Aims To investigate the possibility of identifying a subtype of latent autoimmune diabetes in adults (LADA), T-LADA (T cell responses-positive and autoantibody-negative) from patients with phenotypic type 2 diabetes (T2D) by enzyme-linked immunospot (ELISPOT). Methods Eighty-two patients with phenotypic T2D were studied. Autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 and zinc transporter 8 were measured by radioligand assay. Thirty-nine Ab(+) and 43 Ab(-) patients with phenotypic T2D were enrolled for T cell assay of responses to GAD65 and C-peptide antigen by ELISPOT. Results (1) Eleven of 43 Ab(-) participants with phenotypic T2D were demonstrated interferon (IFN)-gamma secreting T cells by ELISPOT, while 13 of 39 Ab(+) patients with phenotypic T2D were positive for T cells responses to islet antigens. (2) The onset ages of T cell(+) people with phenotypic T2D were younger than that of T cell(-) individuals (42.7 +/- 9.3 vs. 48.2 +/- 10.2 years, P = 0.025). Moreover, T cell(+) patients with T2D displayed a significantly lower fasting C-peptide (FCP) compared with T cell(-) participants [0.28 (0.02-0.84) vs. 0.42 (0.05-1.26) nmol/L, P = 0.013]. (3) Ab(-)T(+) group had a significantly lower FCP compared with Ab(-)T(-) group [0.31 (0.13-0.84) vs. 0.51 (0.07-1.26) nmol/L, P = 0.023]. Conclusions By measuring T cell responses to islet antigens in patients with phenotypic T2D, we identified a specific subtype of LADA who may be associated with worse basal beta-cell function than classic T2D (Ab(-)T(-)).
Aims This study aimed to assess islet insulin secretion and insulin resistance in Chinese patients with latent autoimmune diabetes in adults (LADA). Methods Twelve patients with LADA, 10 with type 1 diabetes mellitus (T1DM), 10 with type 2 diabetes mellitus (T2DM), and 10 nondiabetic healthy controls (HCs) were included. Patients with LADA were subtyped according to the glutamic acid decarboxylase antibody (GADA) titer (LADA1, GADA titer >= 180 U/mL; LADA2, GADA titer 18-180 U/mL). Insulin secretion and sensitivity were assessed using hyperglycemic and hyperinsulinemic-euglycemic clamp tests, respectively. Results The first-phase insulin secretion gradually increased in patients with T1DM, LADA1, LADA2, and T2DM to HCs (29.32 +/- 6.00 mU/L vs. 68.71 +/- 4.50 mU/L vs. 87.60 +/- 11.60 mU/L vs. 138.27 +/- 13.18 mU/L vs. 248.49 +/- 21.97 mU/L; P < 0.05). The second-phase insulin secretion (2 ph) and maximum insulin secretion (MIS) were significantly lower in patients with LADA2 and T2DM than in HCs, but higher in those with LADA1 and T1DM. No significant differences in 2 ph and MIS were observed between patients with LADA1 and T1DM, and between those with LADA2 and T2DM. The levels of insulin sensitivity index (ISI) during hyperinsulinemic-euglycemic clamps were lower in patients with LADA and T2DM than in those with T1DM. Patients with T1DM displayed lower ISI compared with HCs. Conclusions Chinese patients with LADA and T1DM had impaired insulin sensitivity and beta-cell function. Furthermore, the hypothesis that diabetes is a continuous spectrum from T1DM, LADA1, LADA2 to T2DM was confirmed in this study.
Aims Hyperglycemia induces endothelial cell apoptosis and blood vessel damage, while diallyl trisulfide (DATS) has shown cardiovascular protection in animal models and humans. The aim of this study was to investigate the effects of DATS on inhibition of high glucose-induced endothelial cell apoptosis and the underlying molecular events. Methods Human umbilical vein endothelial cells (HUVECs) were incubated with DATS (100 mu M) for 30 min and then cultured in high-glucose medium (HG, 33 mM) for 24 h for assessment of apoptosis, glutathione (GSH), reactive oxygen species (ROS), superoxide dismutase (SOD), and gene expression using the terminal deoxyuridine triphosphate nick end labeling (TUNEL), flow cytometry, caspase-3 activity, ROS, SOD, and western blot assays as well as JC-1 and MitoTracker Red staining, respectively. Results DATS treatment significantly inhibited high glucose-induced HUVEC apoptosis by blockage of intracellular and mitochondrial ROS generation, maintenance of the mitochondrial membrane potential, and suppression of high glucose-induced dynamin-related protein 1 (Drp1) expression. Furthermore, DATS blockage of high glucose-induced mitochondrial fission and apoptosis was through adenosine monophosphate-activated protein kinase (AMPK) activation-inhibited Drp1 expression in HUVECs. Conclusions DATS demonstrated the ability to inhibit high glucose-induced HUVEC apoptosis via suppression of Drp1-mediated mitochondrial fission in an AMPK-dependent fashion.
