Gan Huang

The Second Xiangya Hospital of Central South University, Ch’ang-sha-shih, Hunan, China

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Publications (71)129.02 Total impact

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    ABSTRACT: Background: Latent autoimmune diabetes in adults (LADA) is a form of autoimmune diabetes with heterogeneous features. This study aimed to investigate the persistent status of glutamic acid decarboxylase antibody (GADA) in patients with LADA and its association with clinical characteristics. Methods: This 3-year follow-up study enrolled 107 LADA and 40 type 2 diabetes mellitus (T2DM) patients from Oct 2005 to Dec 2013. GADA titer, epitopes, and clinical characteristics (including fasting C-peptide and HbA1c) in LADA patients were assayed annually. HLA-DQ genotypes were also analyzed. The relationship between the persistence of GADA and clinical characteristics were investigated in LADA patients. Results: After 3-year follow-up, 36.5% (39/107) LADA patients remained GADA-positive (persistently positive group); 19.6% (21/107) patients fluctuated positively and negatively (fluctuating group); while 43.9% (47/107) patients became GADA-negative, among which 61.7% (29/47) seroconversions occurred within 6 months follow-up (transiently positive group). The GADA persistently positive group possessed higher titer of GADA than transiently positive group and fluctuant group (all P =0.000),higher reactivities to middle and C-terminal regions of GAD65 than those in transiently positive group (P = 0.001 and P = 0.000, respectively), and lower baseline fasting C-peptide level than T2DM patients and transiently positive group [415(31-1862) vs. 620(220-1658) pmol/L, P = 0.014; 415(31 ~ 1862) vs. 705(64 ~ 1541) pmol/L, P = 0.017, respectively]. The GADA transiently positive group retained a higher HbA1C level when compared to T2DM patients (P = 0.023). In addition, the three LADA groups shared similar frequencies of HLA-DQ susceptible haplotypes that were higher as compared with T2DM. The GADA persistently positive group had a higher annual declining rate in fasting C-peptide than T2DM patients [-14%(-174% ~ 33%) vs. -1%(-27% ~ 28%), P = 0.007]. Conclusion: LADA patients with GADA transient positivity account for a large proportion, whose clinical characteristics and HLA-DQ haplotypes are different from that of T2DM. The patients with high titer GADA and reactivities to GADA65 middle and C-terminal regions showed a persistent GADA positivity, in which a worse baseline and accelerated decline of beta cell function need early intervention in the practice. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Diabetes/Metabolism Research and Reviews
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    ABSTRACT: Objective: B lymphocytes play an important role in the immunopathogenesis of autoimmune diabetes. We hypothesized that the altered B-cell subset phenotype is associated with autoimmune diabetes. Research design and methods: Patients with type 1 diabetes (T1D) (n = 81), latent autoimmune diabetes in adults (LADA) (n = 82), or type 2 diabetes (T2D) (n = 95) and healthy control subjects (n = 218) with normal glucose tolerance (NGT) were recruited. We determined the percentage of circulating B-lymphocyte subsets, including CD19(+)CD23(-)CD21(+) (marginal zone B [MZB]), CD19(+)CD23(+)CD21(-) (follicular B [FoB]), and CD19(+)CD5(+)CD1d(hi) (interleukin-10-producing regulatory B [B10]) cells by flow cytometry. Results: Patients with T1D or LADA had increased percentages of MZB cells and decreased percentages of FoB cells compared with healthy control subjects with NGT and patients with T2D. Moreover, patients with T1D showed the lowest frequency of B10 cells compared with patients with LADA or T2D, whereas healthy control subjects expressed the highest frequency of B10 cells. Of note, the frequency of MZB cells was negatively associated and the frequency of FoB cells was positively associated with fasting C-peptide (FCP). The frequency of B10 cells was positively correlated with FCP and hemoglobin A1c. Conclusions: The data show that patients with T1D or LADA express an altered frequency of B-cell subsets, which is associated with islet function and glycemia. These findings suggest that B lymphocytes may be involved in loss of self-tolerance and β-cell destruction and could be used as a biomarker and potential target for immunological intervention.
