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Aims/hypothesis: Mutations in Isl1, encoding the insulin enhancer-binding protein islet-1 (ISL1), may contribute to attenuated insulin secretion in type 2 diabetes mellitus. We made an Isl1E283D mouse model to investigate the disease-causing mechanism of diabetes mellitus. Methods: The ISL1E283D mutation (c. 849A>T) was identified by whole exome sequencing on an early-onset type 2 diabetes family and then the Isl1E283D knockin (KI) mouse model was created and an IPGTT and IPITT were conducted. Glucose-stimulated insulin secretion (GSIS), expression of Ins2 and other ISL1 target genes and interacting proteins were evaluated in isolated pancreas islets. Transcriptional activity of Isl1E283D was evaluated by cell-based luciferase reporter assay and electrophoretic mobility shift assay, and the expression levels of Ins2 driven by Isl1 wild-type (Isl1WT) and Isl1E283D mutation in rat INS-1 cells were determined by RT-PCR and western blotting. Results: Impaired GSIS and elevated glucose level were observed in Isl1E283D KI mice while expression of Ins2 and other ISL1 target genes Mafa, Pdx1, Slc2a2 and the interacting protein NeuroD1 were downregulated in isolated islets. Transcriptional activity of the Isl1E283D mutation for Ins2 was reduced by 59.3%, and resulted in a marked downregulation of Ins2 expression when it was overexpressed in INS-1 cells, while overexpression of Isl1WT led to an upregulation of Ins2 expression. Conclusions/interpretation: Isl1E283D mutation reduces insulin expression and secretion by regulating insulin and other target genes, as well as its interacting proteins such as NeuroD1, leading to the development of glucose intolerance in the KI mice, which recapitulated the human diabetic phenotype. This study identified and highlighted the Isl1E283D mutation as a novel causative factor for type 2 diabetes, and suggested that targeting transcription factor ISL1 could offer an innovative avenue for the precise treatment of human type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective • To screen the mutations of NEUROD1 gene in families of maturity-onset diabetes of the young (MODY), and investigate the correlation between the mutation and MODY6 and its potential pathogenesis in Chinese. Methods • PCR-direct sequencing was used for screening NEUROD1 mutations from 96 MODY probands who were negative for mutations in the GCK/ MODY2, HNF1A/MODY3 and HNF1B/MODY5 genes, and the genotypic frequency of NEUROD1 variations were compared between the 96 MODY probands and 100 non-diabetic control subjects. A de novo modeling method was used to predict the three-dimensional (3D) structures of wild type (WT) and mutated NEUROD1 proteins. Transcriptional activities of both WT and mutant of NEUROD1 on insulin gene were detected by using dual luciferase reporter gene system. Results • Glu59Gln (NM&lowbar;002500.5, c. 175G>C), a heterozygous missense mutation in the NEUROD1 gene, was identified in a MODY pedigree. 3D structural analysis showed that the mutation transformed the negatively charged Glu59 of WT into uncharged mutation Gln59, leading to the loss of Glu59-Arg54 and Glu59-Lys88, two salt bridge bonds, and the formation of Gln59-Arg54, one new hydrogen bond. Transcriptional activity of Glu59Gln mutant for insulin gene was reduced by 36.3% when compared with that of WT (P<0.05). A common variation Ala45Thr (G-A) was identified, and AA+GA genotypic frequency of the variation was significantly elevated in the 96 MODY probands in comparison to non-diabetic control subjects (P=0.002). Conclusion-Glu59Gln mutation alters the N-terminal molecular conformation of NEUROD1 protein, resulting in decreased transcriptional activity of insulin gene, which is the cause of the defective insulin secretion in mutation carriers of the MODY6 pedigree. The Ala45Thr variation is associated with earlier age of onset of diabetes in MODY6 probands. [ABSTRACT FROM AUTHOR]

