The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Zhiguang Zhou - One of the best experts on this subject based on the ideXlab platform.
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neutrophil elastase triggers the development of Autoimmune Diabetes by exacerbating innate immune responses in pancreatic islets of non obese diabetic mice
Clinical Science, 2020Co-Authors: Lingling Shu, L Zhong, Yang Xiao, Yang Liu, Xue Jiang, Tao Tang, Rubylaichong Hoo, Zhiguang ZhouAbstract:Type 1 Diabetes is an Autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the Autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 Diabetes. The present study aims to investigate the impact of NE inhibition on development of Autoimmune Diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and Autoimmune Diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated Autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of Autoimmune Diabetes.
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altered peripheral b lymphocyte subsets in type 1 Diabetes and latent Autoimmune Diabetes in adults
Diabetes Care, 2016Co-Authors: Chao Deng, Gan Huang, Yufei Xiang, Tingting Tan, Zhihui Ren, Chuqing Cao, Li Wen, Zhiguang ZhouAbstract: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 negatively correlated with hemoglobin A 1c . 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.
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dipeptidyl peptidase 4 inhibitor sitagliptin maintains β cell function in patients with recent onset latent Autoimmune Diabetes in adults one year prospective study
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Yunjuan Zhao, Gan Huang, Yufei Xiang, David R G Leslie, Lin Yang, Lingjiao Liu, Zhaofeng Long, Xiangbing Wang, Zhiguang ZhouAbstract: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: The objective of the study was to investigate the effects of the 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/d 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, glycosylated hemoglobin, and C-peptide levels. Results: There were no dif...
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frequency immunogenetics and clinical characteristics of latent Autoimmune Diabetes in china lada china study a nationwide multicenter clinic based cross sectional study
Diabetes, 2013Co-Authors: Zhiguang Zhou, Gan Huang, Yufei Xiang, Lin Yang, Weiping Jia, Guang Ning, Jian Lin, Zhenqi Liu, William Hagopian, David R G LeslieAbstract: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 ( 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.
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protective effects of 1 α hydroxyvitamin d3 on residual β cell function in patients with adult onset latent Autoimmune Diabetes lada
Diabetes-metabolism Research and Reviews, 2009Co-Authors: Lan Liao, Gan Huang, Xiangbing Wang, Jian Lin, Xiang Yan, Minxiang Lei, Zhiguang ZhouAbstract:Background Previous in vitro and in vivo studies have demonstrated that vitamin D could prevent pancreatic β-cell destruction and reduce the incidence of Autoimmune Diabetes. In children with type 1 Diabetes, vitamin D treatment produces moderate protective effects on residual β-cell function and has proven to be safe. Therefore, we hypothesized that vitamin D might have protective effects on β-cell function in patients with latent Autoimmune Diabetes in adults (LADA), a form of slowly progressive Autoimmune type 1 Diabetes. Methods Thirty-five patients with LADA were randomly assigned to receive subcutaneous insulin alone (n = 18) or insulin plus 1-α-hydroxyvitamin D3 (1-α(OH)D3; 0.5 µg per day) (n = 17) for 1 year. Plasma C-peptide levels in fasting state (FCP) and 2 h after 75-g glucose load (PCP) were measured every 6 months with radioimmunoassay. Results Both FCP and PCP levels stayed steady in the insulin plus 1-α(OH)D3 group, while FCP decreased in insulin-alone group (P = 0.006) during the 12-month intervention. Seventy percent of patients treated with 1-α(OH)D3 maintained or increased their FCP concentrations after 1 year of treatment, while only 22% of patients treated with insulin alone maintained stable FCP levels (P < 0.01). Further analysis on LADA subgroups with different durations of Diabetes demonstrated that islet β-cell function was better preserved (as reflected by significantly higher FCP and PCP levels) in the 1-α(OH)D3 plus insulin group only in patients with Diabetes duration no longer than 1 year. No severe side effects were observed in any group. Conclusion Our data suggest that 1-alpha(OH)D3 plus insulin therapy can preserve pancreatic β-cell function in patients with LADA. Copyright © 2009 John Wiley & Sons, Ltd.
Ernesto Maddaloni - One of the best experts on this subject based on the ideXlab platform.