AimTo analyse the expression of lncRNA-ANRIL and other related factors in different human body fluids, explore the clinical significance of ANRIL and validate whether ANRIL is interrelated with the renin-angiotensin system and NF-kappa B signalling pathway.MethodsNinety-one patients were included in this cross-sectional study and were divided into the NDM group (20 patients), DM group (25 patients), NPDR group (21 patients) and PDR group (25 patients). Basic information and samples of serum, aqueous fluid and vitreous fluid were collected before vitrectomy or intravitreal injection. The transcription and levels of ANRIL and other related factors were detected by RT-PCR and ELISA. Statistical Package for Social Sciences software was used for statistical analysis.ResultsANRIL expression varied among different groups and body fluids. There was no difference in ANRIL expression between the NDM and DM groups, but the level of ANRIL was significantly lower in the DM group than in the NPDR and PDR group. In vitreous fluid, ANRIL expression was positively correlated with Ang II, p65 and VEGF expression in the PDR group. The expression of ANRIL in serum was not significantly correlated with age or the random blood sugar but was positively correlated with diabetic duration and HbAc1 level.ConclusionsLevels of lncRNA-ANRIL are higher in DR patient and correlated with the progression of DR that may be used as an indicator to predict the development of DR. The activation of the RAS and the NF-kappa B pathway may be closely related to the upregulation of ANRIL.Clinical trial number ChiCTR1800017500. Registry Chinese Clinical Trial Registry.
AimsPrevious studies indicated that urinary glucose (UG) had a limited efficacy in diabetes screening. This study was designed to have a re-evaluation of its efficacy, taking into consideration the collection method of urine and the measurement approach for UG among Chinese adults.MethodsThis cross-sectional study enrolled a total of 7689 participants without known diabetes, who were fasted and asked to empty bladders before a 75g glucose loading. Urine was collected 2 h post glucose loading, and UG was measured using quantitative and qualitative approaches. The efficacy of UG in detecting diabetes was assessed by the receiver operating characteristic (ROC) curve.ResultsThe area under the ROC curve was 0.89 for quantitative UG and 0.87 for qualitative UG. Quantitative UG was positively correlated with fasting plasma glucose (FPG) and 2h plasma glucose (2h PG) (r=0.55 and 0.56, respectively, both P<0.001). Quantitative UG displayed a sensitivity of 82.9% and a specificity of 84.7% in detecting diabetes at the corresponding optimal cutoff of 130mg. Qualitative UG exhibited a sensitivity of 80.2% and a specificity of 85.6% at the optimal cutoff of glycosuria+1. In addition, the sensitivity of both quantitative and qualitative UG was significantly higher than that of HbA1c (6.5%) (P<0.001) and had a comparable sensitivity to 2h PG (11.1mmol/L) (P=0.493).ConclusionsUG, either quantitatively or qualitatively measured at 2 h post glucose loading, was effective in diabetes screening. This indicates that UG is a feasible approach for diabetes screening.
AimsTo evaluate the methodological quality of systematic reviews (SRs), and summarize evidence of important outcomes from dipeptidyl peptidase-4 inhibitors (DPP4-I) in treating type 2 diabetes mellitus (T2DM).MethodsWe included SRs of DPP4-I for the treatment of T2DM until January, 2018 by searching the Cochrane Library, PubMed, EMBASE and three Chinese databases. We evaluated the methodological qualities with the AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool and the GRADE (The Grading of Recommendations Assessment, Development and Evaluation) approach.ResultsSixty-three SRs (a total of 2,603,140 participants) receiving DPP4-I for the treatment of T2DM were included. The results of AMSTAR showed that the lowest quality was a list of studies (included and excluded) item with only one (1.6%) study provided, followed by the providing a priori design item with only four (6.3%) studies conforming to this item, the next were the status of publication (gray literature) used as an inclusion criterion item, with only 18 (28.9%) studies conforming to these items. Only seven (11.1%) studies scored more than nine points in AMSTAR, indicating high methodological quality. For GRADE, of the 128 outcomes, high quality evidence was provided in only 28 (21.9%), moderate in 70 (54.7%), low in 27 (21.1%), and very low in three (2.3%).ConclusionsThe methodological quality of SRs of DPP4-I for type 2 diabetes mellitus is not high and there are common areas for improvement. Furthermore, the quality of evidence level is moderate and more high quality evidence is needed.
