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Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice. [ABSTRACT FROM AUTHOR]

novel circuit architecture which describes millimeter wave varactor-tuned Gunn oscillator stabilized with a transmission cavity has been proposed in this paper. A corresponding equivalent circuit model has been presented in order to study its performance characteristics. The circuit model consists of four parts which are varactor cavity, main cavity, transmission waveguide and transmission cavity. Based upon this model, electrical tuning characteristics have been studied at first. Mode jumping problems during electrical tuning process have been analyzed qualitatively. Moreover, quality factor and efficiency of the circuit model have been derived by virtue of relevant circuit parameters. The effects of some important circuit parameters affecting circuit performance parameters have been discussed. The circuit model can describe the circuit architecture accurately and effectively. This circuit architecture, which can generate signals exhibiting low frequency modulation noise, high frequency stabilization and electrical tunable characteristics, is applicable to various practical situations. [ABSTRACT FROM AUTHOR]

Abstract  A new circuit configuration for millimeter wave varactor-tuned transmission cavity-stabilized oscillator has been proposed in this paper. Compared to conventional varactor-tuned reflection cavity-stabilized oscillator, in this configuration, a high quality factor transmission cavity directly coupled to varactor diode is employed to improve the performances of the oscillator. The operation frequency of this oscillator can be tuned by varying the resonant frequency of the transmission cavity through changing bias voltage of the varactor diode. An equivalent circuit model for the oscillator has been presented in order to theoretically investigate the performance characteristics of the oscillator. On the basis of this model, electrical tuning characteristics have been studied. Mode jumping phenomena during electrical tuning process have been analyzed for obtaining stable operations of the oscillator. The analytical formulae of quality factor and efficiency have been derived in terms of relevant circuit parameters. Particular emphasis has been paid on several circuit parameters which have a substantial impact on circuit performance. Some design considerations have been pointed out according to the simulation results, which are useful to the design and fabrication of this type of oscillators. [ABSTRACT FROM AUTHOR]

Abstract  In the design of millimeter wave voltage control oscillators (VCOs), mutual coupling effect is of great importance for it influences the tuning and power characteristics of VCOs significantly. In this paper, mutual coupling between two in-line radial line transformers (RLTs) in rectangular waveguide cavities of millimeter wave VCOs has been evaluated with mode matching methods. Mutual coupling characteristics varying with various parameters of resonate cavity such as the distance between two diodes, the position of sliding short, the radii of bias pins, the radii of RLTs, and the height of diodes are presented. Some useful conclusions concerning two RLTs configuration have been derived, which is helpful to design millimeter wave VCO of this structure. [ABSTRACT FROM AUTHOR]

Obesity is strongly associated with insulin resistance, type 2 diabetes, cardiovascular diseases and dyslipidemia. How these seemingly distinctive diseases cluster together as the metabolic syndrome is a scientifically intriguing and clinically important question, but not well understood. Recent studies indicate that chronic systemic inflammation may be a cause behind the syndrome and that the adipose tissue may contribute to the inflammation since it is not only a storage depot for excess fat, but also is an endocrine organ secreting many polypeptides, known as adipokines. Dysregulation of adipokines may be responsible for the elevation of the inflammatory state in obesity and obesity-associated comorbidities. Numerous studies have investigated the change of adipokines in obesity and diabetes conditions, but the data from Chinese patients are very limited. In this study, we measured the serum levels of several representative adipokines in obese and diabetic Chinese patients treated with rosiglitazone. In non-diabetic subjects, the serum levels of serum amyloid A (SAA), C-reactive protein (CRP) and TNFa in obese people (BMI ≥ 24, n = 24) was significantly higher than the lean subjects (BMI < 24, n = 26, p < 0.01). In contrast, adiponectin levels were significantly lower in the obese group (p < 0.01). On the other hand, no difference in IL-6 and resistin levels was found between the lean and obese groups. Moreover, these adipokines were measured in 34 impaired glucose regulation (IGR) patients and 44 new-onset type 2 diabetes patients (T2D) patients before and after the treatment with rosiglitazone at 4 mg/day for 12 weeks. The rosiglitazone did not change BMI in both groups but decreased fasting glucose and HbA1c levels in the T2D group. The treatment reduced CRP, TNFa and SAA by 11-39% and increased adiponectin by 82% with statistical significance. In conclusion, we found that inflammatory adipokines were elevated in obesity and decreased in diabetics after rosiglitazone treatment, supporting that adipokines may be a mediator in the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and challenging management. The present study aimed to investigate the expression of programmed death ligand-1 (PD-L1) and V-domain Ig-containing suppressor of T cell activation (VISTA) in ACC and their associations with clinicopathological features and survival outcomes. Immunohistochemistry was performed on formalin-fixed paraffin-embedded specimens from 54 ACC patients. Chi-square/Fisher's exact tests or independent samples t/Mann--Whitney U tests were performed to assess correlations between immunoscores and clinicopathological parameters. The Kaplan--Meier method and Cox regression were conducted for survival analysis and to identify independent predictors of overall (OS) and disease-free (DFS) survival. Results showed that VISTA was expressed in tumor cells (TCs) and tumor-infiltrating immune cells (TICs) in 81.5% (44/54) and 40.7% (22/54) of the patients, respectively. PD-L1 positivity was found in either TCs or TICs in 11.1% (6/54) of the patients. Patients with positive VI STA expression in TCs had a higher tumor stage (56.9% vs 20%, P = 0.036) and Ki-67 index (30.50 ± 23.51% vs 14.76 ± 11.75%, P = 0.006). However, PD-L1 positivity in either TCs or TICs had no association with patient clinicopathological features. A higher VISTA expression intensity, a larger area and a higher immunoscore were associated with increased risks of disease progression and overall mortality, but PD-L1 expression in TCs or TICs was not associated with OS or DFS. In conclusion, positive TC VISTA expression was correlated with pathological parameters related to malignancy in ACC patients. This finding provides novel evidence of the value of VISTA, in addition to PD-L1, as an immunotherapeutic target in ACC. [ABSTRACT FROM AUTHOR]