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time varying risk of microvascular complications in latent Autoimmune Diabetes of adulthood compared with type 2 Diabetes in adults a post hoc analysis of the uk prospective Diabetes study 30 year follow up data ukpds 86
The Lancet Diabetes & Endocrinology, 2020Co-Authors: Raffaella Buzzetti, Ernesto Maddaloni, Ruth L Coleman, Olorunsola F Agbaje, R R HolmanAbstract:Summary Background Latent Autoimmune Diabetes of adulthood (LADA) differs in clinical features from type 2 Diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their Diabetes autoimmunity status. Methods We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with Diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent Autoimmune Diabetes, and those who tested negative for all autoantibodies were identified as having type 2 Diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent Autoimmune Diabetes and those with type 2 Diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. Findings Among the 5028 participants included, 564 had latent Autoimmune Diabetes and 4464 had type 2 Diabetes. After median 17·3 years (IQR 12·6–20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4–18·7) per 1000 person-years in latent Autoimmune Diabetes and 14·2 (13·3–15·2) per 1000 person-years in type 2 Diabetes. Adults with latent Autoimmune Diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 Diabetes (adjusted HR 0·45 [95% CI 0·30–0·68], p Interpretation At Diabetes onset, adults with latent Autoimmune Diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 Diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent Autoimmune Diabetes. Funding European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).
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adult onset Autoimmune Diabetes current knowledge and implications for management
Nature Reviews Endocrinology, 2017Co-Authors: Raffaella Buzzetti, Simona Zampetti, Ernesto MaddaloniAbstract:Adult-onset Autoimmune Diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive Autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 Diabetes mellitus (T1DM). The majority of patients with adult-onset Autoimmune Diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent Autoimmune Diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset Autoimmune Diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset Autoimmune Diabetes and highlight the similarities and differences with classic T1DM and type 2 Diabetes mellitus.
Raffaella Buzzetti - One of the best experts on this subject based on the ideXlab platform.
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time varying risk of microvascular complications in latent Autoimmune Diabetes of adulthood compared with type 2 Diabetes in adults a post hoc analysis of the uk prospective Diabetes study 30 year follow up data ukpds 86
The Lancet Diabetes & Endocrinology, 2020Co-Authors: Raffaella Buzzetti, Ernesto Maddaloni, Ruth L Coleman, Olorunsola F Agbaje, R R HolmanAbstract:Summary Background Latent Autoimmune Diabetes of adulthood (LADA) differs in clinical features from type 2 Diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their Diabetes autoimmunity status. Methods We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with Diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent Autoimmune Diabetes, and those who tested negative for all autoantibodies were identified as having type 2 Diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent Autoimmune Diabetes and those with type 2 Diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. Findings Among the 5028 participants included, 564 had latent Autoimmune Diabetes and 4464 had type 2 Diabetes. After median 17·3 years (IQR 12·6–20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4–18·7) per 1000 person-years in latent Autoimmune Diabetes and 14·2 (13·3–15·2) per 1000 person-years in type 2 Diabetes. Adults with latent Autoimmune Diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 Diabetes (adjusted HR 0·45 [95% CI 0·30–0·68], p Interpretation At Diabetes onset, adults with latent Autoimmune Diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 Diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent Autoimmune Diabetes. Funding European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).
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adult onset Autoimmune Diabetes current knowledge and implications for management
Nature Reviews Endocrinology, 2017Co-Authors: Raffaella Buzzetti, Simona Zampetti, Ernesto MaddaloniAbstract:Adult-onset Autoimmune Diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive Autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 Diabetes mellitus (T1DM). The majority of patients with adult-onset Autoimmune Diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent Autoimmune Diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset Autoimmune Diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset Autoimmune Diabetes and highlight the similarities and differences with classic T1DM and type 2 Diabetes mellitus.
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adult onset Autoimmune Diabetes in europe is prevalent with a broad clinical phenotype action lada 7
Diabetes Care, 2013Co-Authors: Mohammed I Hawa, Raffaella Buzzetti, H Kolb, Nanette C Schloot, Huriya Beyan, Stavroula A Paschou, Didac Mauricio, Alberto De Leiva, Knud Bonnet Yderstraede, Henning BeckneilsenAbstract:OBJECTIVE Specific autoantibodies characterize type 1 Diabetes in childhood but are also found in adult-onset Diabetes, even when initially non–insulin requiring, e.g., with latent Autoimmune Diabetes (LADA). We aimed to characterize adult-onset Autoimmune Diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female ( P 200 World Health Organization IU) ( n = 403) compared with low ( n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) ( P CONCLUSIONS Adult-onset Autoimmune Diabetes emerges as a prevalent form of Autoimmune Diabetes. Our results indicate that adult-onset Autoimmune Diabetes in Europe encompasses type 1 Diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset Autoimmune Diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 Diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.