Aims Relationship between liver enzymes such as gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase and risk of gestational diabetes mellitus (GDM) is a controversial issue. The aim of this systematic review and dose-response meta-analysis was to investigate the association between liver enzymes and risk of GDM in observational studies. Methods A comprehensive systematic literature search was conducted in MEDLINE/PubMed, SCOPUS and Web of Science databases up to September 2019. Combined odds ratios (ORs) with 95% confidence intervals (CIs) were evaluated by DerSimonian and Laird random-effects models. Dose-response analyses of these relationships were also carried out. Results Eight studies with 25,451 participants containing 2549 cases were included in this study. Pooled results showed a significant association between GGT levels and risk of GDM (OR 2.10, 95% CI 1.14-3.86, I-2 84%). In addition, random-effects model indicated a dramatic and direct significant association between GGT and risk of GDM in nonlinear (p < 0.001) and linear (p < 0.001) dose-response analysis. Associations between ALT and AST with risk of GDM were found to be non-significant (OR 1.32, 95% CI 0.91-1.90, I-2 65% and OR 0.76, 95% CI 0.52-1.10, I-2 16%, respectively). Conclusion This systematic review and dose-response meta-analysis highlights GGT as a significant and robust predictor of the incidence of GDM in pregnant women.
AimTo assess whether oral branched-chain amino acids (BCAA) supplementation exerts influence on circulating BCAA and the significance of dietary BCAA in type 2 diabetes and obesity risk.MethodWe searched PUBMED, EMBASE and Cochrane library through June 2018 to retrieve and screen published reports for inclusion in the meta-analysis after methodological assessment. Heterogeneity of studies was evaluated using I-2 statistics, while sensitivity analysis and funnel plot were used to evaluate the potential effect of individual studies on the overall estimates and publication bias, respectively, using RevMan 5.3.ResultEight articles on randomized clinical trial of oral BCAA supplementation, and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analyses. Mean difference and 95% confidence interval (CI) of circulating leucine was 39.65 (3.54, 75.76) mu mol/L, P=0.03 post-BCAA supplementation. Also, OR and 95% CI for higher total BCAA intake and metabolic disorder risks were, 1.32 (1.14, 1.53), P=0.0003type 2 diabetes and 0.62 (0.47, 0.82), P=0.0008obesity.ConclusionOral BCAA supplementation exerts modest influence on circulating leucine profile and higher total BCAA intake is positively and contra-positively associated with type 2 diabetes and obesity risk, respectively.
AimsThe study aimed to screen the HNF1A and HNF4A mutation in a large Chinese cohort of high clinical suspicion of maturity-onset diabetes of the young (MODY) patients and characterize the clinical features of those patients. The performance of hsCRP as a biomarker to differentiate MODY3 from early onset T2DM was also evaluated.MethodsA total of 74 patients with a strong clinical suspicion of MODY from 59 families and 33 newly diagnosed early-onset T2DM were included. HNF1A and HNF4A mutations were analyzed by Sanger sequencing. ROC curves were used to identify the optimal cutoff of hsCRP.ResultsOne novel (c.864_865insG) and six recurrent HNF1A mutations (R203H, R263H, P379T, L422P, P519L and c.873delC) in 17 patients from 8 families (13.6%), as well as one novel HNF4A (R331H) mutation were identified. Nonspecific clinical presentations were observed in MODYX compared to MODY3 patients. MODY3 subjects exhibited with younger, lower BMI, TG, fasting and postprandial C-peptide, higher HDL than T2DM. Particularly, we confirmed serum hsCRP was lower in MODY3 than T2DM. ROC curve showed a good discrimination with an AUC of 0.852 and identified a cutoff hsCRP of 0.79 (75% sensitivity and 83% specificity). Good glycemic control was observed in all identified patients after switching to glimepiride therapy.ConclusionsThe prevalence of HNF1A mutation was relatively lower in Mainland China and HNF4A mutation was rare. Serum hsCRP concentrations performed well in discriminating MODY3 from T2DM. Molecular diagnosis of MODY3/1 did transform management in clinical practice and facilitated the glycemic control.