    No preview · Article · Dec 2015 · Diabetes Care
  • Bo Yi · Gan Huang · Zhiguang Zhou
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    ABSTRACT: Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin-containing secretory granules of β-cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β-cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β-cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8-specific T cells and cytokine release by ZnT8-specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus. Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter-8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin containing secretory granules (ICSG) of β cells. In this review, we summarize the literatures about clinical aspects of ZnT8 in pathogenesis of diabetes and suggest that ZnT8 may play the different role between type 1 diabetes mellitus and type 2 diabetes mellitus. © 2016 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
    No preview · Article · Oct 2015
  • Bo Yi · Gan Huang · Zhi-Guang Zhou
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    ABSTRACT: Objective: To evaluate the utility of zinc transporter-8 (ZnT8) in the improvement of type 1 diabetes mellitus (T1DM) diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in T1DM. Data sources: A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows: "ZnT8," "type 1 diabetes," "latent autoimmune diabetes in adults," "type 2 diabetes," "islet autoantibodies," "zinc supplement," "T cells," "β cell," "immune therapy." We also searched the reference lists of selected articles. Study selection: English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed. Results: The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 (ZnT8A) and ZnT8-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy. Conclusions: ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.
    No preview · Article · Aug 2015 · Chinese medical journal
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    ABSTRACT: Adult-onset autoimmune diabetes is prevalent in China, in contrast to childhood-onset type 1 diabetes mellitus. Islet autoantibodies are the most important immune biomarkers to diagnose autoimmune diabetes. We assayed four different islet autoantibodies in recently diagnosed adult non-insulin-requiring diabetes Chinese subjects to investigate the best antibody assay strategy for the correct diagnosis of these subjects. LADA China study is a nation-wide multicenter study conducted in diabetes patients from 46 university-affiliated hospitals in China. Non-insulin-treated newly diagnosed adult diabetes patients (n = 2388) were centrally assayed for glutamic acid decarboxylase autoantibody (GADA), protein tyrosine phosphatase-2 autoantibody (IA-2A), and zinc transporter 8 autoantibody (ZnT8A) by radioligand assay and insulin autoantibody (IAA) by microtiter plate radioimmunoassay. Clinical data were determined locally. Two hundred and six (8.63 %) subjects were autoantibody positive, of which GADA identified 5.78 % (138/2388) of the total, but only 67 % (138/206) of the autoimmune cases. IA-2A, ZnT8A, and IAA were found in 1.51, 1.84, and 1.26 % of the total study subjects, respectively. When assaying three islet autoantibodies, the most effective strategy was the combination of GADA, ZnT8A, and IAA, which could identify 92.2 % (190/206) autoimmune diabetes patients. The clinical data showed that those subjects with positive GADA had lower random C-peptide than autoantibody negative subjects (P < 0.05). As with Europeans, GADA is the dominant autoantibody in this form of autoimmune diabetes in China, but in contrast to Europeans, screening should include other diabetes-associated autoantibodies.
    Full-text · Article · Aug 2015 · Acta Diabetologica
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    ABSTRACT: Fibroblast growth factor 21 (FGF21), a glucose and lipid metabolic regulator, has recently been demonstrated to be associated with cardiovascular diseases (CVD) such as carotid atherosclerosis, coronary heart disease and carotid artery plaques. However, the relationship between circulating FGF21 and subclinical atherosclerosis or atherosclerosis of other arteries such as the femoral and iliac artery remains unclear. In this study, we evaluated the association of serum FGF21 with intima-media thickness (IMT) and subclinical atherosclerosis in type 2 diabetic patients. Serum FGF21 levels were detected by enzyme-linked immunosorbent assay in 212 newly diagnosed type 2 diabetic patients without clinical symptoms of atherosclerosis or cardiovascular diseases. IMT of the carotid, femoral, and iliac arteries were measured by high-resolution B-mode ultrasound to determine the presence of subclinical atherosclerosis, which was defined as having an IMT > 1.0 mm and/or plaque on one or more of the three arteries without any clinical manifestations. The relationship between serum FGF21 levels and subclinical atherosclerosis was analyzed. Serum FGF21 levels were significantly higher in patients with subclinical atherosclerosis compared to those without [261.3 (135.1-396.4) versus 144.9 (95.9-223.0) ng/L, P < 0.001]. These differences were also observed in both men and women with subclinical atherosclerosis compared to their respective groups without [men: 243.2 (107.6-337.0) versus 136.8 (83.6-212.8) ng/L, P = 0.048; women: 292.4 (174.2-419.9) versus 160.4 (115.3-258.5) ng/L, P = 0.001]. Moreover, serum FGF21 levels showed a significantly positive correlation with carotid IMT in women (r = 0.23, P = 0.018) and with iliac IMT in both genders (women: r = 0.27, P = 0.005; men: r = 0.22, P = 0.024). Multiple logistic regression analysis further showed that serum FGF21 was an independent impact factor for subclinical atherosclerosis in patients with type 2 diabetes. Serum FGF21 is elevated in newly diagnosed type 2 diabetes, and positively correlates with carotid and iliac lesions in patients with subclinical atherosclerosis, especially in women. High levels of FGF21 may be a compensatory reaction to offset atherosclerosis.