This paper proposes five indicators to evaluate the effectiveness and viability for adverse glycemic events detection based on predicted blood glucose (BG) values. False negative rate (FNR) and false positive rate (FPR) are defined to evaluate whether it can detect adverse glycemic events (AGEs) based on the predicted value. The temporal overlap (TO) and time difference (TD) are proposed to evaluate whether the predicted model can capture the accurate time duration of AGEs. The sum of squared percent (SSP) measures comprehensive similarity between prediction values and true values. We examined 328 patients with type 2 diabetes, containing real continuous glucose monitoring data with 5-minute time intervals. Autoregressive integrated moving average model has lower FNR and FPR. The gated recurrent unit has better temporal behavior where the mean TO with standard deviation is calculated as 0.84±0.18, and the mean TD with standard deviation is (4.39±4.01) min. Neural models have better effects on SSP (for hypoglycemia, long-short tern memory possesses 0.149 and 0.246). These five indicators are able to evaluate whether we can detect abnormal BG levels and reveal the temporal behavior of AGEs effectively. The proposed neural predictive models have more promising application in AGE detection. [ABSTRACT FROM AUTHOR]

Precise differentiation of glucokinase (GCK) monogenic diabetes from gestational diabetes mellitus (GDM) is critical for accurate management of the pregnancy outcome. We screened GCK-MODY complicating pregnancies in Chinese GDM patients, explored the pathogenesis of novel GCK mutations, and evaluated the patients' pregnancy outcome and management. The GCK gene from 411 GDM patients was screened with PCR–direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and 15 GCK mutations were identified. We also retrospectively analyzed a total of 65 pregnancies from 21 GCK-MODY families, wherein 41 were from 15 maternal families and 24 were from six paternal families. Bioinformatic analysis and biochemical functional study were conducted to identify novel GCK mutations. In total, we identified 21 GCK mutations: 15 from the 411 GDM patients and six from 24 fathers. Of th Asp78Asn (GAC → AAC), Met87Arg (ATG → AGG), Leu451Val (CTT → GTT), Leu451Pro (CTG → CCG) and 1019 + 20G > A e mutations, five, i.e., were novel and deleterious, with markedly decreased enzyme activity and thermal stability. The unaffected offspring of GCK mutation-affected mothers were heavier than affected offspring (p < 0.001). Of 21 insulin-treated affected mothers, 10 had maternal hypoglycemia (47.6%) and seven had perinatal complications (33.3%), and the affected offspring of the insulin-treated affected mothers had significantly lower birth weights than that of the 20 diet-control affected mothers (p = 0.031). In this study, the prevalence of GCK-MODY complicating pregnancy in Chinese GDM patients was 3.6% (15/411). The defective GCK may contribute to the hyperglycemia in GCK-MODY. Insulin therapy is not beneficial for GCK-MODY complicating pregnancy and therefore should not be recommended. [ABSTRACT FROM AUTHOR]

Objective: We aimed to examine the relationship between osteocalcin (OC) and the risk of incident diabetes and the risk of incident diabetic kidney disease (DKD).Research Design and Methods: We followed 5,396 participants without diabetes (nondiabetes subcohort) and 1,174 participants with diabetes and normal kidney function (diabetes subcohort) at baseline. Logistic regression and modified Poisson regression models were used to estimate the relative risk (RR) of baseline OC levels with incident diabetes and DKD.Results: During a mean 4.6-year follow-up period, 296 cases of incident diabetes and 184 cases of incident DKD were identified. In the nondiabetes subcohort, higher OC levels were linearly associated with a decreased risk of diabetes (RR for 1-unit increase of loge-transformed OC 0.51 [95% CI 0.35-0.76]; RR for highest vs. lowest quartile 0.65 [95% CI 0.44-0.95]; P for trend < 0.05). In the diabetes subcohort, OC levels were linearly inversely associated with incident DKD (RR for 1-unit increase of loge-transformed OC 0.49 [95% CI 0.33-0.74]; RR for highest vs. lowest quartile 0.56 [95% CI 0.38-0.83]; P for trend < 0.05), even independent of baseline estimated glomerular filtration rate and urinary albumin-to-creatinine ratio. No significant interactions between OC and various subgroups on incident diabetes or DKD were observed.Conclusions: Lower OC levels were associated with an increased risk of incident diabetes and DKD. [ABSTRACT FROM AUTHOR]