AimsThe aim is to evaluate the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4-I: sitagliptin, saxagliptin, linagliptin, vildagliptin and alogliptin) in patients with type 2 diabetes.MethodsWe searched the Cochrane Library, PubMed, EMBASE, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), and the Wanfang Database from inception to April, 2018. Randomized controlled trials were included if they compared the different versions of DPP4-I with each other or with placebo in treatment of type 2 diabetes. Bayesian network meta-analysis and pairwise meta-analysis were performed to evaluate the efficacy and safety of the different kinds of DPP4-I and placebo. The data were analyzed using STATA 12.0 and WinBUGS1.4 software.ResultsWe identified 58 eligible studies (with 31356 patients) involving 14 treatment arms. Indirect comparison results showed that except for alogliptin, a decrease was found for all DPP4-I versus the placebo for hemoglobin A1c (HbA1c) with vildagliptin50 twice daily (BID) showing the highest probability. Linagliptin5 once daily (QD) decreased the level of fasting plasma glucose (FPG) the most for all DPP4-I versus the placebo; when comparing them with each other, alogliptin25QD was more effective when compared with sitagliptin100QD and vildaglipti50BID; linagliptin5qd had the highest decrease impact on body mass index (BMI). Except for hypoglycemia and upper respiratory tract infection (URTI), there are no statistical significance on incidence of adverse events and the body weight when DPP4-I are compared with each other or with placebo.ConclusionOur network meta-analysis presents the associations of DPP4-I versus placebos on HbA1c, FPG, 2h postprandial blood glucose (2HPPG), BMI, body weight and adverse events. DPP4-I have a lowering effect on the glycemic level (HbA1c, FPG), especially vildaglipti50BID and linagliptin10QD, respectively. Besides, linagliptin5QD has the greatest probabilities of reducing BMI. In addition, DPP4-I were associated with not increasing the incidence of adverse events. Among them, vildagliptin100QD and sitagliptin100QD have the lowest probability in reducing the incidence of hypoglycemia and URTI, respectively.
AimsMacrocalcification and microcalcification present different clinical risks, but the regulatory of their formation was unclear. Therefore, this study explored the underlying mechanisms of macrocalcification and microcalcification in diabetes mellitus.MethodsAnterior tibial arteries of amputated diabetic feet were collected. According to the calcium content, patients were divided into less-calcification group and more-calcification group. And calcification morphology in plaques was observed. For further study, an in vivo mouse diabetic atherosclerosis model and an in vitro primary mouse aortic smooth muscle cell model were established. After the receptors for AGEs (RAGE) or galectin-3 were silenced, calcified nodule sizes and sortilin expression were determined. Scanning electron microscopy (SEM) was performed to detect the aggregation of matrix vesicles with the inhibition or promotion of sortilin.ResultsBoth macro- and microcalcification were found in human anterior tibial artery plaques. Macrocalcification formed after the silencing of RAGE, and microcalcification formed after the silencing of galectin-3. In the process of RAGE- or galcetin-3-induced calcification, sortilin played an important role downstream. SEM showed that sortilin promoted the aggregation of MVs in the early stage of calcification and formed larger calcified nodules.ConclusionRAGE downregulated sortilin and then transmitted microcalcification signals, whereas galectin-3 upregulated sortilin, which accelerated the aggregation of MVs in the early stage of calcification and mediated the formation of macrocalcifications, These data illustrate the progression of two calcification types and suggest sortilin as a potential target for early intervention of calcification and as an effective biomarker for the assessment of long-term clinical risk and prognosis.