The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid (GA) in diabetic peripheral neuropathy (DPN). GA significantly mitigated nerve conduction velocity (NCV) deficit and morphological abnormality and reduced high-mobility group box-1 (HMGB1) expression in the sciatic nerves of diabetic rats independent of blood glucose and body weight. Notably, GA alleviated the increase of HMGB1 and the decrease of cell viability in high glucose-stimulated RSC96 cells. Furthermore, GA obviously reduced the concentration of inflammatory cytokines in the sciatic nerves of diabetic rats and supernatants of high glucoseexposed RSC96 cells, then restored the decreased expression levels of nerve growth factor (NGF) and neuritin-1, and the increased expression levels of cleaved caspase-3 and neuron-specific enolase. Additionally, GA markedly inhibited receptor for advanced glycation end products (RAGE) expression, p38MAPK phosphorylation, and the nuclear translocation of NF-κBp65 in diabetic rats and high glucose-exposed RSC96 cells. The promotional effect of high glucose in RSC96 cells was diminished following Hmgb1 siRNA treatment. Our findings indicate that GA may exert neuroprotection on DPN by suppressing HMGB1, which lead to extenuation of inflammation response, balance of NGF, neuritin-1 and caspase-3, as well as inactivation of RAGE/p38MAPK/NF-κBp65 signaling pathway. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is difficult to manage due to the lack of effective treatments. Increased oxygen consumption caused by ove rnutrition, along with reduced oxygen delivery to liver cells induces hepatic steatosi s. Here, we investigated the efficacy of oxygen therapy (OT) to alleviate hepatic steatosi s. The effect of OT on hepatic steatosis was evaluated in high-fat-diet (HFD)-fed mice and palmitic acid (PA)- treated primary hepatocytes. Liver biopsy tissue samples were u sed to determine the relationship between the expression of hypoxia-inducible fa ctor-2α (HIF-2α) and the progression of NAFLD. The role of HIF-2α in the OT group was determined based on the overexpression of HIF-2α in vitro. OT safely alleviated hepatic hypoxia and improved hepatic steatosis by inhibiting hepatic de novo lipogenesis in HFD-fed mice and PA-treated primary hepatocytes, and this was accompanied by red uced expression of HIF-2α and hepatic de novo lipogenesis. The analysis of liver tissues from individuals wi th or without NAFLD revealed a positive correlation between hepati c HIF-2α expression and NAFLD progression. Overexpression of HIF-2α in vitro inhibited the beneficial effect of OT against hepatic lipogenesis and steatosis. OT might be a via ble treatment option for NAFLD and functions by alleviating hypoxia and inhibiting the l iver HIF-2α signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks.Research Design and Methods: Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes.Results: Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation.Conclusions: Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients. [ABSTRACT FROM AUTHOR]