Aim. To investigate the effects of alcohol on serum glycated albumin (GA) levels in Chinese men. Methods. A total of 2314 male subjects from the Jinuo ethnic group in China were enrolled. Of these, 986 subjects drank alcohol frequently and 404 subjects did not. Lifestyle information was gathered by using a questionnaire, and measurements of blood pressure, body mass index, blood glucose level, liver function, and kidney function were collected. GA was measured by using an enzymatic method. Frequent drinking was defined as a history of drinking ethanol > 80 g/d within the past two weeks. Nondrinking was defined as no alcohol consumption in the past three months. Subjects with an alcohol intake between 0 and 80 g/d in the past two weeks were included in the drinking-occasionally group. Analysis of variance (ANOVA), correlation analysis, and linear regression were used to evaluate the effects of drinking on serum GA levels. Decision tree regression (DTR) algorithm was used to evaluate the effect of features (variables) on GA levels. Results. We found that male subjects who drank frequently had significantly lower serum GA levels than subjects who did not drink (13.0 ± 1.7 vs. 14.1 ± 3.7, p < 0.05). Spearman's correlation analysis calculated a coefficient of −0.152 between drinking and GA (p < 0.005). Linear regression established that drinking was an independent predictor for GA levels with a standardized regression coefficient of −0.144 (p < 0.05). Decision tree regression showed that the effect of drinking on GA levels (0.0283) is five times higher than that of smoking (0.0057). Conclusions. Frequent alcohol consumption could result in decreased GA levels in men of the Jinuo ethnic group in China. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is characterized by hyperglycemia which displays insufficiency or resistance to insulin. One of the complications of diabetes is the increased risk of fracture and the impairment of bone repair and regulation. There have been evidences from previous studies that mesenchymal stem cells (MSCs) from bone marrow promote cartilage and callous formation. In addition, IL-10, an anti-inflammatory cytokine, has been observed to relieve inflammation-related complications in diabetes. Methods: In this study, the role of IL-10-overexpressing bone marrow-derived MSCs (BM-MSCs) was examined in the diabetic mice model with femur fracture. MSCs were isolated from the BALB/c mice and IL-10 over expression was conducted with lentivirus transduction. The streptozotocin (STZ)-induced diabetes model with femoral fracture was established. BM-MSCs with IL-10 over expression were transplanted into the fracture area. The expressions of inflammatory factors IL-6, TNF-α and INF-γ were examined by qPCR and immunoblot; the biomechanical strength of the fracture site of the mice was examined and evaluated. Results: Data showed that IL-10 overexpressed BM-MSCs transplantation decreased inflammatory response, promoted bone formation, and increased the strength of the fracture site in STZ-induced diabetic mice with femoral fracture. Conclusion: IL-10 overexpressed BM-MSCs transplantation accelerated fracture repair in STZ-induced diabetic mice, which in turn provides potential clinical application prospects. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of all diabetic patients, and osteoporosis is one of the complications during T2DM process. ATP6V1H (V-type proton ATPase subunit H) displays crucial roles in inhibiting bone loss, but its role in osteogenic differentiation remains unknown. Therefore in this study, we aimed to explore the biological role of ATP6V1H in osteogenic differentiation. OM (osteogenic medium) and HG (high glucose and free fatty acids) were used to induce the MC3T3-E1 cells into osteogenic differentiation in a T2DM simulating environment. CCK8 assay was used to detect cell viability. Alizarin Red staining was used to detect the influence of ATP6V1H on osteogenic differentiation. ATP6V1H expression increased in OM-MC3T3-E1 cells, while decreased in OM+HG-MC3T3-E1 cells. ATP6V1H promoted osteogenic differentiation of OM+HG-MC3T3-E1 cells. Overexpression of ATP6V1H inhibited Akt/GSK3β signaling pathway, while knockdown of ATP6V1H promoted Akt/GSK3β signaling pathway. ATP6V1H overexpression promoted osteogenic differentiation of OM+HG-MC3T3-E1 cells. The role of ATP6V1H in osteogenic differentiation in a T2DM simulating environment involved in Akt/GSK3β signaling pathway. These data demonstrated that ATP6V1H could serve as a potential target for osteogenic differentiation in a T2DM simulating environment. [ABSTRACT FROM AUTHOR]