AimsTo evaluate the microvascular and neural differences of the optic nerve head (ONH) between type 2 diabetes mellitus (T2DM) subjects and controls.MethodsThis was a cross-sectional observational study. One hundred and eight eyes of 108 T2DM subjects with or without diabetic retinopathy (DR) (54 preclinical DR and 54 mild-to-moderate DR) were included. Fifty-two eyes of 52 healthy subjects were included as controls. The 4.5-mm Angio Disc scan mode and the ganglion cell complex scan mode were performed with all participants using AngioVue software 2.0 of the optical coherence tomography angiography (OCTA) device.ResultsRegarding ONH radial peripapillary capillary (RPC) density, the peripapillary region was mainly significantly reduced in the No-DR (NDR) group. Moreover, the RPC density of the peripapillary region and the inside optic disc area were significantly reduced in the non-proliferative DR (NPDR) group. When compared to the controls, significantly reduced peripapillary capillary density in six sections was observed in the NPDR group. However, reduced density was observed in only two sections in the NDR group. The NPDR group had significantly increased focal loss volume (FLV) and reduced peripapillary RNFL thickness in the inferior nasal section compared to those in the controls, but similar changes were not observed in the NDR group. A regression model identified RPCs inside the optic disc as a significant parameter in early-stage DR detection. In the NPDR group, BCVA showed a significantly negative correlation with RPCs inside the optic disc and a significantly positive correlation with FLV.ConclusionsOCTA findings of the ONH area may provide evidence that microvascular changes occur preceding neural impairment in early-stage DR. However, further researches are still needed to support the statement. Reduced ONH perfusion inside the optic disc may be one of the crucial biomarkers in early-stage DR detection and is a possible sensitive visual acuity predictor in early-stage DR subjects. With the ONH mode, OCTA may be a more promising tool in DR screening.
AimsTo compare the vitreous levels of chemokines in diabetic patients with and without retinopathy. To find the relationship between stages of diabetic retinopathy (DR) and levels of vitreous chemokines.MethodsThe study involved 20 non-diabetic and 20 diabetic patients without clinical signs of DR (NDR) and 40 diabetic patients with proliferative diabetic retinopathy (PDR). The vitreous humor was collected and the levels of 40 chemokines were measured using magnetic color-bead-based multiplex assay.ResultsThe control group, NDR group, PDR with vitreous hemorrhage (VH) group, and PDR with tractional retinal detachment group comprised 20, 20, 21, and 19 eyes, respectively. Only the concentration of CCL3 was significantly higher in the NDR group compared with the controls (p=0.038). Twenty-five types of chemokines were statistically higher in the PDR with VH group in comparison to NDR group (all p<0.05). All chemokines were statistically higher in the PDR with TRD group in comparison to NDR group (all p<0.05) apart from 3 chemokines: GM-CSF, MIF, and CCL3(p=0.086, p=0.109, p=0.094, respectively). The concentration of CCL21, CCL15 in PDR with TRD group was significantly higher compared with PDR with VH group, while other 36 chemokines were not significantly different between PDR with VH group and PDR with TRD group.ConclusionsThe inflammation gradually worsen with the progression of DR. CCL3 may be associated with the onset of early diabetic retinal damage, and CCL15 and CCL21 may be closely related to the formation of fibrovascular membrane and the progression of the end stage of DR.
AimsCirculating endothelial progenitor cells (EPCs) play a key role in maintaining endothelial function. Dysfunction of EPCs is associated with the cardiovascular complication of diabetes. The purpose of this study is to investigate the direct effects of hyperinsulinemia on EPCs and the underlying mechanisms.MethodsEPCs isolated from healthy adults were cultured with various concentrations of insulin (control group, without insulin; physiological insulin group, 10nM insulin and hyperinsulinemia group, 100nM insulin) with or without phosphatidylinositol-3-kinase (PI3-K) inhibitor (LY294002, 5 mu M), endothelial nitric oxide synthase (eNOS) inhibitor (l-NG-nitro-arginine methyl ester (l-NAME), 100 mu M), sodium nitroprusside (SNP, 25 mu M), p38 mitogen-activated protein kinase(MAPK) inhibitor (SB203580, 5 mu M) or extracellular signal-regulated kinases (ERK) 1/2 inhibitor (PD98059, 10 mu M). Proliferation, tube formation, and apoptosis of EPCs were determined. Expressions of eNOS, PI3-K, protein kinase B (Akt), p38 MAPK, and ERK 1/2 were assessed.ResultsHyperinsulinemia caused a significant decrease in proliferation and tube formation abilities than control group. Hyperinsulinemia increased apoptosis rate of EPCs than control group. Furthermore, hyperinsulinemia downregulated phosphorylation of eNOS, PI3-K and Akt, and upregulated phosphorylation of p38 MAPK and ERK. SNP could restore impaired tube formation induced by hyperinsulinemia. P38 MAPK inhibitor but not ERK inhibitor could decrease apoptosis induced by hyperinsulinemia.ConclusionHyperinsulinemia impaired EPCs' tube formation ability by downregulation of PI-3K/Akt/eNOS pathway. Hyperinsulinemia induced apoptosis of EPCs via upregulation of p38 MAPK.