Purpose Diabetic peripheral neuropathies are the common chronic complications of diabetes, but the diagnosis is insensitive by physical examination in busy outpatients. Here we evaluated the performance of SUDOSCAN in screening diabetic peripheral neuropathies in Chinese type 2 diabetic patients. Methods The study enrolled 180 patients for annually screening. All patients underwent neurological symptoms assessment, clinical examination, nerve conduction studies and cardiovascular autonomic reflex tests. SUDOSCAN was tested and evaluated with electrochemical skin conductance in hands and feet, asymmetry ratio in hands and feet and predicted cardiac neuropathy. Results Patients enrolled had an average age of 56.1 years, 9.8 years of diabetic duration. Patients with diabetic sensorimotor polyneuropathy showed significantly lower electrochemical skin conductance in feet and higher asymmetry ratio in feet compared with those without. Sensitivity and specificity of asymmetry ratio in feet for diagnosing diabetic sensorimotor polyneuropathy were 88.2 % and 46.9 % and area under ROC curve was 0.713. Patients with cardiovascular autonomic neuropathy showed significantly lower electrochemical skin conductance in hands and feet, and higher asymmetry ratio in feet and predicted cardiac neuropathy compared with those without. Sensitivity and specificity of electrochemical skin conductance in feet in diagnosing cardiovascular autonomic neuropathy were 85.6 % and 76.1 % with an area under ROC curve of 0.859. Conclusions SUDOSCAN is a sensitive test to detect diabetic peripheral neuropathy in China and could be an effective screening tool in in busy outpatients and primary health care. [ABSTRACT FROM AUTHOR]

Background Previous national survey suggested that dyslipidemia is an increasing burden in China and more severe in urban population. In this study, we retrospectively analyzed the gender and age differences in lipids and lipoproteins in a large Chinese urban population in Nanjing city. Methods A total of 236, 945 adults (age ≥ 20 years old) who undertook a health check between 2009 and 2015 in our medical examination center were involved in the analysis. Fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride (TG) were measured by standard methods. Results The age-standardized estimates of serum total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride were 4.77 (4.76-4.79), 1.19 (1.18-1.19), 2.53 (2.52-2.54) and 1.74 (1.72-1.76) mmol/L in males (n = 130954), and 4.79 (4.78-4.80), 1.46 (1.45-1.46), 2.44 (2.43-2.45) and 1.21 (1.19-1.22) mmol/L in females (n = 105991), respectively. The prevalence of dyslipidemia was significantly elevated in females above 50 years old, and the peak prevalence of dyslipidemia in males was in the age group of 40-59 years, earlier as compared to females (peaked at 60-69 years old). In addition, an increasing secular trend was observed in LDL cholesterol levels from 2009 to 2015 in both males and females. Conclusions Dyslipidemia is an increasing epidemic in China, characterized by a rising trend of LDL cholesterol. The gender and age differences in serum levels of lipid profile as well as prevalence of dyslipidemia suggested that the middle-age men and postmenopausal women should be the prioritized target for better control of dyslipidemia and early prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes. [ABSTRACT FROM AUTHOR]

NTRODUCTION: In Asia, patients with type 2 diabetes mellitus (T2DM) often have suboptimal glycemic control for many years prior to initiating basal insulin. Active titration of basal insulin is also required to improve glycemic outcomes. This pooled analysis was conducted to determine the impact of patient baseline covariates on the required dose of basal insulin and treatment response, for the improved management of Asian patients with T2DM. METHODS: Data on insulin-naïve Asian patients with T2DM who initiated and fully titrated insulin glargine 100 U/mL (Gla-100) for ≥ 20 weeks were pooled from seven randomized, controlled, treat-to-target trials. Covariance and multivariate linear/logistic regression analyses were applied to determine the impact of the baseline covariates on Gla-100 dose (primary outcome) and treatment response (secondary outcomes) at week 24 for patients from Asia (N = 724) and from China alone (n = 249). Based on the multivariate analysis for the primary outcome in the Asian population, a nomogram was developed. RESULTS: The dose of Gla-100 at week 24 was negatively correlated with age and positively correlated with body mass index (BMI) and fasting plasma glucose (FPG) at baseline in both Asian and Chinese populations. In both populations, higher baseline glycated hemoglobin (HbA1c) was associated with a lower reduction in HbA1c from baseline, higher HbA1c at week 24, and a lower chance of achieving HbA1c < 7% at week 24. The constructed nomogram enables calculation of the likely dose of Gla-100 required by Asian patients with T2DM to achieve HbA1c < 7% at week 24. CONCLUSIONS: Higher doses of Gla-100 are likely to be required in younger patients or patients with higher baseline BMI or FPG. The nomogram developed in this study can aid clinicians to titrate the dose of Gla-100 appropriately. Evidence in this pooled analysis also indicates that initiating basal insulin at a lower HbA1c can lead to greater glycemic control. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) contributes to insulin resistance in fat and muscle. In the present study, the role and mechanism of EPO in hepatic insulin resistance were investigated in HepG2 cells. Hepatic insulin resistance was induced by palmitic acid (PA) in the HepG2 cells, which were then treated with EPO (5 or 10 U/ml) or specific phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin or LY294002. EPO treatment significantly increased glycogen levels and reduced the protein expression of phosphoenolpyruvate carboxykinase in the PA-induced HepG2 cells. EPO also inhibited the serine phosphorylation of insulin receptor substrate (IRS)-1 (Ser307) and IRS-2 (Ser473), and increased the protein expression levels of PI3K, phosphorylated (p)-protein kinase B (AKT), p-forkhead box O1 (FOXO1) and p-glycogen synthase kinase 3 (GSK-3) β. In agreement with these result, the expression of p-FOXO1 (Ser256) and p-GSK-3β (Ser9), downstream molecules of AKT, were enhanced by EPO treatment (P<0.05). The specific PI3K inhibitors, LY294002 and wortmannin, markedly inhibited the EPO-mediated increases in p-AKT (Ser473), p-FOXO1 (Ser256) and p-GSK-3β (Ser9) in the PA-induced HepG2 cells (P<0.05). The gene expression levels of tumor necrosis factor-a, interleukin-1β and monocyte chemoattractant protein-1, and the p-c-Jun N-terminal kinase (JNK)/total-JNK ratio were markedly suppressed by EPO treatment. These findings suggested that EPO treatment improved hepatic glucose metabolism, potentially through the IRS/AKT/FOXO1 and GSK-3β signaling pathway, which may be associated with its inhibitory effect on the inflammation-associated response. [ABSTRACT FROM AUTHOR]