We aim to investigate the relationship between serum somatostatin (SST) levels and glucose-lipid metabolism at various stages of glucose tolerance in the Jino ethnic minority (n=111) and Han population (n=113) of Yunnan Province, southwest China. Anthropometric parameters and biochemical traits were measured. Serum SST and plasma glucagon levels were tested. Participants were divided into three subgroups: isolated fasting hyperglycemia (IFH), isolated post challenge hyperglycemia (IPH) and normal glucose tolerance (NGT). SST levels were found lower while glucagon levels were significantly higher in the Jino ethnic with IPH (P=0.0026 and P=0.0069, respectively). Fasting glucose and high density lipoprotein-cholesterol (HDL-C) levels were higher (P=0.0055 and P=0.0021, respectively) and fasting insulin levels and homeostasis model assessments β-cell function were lower (P=0.0479 and P=0.0007, respectively) in the Jino population. After adjusting for confounding factors, the serum SST level was associated with glucagon (P<0.0001) in both populations. The SST level was correlated with fasting Cpeptide (P=0.0267) in Jino and HDL-C levels in Han (P=0.0079). Our findings suggest that serum SST levels and plasma glucagon levels may vary in subjects with IPH between two ethnics. [ABSTRACT FROM AUTHOR]

Aims: To explore the factors mediating the relationship between body mass index (BMI) and diabetic retinopathy (DR) in Chinese type 2 diabetes patients. Methods: This is a cross-sectional study. Data of 2,533 patients with type 2 diabetes were studied from the Shanghai Diabetes Registry Database. DR was assessed using non-mydriatic fundus photography and graded as non-DR, mild-moderate (DR I-II), and sight-threatening (DR III-IV). BMI (kg/m) was classified as normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). β cell function was evaluated by fasting C-peptide (FCP). Results: DR was present in 701 (27.7 %) patients. Patients with DR had lower BMI (24.3 vs. 24.9 kg/m, P = 0.001) and fasting C-peptide (1.46 vs. 1.86 ng/ml, P < 0.001) than those without DR. The association between BMI (2 kg/m interval) and DR was U-shaped; patients with BMI 28-29.9 kg/m had the lowest DR rate. Compared with normal weight, overweight was associated with reduced risk of any DR [odds ratio (OR) 0.73], DR I-II (OR 0.76), and DR III-IV (OR 0.64) after adjustment for sex, age at diabetes diagnosis, and duration of diabetes. This negative association attenuated after adjustment for other confounders and became nonsignificant after further adjustment for FCP. Patients with different BMI categories had similar DR risk when stratified by FCP tertiles. Conclusion: Overweight patients have lower DR prevalence than normal weight individuals, which may be attributable to better β cell function in overweight patients. [ABSTRACT FROM AUTHOR]

Background. Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator, but the physiological role of FGF-21 remains poorly understood. This study was designed to investigate serum FGF-21 levels in type 2 diabetes mellitus (T2DM) patients and explore the correlations between its serum levels and various cardiometabolic parameters in humans. Methods. Fifty-four newly diagnosed patients with T2DM (NDDM), 54 subjects with long duration of T2DM (LDDM), that is, more than 5 years, and 35 normal controls participated in this study. Fasting serum FGF-21 levels were measured using ELISA kits. The anthropometric parameters, glucose, glycosylated hemoglobin A1c, lipids, insulin, and high-sensitive C-reactive protein (hsCRP) levels were also measured in fasting status. Results. Serum FGF-21 levels were significantly higher in patients with NDDM and LDDM than in controls (361.80 ± 140.28 pg//mL and 351.17 ± 133.44 pg//mL vs. 185.89 ± 59.29 pg//mL, both p < 0.01), but there was no difference in serum FGF-21 levels between NDDM and LDDM. Fasting serum FGF-21 was found to correlate positively and significantly with age, waist-to-hip ratio, systolic blood pressure, fasting plasma glucose, glycosylated hemoglobin A1c, homeostasis model assessment (HOMA) of insulin resistance, and hsCRP, but negatively with HOMA of β-cell insulin secretion. Furthermore, multiple regression analyses showed that fasting insulin, HOMA of insulin resistance, low-density lipoprotein cholesterol, and hsCRP were independent factors influencing serum FGF-21 levels. Logistic regression analyses demonstrated that serum FGF-21 was significantly associated with T2DM. Conclusions. Serum FGF-21 levels were significantly increased in patients with T2DM. They may play a role in the pathogenesis of T2DM. [ABSTRACT FROM AUTHOR]

The article presents a study on the photoisomerization behavior and synthesis of thiazolylazo polyimide (PI). It states that post azocoupling reaction scheme was used to prepare the PI with thiazolylazo side chain. Results of the study show that thermal stability of the polymer is quite good from glass-transition temperature and temperature at 10% of weight loss under nitrogen gas of the polymer is 138.9 celsius and 510.6 celsius.