    Full-text · Article · Jun 2015 · Cardiovascular Diabetology
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    ABSTRACT: To investigate whether there existed a healthy obese subtype. A total of 116 healthy subjects were recruited. They were divided into 3 groups according to BMI and metabolic disorders: 40 cases of normal weight and metabolic normality (NMN), 36 cases of obesity and metabolic normality (OMN) and 40 cases of obesity and metabolic abnormality (OMA). Anthropometic parameters as height, weight, waist circumference, hip circumference and blood pressure was recorded. Blood glucose, lipids, insulin, high-sensitivity C-reactive protein (hs-CRP) was detected. Body fat distribution was detected by dual-energy X-ray absorptiometry (DXA). Serum von Willebrand factor (vWF), a marker of endothelial dysfunction, were detected by ELISA. Both serum vWF levels in OMN group [(733.6 ± 86.2)U/L] and OMA group[(809.2 ± 46.3)U/L] are higher than that in NMN group[(466.9 ± 65.3)U/L, P < 0.05] with serum vWF level in OMA group is higher than in OMN group (P < 0.05). Among android fat mass percentage (AFM%), BMI, waist height ratio, waist circumference, hs-CRP, weight, hip circumference and trunk fat mass, AFM%, BMI and hs-CRP are main influencing factors of vWF. Endothelial dysfunction existed in obese adults regardless of their metabolic status. There is no healthy obese subtype. AFM%, BMI and hs-CRP are the main influencing factors of endothelial dysfunction.
    No preview · Article · Apr 2015 · Zhonghua nei ke za zhi [Chinese journal of internal medicine]

  • No preview · Article · Apr 2015 · Zhonghua yi xue za zhi
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    Full-text · Article · Mar 2015 · Diabetes Care
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    ABSTRACT: 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 from 15 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.
    Full-text · Article · Oct 2014 · Diabetes Care
  • Yifen Yang · Gan Huang · Xiang Yan · Zhiju Qing
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    ABSTRACT: Background: Recently, the abnormal presence of thyroglobulin antibody (TG-Ab) and thyroid peroxidase antibody (TPO-Ab) has been reported in vitiligo patients, but presence of TG-Ab and TPO-Ab in patients of different ages and gender, and its association with vitiligo and thyroid autoimmunity has rarely been reported. The aim of our research was to determine whether vitiligo was associated with thyroid autoimmunity and figure out its relationship with age and gender. Materials and Methods: We analyzed TG-Ab, TPO-Ab in age and gender matched 87 vitiligo patients and 90 healthy controls, the patients of vitiligo who were positive for the presence of TG-Ab and TPO-Ab were followed up to confirm autoimmune thyroid disease subsequently. Results: Results showed that the frequencies of TG-Ab (23.0%, 20/87) positivity and TPO-AB (24.1%, 21/87) in vitiligo patients were significantly higher than that in healthy controls (P < 0.05). Moreover, The positivity for of TG-Ab and TPO-Ab was higher in 11-20-year age group and 21-40-year age group than that in age matched healthy controls. We found female patients with vitiligo had higher positive frequencies of TG-Ab and TPO-Ab than healthy female controls. (34.1% vs. 8.8% and 34.1% vs. 11.1%, P = 0.000 and P = 0.011). When 20 patients with TG-Ab and TPO-Ab positivity were followed up for three monthes, 14 of them (70%) were diagnosed as having autoimmune thyroid disease compared with age-matched healthy controls (16.7%, χ2 = 5.4, P = 0.02). Conclusion: TG-Ab and TPO-Ab are likely to be found in female teenagers with vitiligo, and are relevant with respect to subsequent development autoimmune thyroid disease.