Background: Cytokines secreted by adipose tissue macrophages (ATMs) significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. However, little relevant information is available regarding the role of microvesicles (MVs) derived from ATMs in macrophage-adipocyte crosstalk. Methods: MVs were generated by stimulation of M1 or M2 phenotype THP-1 macrophages and incubated with human primary mature adipocytes and differentiated adipocytes. Subsequently, insulin-stimulated phosphorylation of Akt (pAkt) and glucose uptake were determined. Glucose transporter 4 (GLUT4) translocation and nuclear translocation of nuclear factor (NF)-kappa B were also analyzed in treated adipocytes. Results: M1 macrophage-derived MVs (M1 MVs) significantly reduced protein abundance of insulin-induced Akt phosphorylation in human primary mature adipocytes and differentiated adipocytes, when compared with the same concentration of M2 macrophage-derived MVs (M2 MVs). In contrast to M2 MVs, which enhanced the insulin-induced glucose uptake measured by 2-NBDG, M1 MVs decreased this effect in treated adipocytes. M1 MVs treatment also brought about a significant increase in the nuclear translocation of nuclear factor (NF)-kappa B, coupled with a decrease in pAkt level and GLUT4 translocation compared with M2 MVs-treated adipocytes. These effects were reversed by BAY 11-7085, a NF- kappa B specific inhibitor. Conclusions: MVs derived from proinflammatory (M1) macrophages may, at least in part, contribute to the pathogenesis of obesity-induced insulin resistance, reducing insulin signal transduction and decreasing glucose uptake in human adipocytes, through NF-kappa B activation. Therefore, these MVs may be potential therapy candidates for the management of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

OBJECTIVE This study investigated the relationship between GAD autoantibody (GADA) titers and changing of β-cell function in patients with latent autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODS This 3-year prospective study enrolled 95 subjects from15 Chinese cities including 25 high-titer (GADA ≥180 units/mL) LADA patients, 42 low-titer (GADA <180 units/mL) LADA patients, and 28 type 2 diabetic patients, the latter two groups as controls of similar age, sex, and BMI. Clinical characteristics were determined annually, including glycosylated hemoglobin (HbA1c), fasting C-peptide (FCP), and 2-h postprandial C-peptide (PCP). RESULTS Despite similar initial FCP and PCP, FCP and PCP both decreased more in subjects with high GADA titer (FCP from mean 0.49 nmol/L at entry to 0.13 nmol/L at the third year; P < 0.05) than with low GADA titer (FCP from mean 0.48 to 0.38 nmol/L) and type 2 diabetes (FCP from mean 0.47 to 0.36 nmol/L); the latter two groups being similar. After 3 years, residual β-cell function (FCP >0.2 nmol/L) was detected in only 42% with an initial high GADA titer compared with 90% with a low GADA titer and 97%with type 2 diabetes (P < 0.01 for both). GADA positivity at the third year persisted more in subjects with initially high GADA (92%) than with low GADA (26%) titers (P < 0.01). CONCLUSIONS In selected LADA patients, initial GADA titers identified subjects with different degrees of persistent autoimmunity and disease progression. LADA patients with a low GADA titer had metabolic phenotypes and loss of β-cell function similar to type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. RESEARCH DESIGN AND METHODS Liquid chromatography--quadrupole time of flight--mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). RESULTS A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P < 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P < 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. CONCLUSIONS Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is one of the major autoimmune diseases affecting children and young adults worldwide. To date, the different immunotherapies tested have achieved insulin independence in <5% of treated individuals. Recently, a novel hematopoietic stem cell (HSC)-based strategy has been tested in individuals with new-onset T1D. The aim of this study was to determine the effects of autologous nonmyeloablative HSC transplantation in 65 individuals with new-onset T1D who were enrolled in two Chinese centers and one Polish center, pooled, and followed up for 48 months. A total of 59% of individuals with T1D achieved insulin independence within the first 6 months after receiving conditioning immunosuppression therapy (with antithymocyte globulin and cyclophosphamide) and a single infusion of autologous HSCs, and 32% remained insulin independent at the last time point of their follow-up. All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreat-ment. Despite a complete immune system recovery (i.e., leukocyte count) after treatment, 52% of treated individuals experienced adverse effects. Our study suggests the following: 1) that remission of T1D is possible by combining HSC transplantation and immunosuppression; 2) that autologous nonmyeloablative HSC transplantation represents an effective treatment for selected individuals with T1D; and 3) that safer HSC-based therapeutic options are required. [ABSTRACT FROM AUTHOR]

