db mice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU double-positive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even co-localized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (including Pdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression of Pcsk1 (which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation of Pdx1 expression was attenuated by GLP-1 receptor antagonist., Conclusions: Except for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediated via GLP-1 secreted from alpha cells., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Glucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified., Research Design and Methods: REMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways., Results: Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production., Conclusions: The elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D., 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: Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear., Methods: Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6 m/+ ) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment., Findings: Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control., Interpretation: We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. FUND: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The level of serum angiopoietin-like protein 8 (ANGPTL8), a novel hepatokine, is associated with obesity and type 2 diabetes mellitus (T2DM). The aims of this study were to investigate whether serum ANGPTL8 level in patients with T2DM was affected by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, and to determine whether and how GLP-1R agonists regulated ANGPTL8 production in hepatocytes. A multiple-center trial was conducted in China. Among 240 patients with T2DM enrolled in this trial, 195 patients adhered to a 16-week exenatide treatment and follow-up. Human liver cell line HepG2 cells were incubated for 24 h with either exendin-4 (a native form of exenatide) or liraglutide in the presence or absence of GLP-1R antagonist exendin (9-39) and PI3K inhibitor LY294002. Change of serum ANGPTL8 level in patients with T2DM and regulation of ANGPTL8 production by the GLP-1R agonists in HepG2 cells were evaluated. Results showed that compared with baseline, exenatide treatment significantly increased serum ANGPTL8 level, and lowered body weight, fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA1c) in patients with T2DM (all P <  0.05). The exenatide treatment-mediated upregulation of serum ANGPTL8 level was not associated with the levels of its lowering effects on body weight, FBG and HbA1c stratified by the median. Moreover, exendin-4 or liraglutide dose-dependently upregulated the level of ANGPTL8 expression and secretion in HepG2 cells, which was eliminated by adding exendin (9-39) and LY294002. In conclusion, GLP-1R agonists enhance ANGPTL8 production in vivo and in vitro, which is mediated via the PI3K/Akt pathway in a GLP-1R-dependent manner., (Copyright © 2018 Elsevier Inc. All rights reserved.)