    No preview · Article · Jul 2014 · Indian Journal of Dermatology
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    ABSTRACT: Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors have been widely used in type 2 diabetes. An important unanswered question concerns the effect of DPP-4 inhibition on β-cell function in patients with autoimmune diabetes. Objective: To investigate the effects of DPP-4 inhibitor on β-cell function in patients with recent-onset latent autoimmune diabetes in adults (LADA). Design and Setting: This study was an open-label, randomized-controlled study conducted in the Department of Endocrinology, at the Second Xiangya Hospital. Patients and Intervention: Thirty recently diagnosed LADA patients were randomized 1:1 to receive insulin therapy with 100 mg/day sitagliptin (group A, n=15) or without sitagliptin (group B, n=15) for 12 months. Main Outcome Measures: Fasting and 2-hour postprandial blood samples were obtained at baseline, and after 3, 6, 9 and 12 months of treatment to determine blood glucose, HbA1C and C-peptide levels. Results: There were no differences in the clinical baseline data between the 2 groups. During the 12 months follow-up, there were no significant differences in glucose and HbA1C levels between the 2 groups. At 12 months, fasting C-peptide (FCP), 2-h postprandial C-peptide (2h CP) and ΔCP (ΔCP = 2h CP- FCP) levels were not different in group A (P>0.05) compared to baseline, while in group B the levels of FCP, 2h CP and ΔCP were significantly decreased compared to baseline (P<0.05). Levels of 2h CP were higher in group A than group B at 12 months (P<0.05). Conclusions: LADA patients treated with sitagliptin and insulin maintained β-cell function by comparison with insulin alone.
    Full-text · Article · Jan 2014 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Glutamic acid decarboxylase antibody (GADA) and protein tyrosine phosphatase antibody (IA-2A) are two major autoantibodies, which exert important roles in the process of type 1 diabetes mellitus (T1D). Our study aimed to investigate the changes in positivity and titers of GADA and IA-2A during the course of Chinese acute-onset T1D patients and their relationships with clinical features. Two hundreds and forty-seven Chinese newly diagnosed acute-onset T1D patients were consecutively recruited. GADA and IA-2A were detected at the time of diagnosis, one year later, 3-5 years later after diagnosis during the follow-up; all the clinical data were recorded and analyzed as well. During the course of acute-onset T1D, the majority of patients remained stable for GADA or IA-2A, however, a few patients changed from positivity to negativity and fewer patients converted from negativity to positivity. The prevalence of GADA was 56.3% at diagnosis, decreasing to 50.5% one year later, and 43.3% 3-5 years later while the corresponding prevalence of IA-2A were 32.8%, 31.0% and 23.3%, respectively. The median GADA titers were 0.0825 at diagnosis, declining to 0.0585 one year later and 0.0383 3-5 years later (P < 0.001), while the corresponding median titers were 0.0016, 0.0010, 0.0014 for IA-2A, respectively. Fasting C-peptide (FCP) and postprandial C-peptide 2 hours (PCP2h) levels of GADA or IA-2A negativity persistence patients were higher than those of positivity persistence and negativity conversion patients (P < 0.05) which indicated GADA or IA-2A negativity persistence T1D patients had a less loss of β cell function. Our data suggest that repeated detection of GADA and IA-2A are necessary for differential diagnosis of autoimmune diabetes and the indirect prediction of the β cell function in Chinese patients.
    No preview · Article · Nov 2013 · Chinese medical journal
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    ABSTRACT: Mitochondrial oxidative stress is the basis for pancreatic β-cell apoptosis and a common pathway for numerous types of damage, including glucotoxicity and lipotoxicity. We cultivated mice pancreatic β-cell tumor Min6 cell lines in vitro and observed pancreatic β-cell apoptosis and changes in mitochondrial function before and after the addition of Exendin-4. Based on these observations, we discuss the protective role of Exendin-4 against mitochondrial oxidative damage and its relationship with Ca(2+)-independent phospholipase A2. We established a pancreatic β-cell oxidative stress damage model using Min6 cell lines cultured in vitro with tert-buty1 hydroperoxide and hydrogen peroxide. We then added Exendin-4 to observe changes in the rate of cell apoptosis (Annexin-V-FITC-PI staining flow cytometry and DNA ladder). We detected the activity of the caspase 3 and 8 apoptotic factors, measured the mitochondrial membrane potential losses and reactive oxygen species production levels, and detected the expression of cytochrome c and Smac/DLAMO in the cytosol and mitochondria, mitochondrial Ca2-independent phospholipase A2 and Ca(2+)-independent phospholipase A2 mRNA. The time-concentration curve showed that different percentages of apoptosis occurred at different time-concentrations in tert-buty1 hydroperoxide- and hydrogen peroxide-induced Min6 cells. Incubation with 100 µmol/l of Exendin-4 for 48 hours reduced the Min6 cell apoptosis rate (p<0.05). The mitochondrial membrane potential loss and total reactive oxygen species levels decreased (p<0.05), and the release of cytochrome c and Smac/DLAMO from the mitochondria was reduced. The study also showed that Ca(2+)-independent phospholipase A2 activity was positively related to Exendin-4 activity. Exendin-4 reduces Min6 cell oxidative damage and the cell apoptosis rate, which may be related to Ca(2)-independent phospholipase A2.