Background: Achieving good glycemic control improves clinical outcomes among patients with type 2 diabetes (T2D). This study aimed to explore non-pharmaceutical factors for poor glycemic control in Chinese women with T2D who used antidiabetic drug(s). Methods: A cross-sectional survey was conducted in March to June 2011 in 77 top tertiary hospitals in Beijing, Shanghai, Tianjin, and Guangzhou, People's Republic of China (the coverage rates of the 3A hospitals: 74.4%, 76%, 55%, and 29.3%, respectively). Of 29,502 patients with T2D who used oral antidiabetic drugs (OADs) alone or combined with insulin, 13,970 were women and used in the analysis. Logistic regression analysis was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of factors for hyperglycemia defined as HbA1c (glycated hemoglobin) ⩾77 mmol/mol (7.0%). Results: The mean age was 60.3 (standard deviation 11.0) years, with a median of 4 (interquartile range 2-9) years of duration of diabetes, and 65.1% had hyperglycemia. In multivariable analysis, body height of ⩾164 cm (OR 1.26, 95% CI 1.15-1.37) and obesity (OR 1.16, 95% CI 1.04-1.31) was associated with increased risk of hyperglycemia, while self-monitoring blood glucose (SMBG) decreased the risk of hyperglycemia (OR 0.78, 95% CI 0.73-0.84). Duration of diabetes ⩾3 years (⩾3 to ⩾6 years, OR 1.46, 95% CI 1.32-1.62; ⩾6 to ⩾10 years, OR 1.65, 95% CI 1.44-1.89), especially ⩾10 years (OR 1.95, 95% CI 1.73-2.19), was associated with higher risks of hyperglycemia. Conclusion: Body height ⩾164 cm, obesity, and duration of diabetes ⩾3 years increased while SMBG decreased risk of hyperglycemia in Chinese women with OAD-treated T2D. [ABSTRACT FROM AUTHOR]

Aims: To examine the associations of BMI and waist circumference with glucose metabolism and (pre) diabetes among adults with BMI < 25 kg/m². Methods: We conducted a cross-sectional study in a nationally representative sample (10,098 men and 17,454 women) of Chinese adults aged ≥20 years with BMI > 25 kg/m². Glucose levels after at least 10 hours of overnight fasting, at 30 minutes and at 120 minutes after a standard 75-g oral glucose load were measured. Associations of BMI and waist circumference with outcomes were examined by general linear models for continuous outcomes and by logistic regression models for dichotomous outcomes. Results: Among those with BMI < 25 kg/m², 18.8% of men and 17.1% of women had abnormal glucose metabolism, including 4.9% of men and 3.8% of women with undiagnosed type 2 diabetes. For each SD increase in BMI (2.1 kg/m²) and waist circumference (8.3 cm), fasting glucose levels increased by 0.128 and 0.170 mmol/L in men, and by 0.112 and 0.167 mmol/L in women, respectively; the corresponding increases for 2-hour post-load glucose levels were 0.121 and 0.217 mmol/L in men, and 0.241 and 0.362 mmol/L in women. When simultaneously included in the same model, these associations with waist circumference were stronger than with BMI. Conclusion: Obesity measures are associated with abnormal glucose metabolism and diabetes, with central obesity playing a more prominent role than general obesity in Chinese population with BMI < 25 kg/m². Chinese diabetes prevention and treatment programs should incorporate targeting of normal weight adults with central obesity. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The two major classes of antidiabetic drugs, sulfonylureas and metformin, may differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type 2 diabetic patients who had a history of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS--This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = 63.3 years (range, 36-80 years), were enrolled. Participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. RESULTS--At the end of study drug administration, both groups achieved a significant decrease in the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat analysis showed an adjusted hazard ratio (HR) of 0.54 (95 % CI 0.30-0.90; P = 0.026) for the composites of cardiovascular events among the patients that received metformin, compared with glipizide. The secondary end points and adverse events were not significantly different between the two groups. CONCLUSIONS--Treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (AHSCT) was beneficial for type 1 diabetic adolescents with diabetic ketoacidosis (DKA) at diagnosis. RESEARCH DESIGN AND METHODS--We enrolled 28 patients with type 1 diabetes, aged 14--30 years, in a prospective AHSCT phase II clinical trial. HSCs were harvested from the peripheral blood after pretreatment consisting of a combination of cyclophosphamide and antithymocyte globulin. Changes in the exogenous insulin requirement were observed and serum levels of HbA1c, C-peptide, and anti-glutamic acid decarboxylase antibody were measured before and after the AHSCT. RESULTS--After transplantation, complete remission (CR), defined as insulin independence, was observed in 15 of 28 patients (53.6%) over a mean period of 19.3 months during a follow-up ranging from 4 to 42 months. The non-DKA patients achieved a greater CR rate than the DKA patients (70.6% in non-DKA vs. 27.3% in DKA, P = 0.051). In the non-DKA group, the levels of fasting C-peptide, peak value during oral glucose tolerance test (Cmax), and area under C-peptide release curve during oral glucose tolerance test were enhanced significantly 1 month after transplantation and remained high during the 24-month follow-up (all P < 0.05). In the DKA group, significant elevation of fasting C-peptide levels and Cmax levels was observed only at 18 and 6 months, respectively. There was no mortality. CONCLUSIONS--We have performed AHSCT in 28 patients with type 1 diabetes. The data show AHSCT to be an effective long-term treatment for insulin dependence that achieved a greater efficacy in patients without DKA at diagnosis. [ABSTRACT FROM AUTHOR]

Background--Because of rapid change in lifestyle risk factors, cardiovascular disease has become the leading cause of death in China. We sought to estimate the national levels of serum lipids and lipoproteins among the Chinese adult population. Methods and Results--We conducted a cross-sectional study in a nationally representative sample of 46 239 adults aged >20 years. Fasting serum total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were measured by standard methods. The age-standardized estimates of total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were 4.72 (95% confidence interval, 4.70-4.73), 1.30 (1.29-1.30), 2.68 (2.67-2.70), and 1.57 (1.55-1.58) mmol/L, respectively, in the Chinese adult population. In addition, 22.5% (21.8-23.3%) or 220.4 million (212.1-228.8) Chinese adults had borderline high total cholesterol (5.18-6.21 mmol/L), and 9.0% (8.5-9.5%) or 88.1 million (83.4-92.8) had high total cholesterol (>6.22 mmol/L). The population estimates for borderline high (3.37-4.13 mmol/L), high (4.14-4.91 mmol/L), and very high (>4.92 mmol/L) low-density lipoprotein cholesterol were 13.9% (13.3-14.5%) or 133.5 million (127.0-140.1), 3.5% (3.3-3.8%) or 33.8 million (31.2-36.5), and 3.0% (2.8-3.3%) or 29.0 million (26.3-31.8) persons, respectively. In addition, 22.3% (21.6-23.1%) or 214.9 million (207.0-222.8) persons had low high-density lipoprotein cholesterol (<1.04 mmol/L). The awareness, treatment, and control of borderline high or high total cholesterol were 11.0%, 5.1%, and 2.8%, respectively, in the Chinese adult population. Conclusions--Serum total and low-density lipoprotein cholesterol levels were high and increasing in the Chinese population. Without effective intervention, atherosclerotic cardiovascular diseases may soar in the near future in China. [ABSTRACT FROM AUTHOR]