    Full-text · Article · Oct 2013 · PLoS ONE
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    ABSTRACT: To explore the relationship between body fat distribution, insulin resistance, islet β cell function and metabolic disorders in adult population. From February to November 2012, a total of 174 subjects aged 20-68 years were recruited. Their anthropometric parameters, blood biochemical indices and the results of oral glucose tolerance test (OGTT) and insulin releasing test (IRT) were collected. Body fat distribution was measured with dual energy X-ray absorptiometry (DEXA). The values of trunk/total fat mass (T/B) and android/gynoid fat mass ratio (A/G) were positively correlated with blood pressure, blood lipid, plasma glucose, insulin resistance index (HOMA-IR) and high-sensitivity C-reactive protein. Compared with the group of normal metabolism, the group of metabolic disorders had higher T/B and A/G (P < 0.05). After multiple stepwise regression analysis, the main influencing factors of lnHOMA-IR and lnHOMA-β were T/B and Grespectively.Logistic regression showed that A (OR = 3.01, 95%CI 1.86-8.17) was a risk factor for diabetes and A/G (OR = 2.71, 95%CI 1.75-6.56) a risk factor for dyslipidemia. Trunk and android fat deposition aggravates insulin resistance, metabolic disorders. And the main influencing factors of insulin resistance and islet β cell function are trunk and gynoid fat respectively. Android fat mass is a major risk factor for glycolipid metabolism.
    No preview · Article · Sep 2013 · Zhonghua yi xue za zhi
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    ABSTRACT: Background: The ZnT8A is an independent marker for diagnosis of type 1 diabetes mellitus. We investigated the distribution and clinical features of ZnT8A positive latent autoimmune diabetes in adult (LADA) patients to explore the potential diagnostic application. Methods: A total of 3062 phenotypic T2DM patients were randomly selected from a national multicenter study - the LADA China Study. Radioligand binding assays were applied to detect the presence of ZnT8A, GADA and IA-2A. HbA1c , fasting C-peptide and serum lipid levels were followed up with ZnT8A positive patients. Results: The positive prevalence of ZnT8A, GADA and IA-2A in phenotypic T2DM patients was 1.99% (61/3062), 6.43% (197/3062) and 1.96% (60/3062), respectively. The ZnT8A positivity was lower than that of GADA(x² = 74.8, p < 0.001) but was comparable with that of IA-2A (p > 0.05). The positivity of ZnT8A in IA-2A positive patients was higher than that in GADA positive patients (38.3% vs. 10.7%, x² = 24.8, p < 0.001). On the basis of GADA and IA-2A positivity, the ZnT8A assay enhanced the diagnostic prevalence of LADA from 7.58 to 8.62%. The LADA patients who were positive for ZnT8A had higher systolic blood pressure when compared with GADA positive cases (p = 0.049) and higher total cholesterol levels when compared with antibody-negative T2DM patients (p = 0.035). Conclusion: The detection of ZnT8A at the basis of GADA and IA-2A can improve diagnostic sensitivity of Chinese LADA.
    No preview · Article · Jul 2013 · Diabetes/Metabolism Research and Reviews
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    ABSTRACT: The lipocalin family proteins, including lipocalin-2 and retinol-binding protein 4 (RBP4), are adipokines closely associated with obesity-related metabolic disorders. In this study, we evaluated the association of serum lipocalin-2 and RBP4 with intima-media thickness (IMT) and subclinical atherosclerosis in type 2 diabetic patients. Serum levels of lipocalin-2 and RBP4 were measured in 284 type 2 diabetic patients. Subclinical atherosclerosis was assessed by IMT at carotid, femoral and iliac arteries with ultrasound. Patients with subclinical atherosclerosis showed significantly higher circulating concentrations of lipocalin-2 and RBP4 when compared to those without [112.9 (86.4 to 202.1) µg/L versus 77.2(55.0-150.4) µg/L, 37.1(32.3-40.8) mg/L versus 23.2(20.1-29.2) mg/L, respectively; P = 0.002, P<0.001, respectively]. Moreover, positive correlations were observed between carotid IMT and lipocalin-2 (r = 0.170, P = 0.018) or RBP4 (r = 0.132, P = 0.040), femoral IMT and lipocalin-2 (r = 0.160, P = 0.027), as well as between iliac IMT and RBP4 (r = 0.241, P<0.001). Multiple logistic regression analysis further demonstrated that these two adipokines were independent risk factors for subclinical atherosclerosis in type 2 diabetes. Circulating levels of lipocalin-2 and RBP4 are positively correlated with carotid IMT and subclinical atherosclerosis in type 2 diabetes, which suggests a potential role of these two lipid-binding chaperones in the pathogenesis of vascular complications of diabetes.