The efficacy and safety of twice daily (BID: immediately before breakfast and dinner) and thrice daily (TID: immediately before breakfast, lunch and dinner) biphasic insulin aspart 30 (BIAsp30) were assessed in this 24-week randomised, open-labeled, parallel-group trial in China. A total of 321 type 2 diabetics (FBG≥7.8mM;HbA[sub 1c]≥7.5%) inadequately controlled with oral antidiabetic agents (OADs) were randomised (1:1) to receive BID or TID BIAsp30. Subject baseline characteristics were comparable in two groups. HbA[sub 1c] were 9.5±1.4%(BID) and 9.6±.5%(TID). FBG were 11.5±2.7mM(BID) and 11.8±3. 1mM(TID). Insulin dose was adjusted to achieve pre-meal BG target of4.4-6.1mM (APDPG 2002). After 24 weeks, HbA[sub 1c] decreased significantly in both groups (BID:-2.5%;TID:-2.8%). TID group showed superiority in HbA[sub 1c] improvement (0.3%, 95% CI: [-0.53;-0.13], p<0.01). Half of subjects achieved HbA[sub 1c] target <7.0% with BIAsp30 BID. Fifteen percent more subjects reaching HbA[sub 1c]<7.0% with BIAsp30 TID. FBG in both groups showed significant reduction (BID&TID:-4.7±0.1mM). There was no significant difference in major and minor hypoglycaemic episodes between treatments, but a significant lower risk (p<0.05) for TID treatment in the subgroup of subjects achieving the target of HbA[sub 1c]< 7.0%. Risk of nocturnal events was similar in both groups (RR=0.83,p=0.60). TID group revealed significantly lower risk of overall (RR=0.62, p<0.05) and diurnal hypoglycaemic events (RR=0.58, p<0.01). The trend of significantly lower hypoglycaemic episodes was also observed in subjects achieving target of HbA[sub 1c]<7.0%. There was no significant difference for weight gain in two groups. Mean daily insulin doses were 0.82U/kg in BID group and 0.86U/kg in TID group at the end of study. In conclusion, both twice daily and thrice daily BIAsp30 were efficacious in glycaemic control in insulin naive type 2 diabetics. The regimen of thrice daily BIAsp30 could offer greater reduction in HbA[sub 1c] and lower risk of hypoglycaemic events. More patients can reach target with treatment regimen of BIASP30 TID without increasing insulin dose and weight gain compared to BID group. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and β-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS--Forty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up. RESULTS--IT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 ± 1.4 (mean ± SD)to 1.72 ± 0.8, a level comparable to the IGT (1.96 ± 1.1) and NGT (1.37 ± 0.6) subjects in the remission group: however, no HOMA-β improvement was observed in nonpermission subjects. HOMA-β in the remission group was improved (mean, interquartile range) from 18.4 (8.3-28.5) to 44.6 (32.1-69.1) and acute insulin response of insulin (AIRins) from 1.50 ± 0.22 to 1.83 ± 0.19 µIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-β: 86.4 [56.7-185.2], P < 0.01; AIRins: 2.54 ± 0.39 µIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-β and HOMA sensitivity of remission subjects shifted close to that of IGT subjects. CONCLUSIONS--IT in newly diagnosed type 2 diabetes not only partially restored β-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, β-cell function was less restored than insulin sensitivity after IT in the remission subjects. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association study (GWAS) has identified more than 30 loci associated with type 2 diabetes (T2D) in Caucasians. However, genomic understanding of T2D in Asians, especially Han Chinese, is still limited. Methods and Principal Findings: A two-stage GWAS was performed in Han Chinese from Mainland China. The discovery stage included 793 T2D cases and 806 healthy controls genotyped using Illumina Human 660- and 610-Quad BeadChips; and the replication stage included two independent case-control populations (a total of 4445 T2D cases and 4458 controls) genotyped using TaqMan assay. We validated the associations of KCNQ1 (rs163182, p = 2.085*10-17, OR 1.28) and C2CD4A/ B (rs1370176, p = 3.677*10-4, OR 1.124; rs1436953, p = 7.753*10-6, OR 1.141; rs7172432, p = 4.001*10-5, OR 1.134) in Han Chinese. Conclusions and Significance: Our study represents the first GWAS of T2D with both discovery and replication sample sets recruited from Han Chinese men and women residing in Mainland China. We confirmed the associations of KCNQ1 and C2CD4A/B with T2D, with the latter for the first time being examined in Han Chinese. Arguably, eight more independent loci were replicated in our GWAS. [ABSTRACT FROM AUTHOR]

Background: Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. Methods: A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. Results: The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and ≥60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of <18.5, 18.5 to 24.9, 25.0 to 29.9, and ≥30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). Conclusions: These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed. N Engl J Med 2010;362:1090-101. [ABSTRACT FROM AUTHOR]

The article discusses a study performed to test the impact of intensive insulin therapy glycemic control and beta cell function in persons recently determined to have type 2 diabetes. Participants included 382 patients in China between September, 2004 and October, 2006. Patients were randomly assigned to receive either insulin therapy or oral hypoglycemic agents. Subsequent to normoglycemia being established, a follow-up regimen of diet and exercise was introduced. Results indicate early insulin therapy produced better outcomes than oral hypoglycemic agents.

Previous studies have showed that hypertriglyceridemia may be a stronger risk factor for coronary heart disease in diabetic patients than non-diabetic individuals. Multiple genomic loci have been identified to be associated with lipid levels among general populations by genome-wide association studies. It is unclear about their effects on lipid levels among type 2 diabetes (T2D) patients. The present study aimed to investigate the associations of lipid related genomic loci and hypertriglyceridemia (defined as triglycerides ≥ 1.70mmol/L or taking lipidlowering medications) among 5,338 T2D patients from China. We genotyped 9 single nucleotide polymorphisms (SNPs) within or near ABCA1, DOCK7, TOMM40, GCKR, HNF1A, HNF4A, LDLR, BAZ1B and BUD13 genes. Under an additive genetic model, logistic and linear regression models were used to examine the associations of these genomic loci with hypertriglyceridemia and the triglycerides level (among 4,908 individuals without taking any lipid-lowering medications) with adjustment for age, sex, and body mass index, respectively. Five SNPs near ABCA1 (rs3890182), TOMM40 (rs157580), GCKR (rs780094), BAZ1B (rs2240466) and BUD13 (rs28927680) genes were significantly associated with hypertriglyceridemia among T2D patients (OR [95% CI] = 0.79 [0.67, 0.93] for per A allele of rs3890182, P = 4.03х10-3; 1.13 [1.04, 1.22] for per A allele of rs157580, P = 2.81х10-3; 0.87 [0.80, 0.94] for per G allele of rs780094, P = 4.26х10-4; 0.77 [0.68, 0.87] for per T allele of rs2240466, P = 1.28х10-5; 3.83 [1.39, 10.50] for per C allele of rs28927680, P = 9.27х10-3). Six SNPs within or near ABCA1, GCKR, BAZ1B, TOMM40, HNF1A and LDLR were significantly associated with the triglycerides level. For example, minor alleles of GCKR and BAZ1B were associated with lower triglycerides level (β [SE] = -0.025 [0.005] for per G allele of rs780094, P = 7.88х10-7; -0.035 [0.007] for per T allele of rs2240466, P = 2.03х10-6). To test the robustness of these findings, we conducted a sensitivity analysis to only include newly diagnosed T2D patients (2,646 out of 4,908 patients without taking any lipid-lowering medications). The associations between ABCA1, TOMM40, GCKR and BAZ1B with hypertriglyceridemia maintained significant (P value ranged from 7.79х10-4 to 1.29х10-2), as well as their associations with the triglycerides level (P value ranged from 2.76х10-5 to 2.89х10-2). In conclusion, our study provides the first data for the effects of lipid-related genomic loci on hypertriglyceridemia and the triglycerides level among T2D patients of the Chinese population. Further studies were warranted to replicate these findings. [ABSTRACT FROM AUTHOR]

Obesity is one of the most important risk factors for type 2 diabetes (T2D). The aim of this study is to examine the associations between established obesity-related genomic loci and T2D as well as multiple quantitative glycemic traits among Chinese population. Single nucleotide polymorphisms (SNPs) near or within genes NEGR1, SEC16B, TMEM18, ETV5/DGKG, BAT2,BDNFOS, BDNF, FAIM2, MC4R, KCTD15, MTCH2, GNPDA2, NPC1, MAF, PTER, PRL, PCSK1, PFKP, CTNNBL1, NRXN3, MSRA, SLC30A10 and TFAP2B from 23 independent genomic loci were genotyped among 5,338 T2D patients and 4,663 controls. An additive genetic model was assumed. Logistic and linear regression models were used to examine the associations of these genomic loci with T2D and glycemic traits, respectively. Two SNPs near MC4R (rs 12970134) and GNPDA2 (rs 10938397) genes were significantly associated with T2D after adjusting for age and gender (OR [95% CI] = 1.14 [1.06, 1.22] for per A allele of rs 12970134, P = 4.75×10-4 ; OR [95% CI] = 1.10 [1.03, 1.17] for per G allele of rs 10938397, P = 4.54×10-3). When body mass index (BMI) and waist circumference was further adjusted for in logistic regression models, the association of MC4R with T2D maintained significant (OR [95% CI] = 1.10 [1.02, 1.20], P = 1.81×10-2) and that of GNPDA2 attenuated to non-significance (OR [95% CI] = 1.06 [0.98, 1.14], P = 1.26×10-1). In addition, eight loci (near or within SEC16B, BDNF, KCTD15, MAF, PRL, PCSK1, CTNNBL1 and NRXN3 genes) showed significant associations with quantitative glycemic traits in the controls even after adjusting for BMI and waist circumference (P < 0.05). For example, the G allele of SNP rs 10146997 in the NRXN3 gene was associated with higher fasting insulin level (β [SE] = 0.064 [0.026], P = 1.31×10-2), HOMA-IR (β [SE] = 0.064 [0.027], P = 1.71×10-1) and lower insulin sensitivity (assessed by Matsuda index, β [SE] = -0.051 [0.026], P = 4.67×10-2) compared to the A allele. The T allele of SNP rs 6013029 in the CTNNBL1 was associated with greater fasting insulin(β [SE] = 0.098 [0.038], P = 1.02×10-2), HOMA-IR (β [SE] = 0.100 [0.039], P = 1.13×10-2) and HOMA-B (β [SE] = 0.104 [0.053], P = 4.73×10-2), as well as lower insulin sensitivity (β [SE] = -0.096 [0.039], P = 1.47×10-2) compared to G allele, suggesting its potential role in insulin resistance. In conclusion, these data suggest that these obesity-related genomic loci may be associated with T2D and glycemic traits after accounting for BMI and waist circumference among Chinese population. [ABSTRACT FROM AUTHOR]