    Full-text · Article · Jun 2013 · PLoS ONE
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    ABSTRACT: Fulminant type 1 diabetes (FT1D) is an extremely aggressive disease characterized by the abrupt onset of insulin-deficient hyperglycemia. However, the precise mechanisms underlying disease etiology almost remain unclear. As mice deficient in regulatory T cells (Tregs) are prone to the development of an FT1D-like phenotype, we thus investigated whether FT1D patients manifest Treg deficiency and explored the related mechanisms. We first noted a significant reduction for Foxp3 and CTLA4 expression levels in PBMCs of FT1D patients. IRF-7 was found to selectively bind to the Foxp3 promoter, and by which it promotes Foxp3 transcription. Therefore, ectopic IRF-7 expression significantly promoted Foxp3 and CTLA4 expression in PBMCs, while knockdown of IRF-7 manifested opposite effect. Importantly, stimulation of PBMCs with CpG ODN, a ligand for TLR9, significantly induced Foxp3 expression, demonstrating that TLR9 signaling positively regulates Treg development. However, knockdown of IRF-7 expression almost completely diminished the enhancing effect of TLR9 signaling on Foxp3 expression, suggesting that IRF-7 is a downstream molecule of TLR9 signaling and is essential for TLR9 induced Treg generation. Of interestingly note, the Foxp3 promoter in FT1D patients was hypermethylated, indicating that DNA methylation could be a causative factor responsible for the reduced Foxp3 expression in FT1D patients. Indeed, our mechanistic studies revealed that DNA methylation blocked IRF-7 binding to the Foxp3 promoter. Together, our data support the notion that environmental insults in genetic predisposed subjects trigger Foxp3 promoter hypermethylation, which then prevents IRF-7 binding to the Foxp3 promoter and impairs Treg development/functionality contributing to the pathogenesis of FT1D.
    No preview · Article · Mar 2013 · Journal of Autoimmunity
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    Xia Li · Gan Huang · Jian Lin · Lin Yang · Zhiguang Zhou
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    ABSTRACT: Background Diabetic patients with positive glutamic acid decarboxylase antibody (GAD-Ab) could be classified as autoimmune diabetes, which is discriminated into acute-onset classical type 1 diabetes (T1DM) and latent autoimmune diabetes in adults (LADA). However, whether the decay rate of beta cell function is relevant with the mode of onset (acute or latent-onset) is unclear. We aimed to investigate whether initial C peptide levels could help differentiate variation of C peptide decay rate. Methods Five hundred and twenty-seven newly diagnosed GAD-Ab positive diabetic patients were followed up to assess the natural course of beta cell function. Beta cell function failure was defined as fasting C peptide and postprandial C peptide levels less than 100 pmol/L and 150 pmol/L respectively. Results All these diabetic patients were discriminated according to initial fasting C peptide of 300 pmol/L, that is B+ (larger than 300 pmol/L) and B- (less than 300 pmol/L) group. The proportion of developing beta cell function failure was 13.1% in B+ group and 90.5% in B- group, which suggested that fasting C peptide levels made a good distinction of the heterogeneity in autoimmune diabetes. Receiver operator characteristic (ROC) analysis suggested that the fasting C peptide level of 300 pmol/L was optimal for determining beta cell function failure with sensitivity of 90.5% and specificity of 86.9%. Conclusions Initial level of fasting C peptide is a good indicator for predicting beta cell function failure in GAD-Ab positive diabetic patients.
    Full-text · Article · Mar 2013 · BMC Endocrine Disorders
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    ABSTRACT: Adult non-insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes-susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.
    Full-text · Article · Oct 2012 · Diabetes