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β cell protection and therapy for latent Autoimmune Diabetes in adults
Diabetes Care, 2009Co-Authors: Simona Cernea, Raffaella Buzzetti, Paolo PozzilliAbstract:Latent Autoimmune Diabetes in adults (LADA) is a term used to describe a form of Autoimmune Diabetes that resembles type 1 Diabetes, but has a later onset and slower progression toward an absolute insulin requirement. Controversies have been surrounding this concept and several attempts have been made to better characterize and classify it. But LADA still remains poorly understood and defined (1). It was even debated whether LADA exists as a distinct disease entity or it just represents the end of a wide spectrum of heterogeneous immune-mediated Diabetes (2,3). Uncertainties concern almost all aspects of this disease, including the nomenclature, diagnostic criteria, epidemiology, natural history, and pathogenesis with genetic, metabolical, and immunological aspects. As a consequence, there is no clear management strategy for it, in terms of therapy and prevention. An ideal therapeutic approach would aim not only at obtaining a good metabolic control, but also at protecting residual β-cell mass and function. Even though ∼10% of adults with presumed type 2 Diabetes at diagnosis in fact have LADA, only a few studies so far have evaluated therapeutic interventions for LADA, using a hypoglycemic or an immunomodulatory agent. Obviously, an important impediment in establishing adequate and effective management strategies is the lack of a good understanding of the disease development and of a clear definition. Difficulties reside from the fact that LADA has features of an Autoimmune disease (mainly presence of autoantibodies at onset), with many genetic, immune, and metabolic features of type 1 Diabetes, but also shares some clinical, anthropometric, and metabolic traits with type 2 Diabetes (Table 1) (2,4). As a matter of fact, LADA was first identified in a subset of phenotypic type 2 Diabetes individuals who were positive for islet cells antibodies (ICAs), failed sulfonylurea therapy, and needed insulin replacement earlier than …
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the protein tyrosine phosphatase nonreceptor 22 ptpn22 is associated with high gad antibody titer in latent Autoimmune Diabetes in adults non insulin requiring Autoimmune Diabetes nirad study 3
Diabetes Care, 2008Co-Authors: Antonio Petrone, Concetta Suraci, Marco Capizzi, Andrea Giaccari, Claudio Tiberti, Paolo Pozzilli, Emanuele Bosi, Efisio Cossu, Alberto Falorni, Raffaella BuzzettiAbstract:OBJECTIVE —We previously demonstrated the presence of two different populations among individuals with adult-onset Autoimmune Diabetes: those having either a high titer or a low titer of antibodies to GAD (GADAs). Protein tyrosine phosphatase nonreceptor type 22 ( PTPN22 ) has been identified as a new susceptibility gene for type 1 Diabetes and other Autoimmune diseases. The aim of the present study was to evaluate whether the phenotypic heterogeneity of adult-onset Autoimmune Diabetes based on the GADA titer is associated with the PTPN22 C1858T polymorphism. RESEARCH DESIGN AND METHODS —Analysis for the C1858T polymorphism using the TaqMan assay was performed in 250 subjects with adult-onset Autoimmune Diabetes, divided into two subgroups with low (≤32 arbitrary units) or high (>32 arbitrary units) GADA titers and 450 subjects with classic type 2 Diabetes (from the Non Insulin Requiring Autoimmune Diabetes [NIRAD] Study cohort of 5,330 subjects with adult-onset Diabetes) and in 558 subjects with juvenile-onset type 1 Diabetes and 545 normoglycemic subjects. RESULTS —Genotype, allele, and phenotype distributions of the PTPN22 C1858T variant revealed similar frequencies in Autoimmune Diabetes with high GADA titer and juvenile-onset type 1 Diabetes. An increase in TT and CT genotypes was observed in individuals with a high GADA titer compared with a low GADA titer, those with type 2 Diabetes, and control subjects ( P PTPN22 1858T allele and phenotype frequencies were increased in high GADA titer compared with a low GADA titer, type 2 diabetic, and control subjects ( P CONCLUSIONS —In adult-onset Autoimmune Diabetes, the PTPN22 1858T variant is associated only with a high GADA titer, providing evidence of a genetic background to clinical heterogeneity identified by GADA titer.
Gan Huang - One of the best experts on this subject based on the ideXlab platform.
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altered peripheral b lymphocyte subsets in type 1 Diabetes and latent Autoimmune Diabetes in adults
Diabetes Care, 2016Co-Authors: Chao Deng, Gan Huang, Yufei Xiang, Tingting Tan, Zhihui Ren, Chuqing Cao, Li Wen, Zhiguang ZhouAbstract: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 negatively correlated with hemoglobin A 1c . 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.
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dipeptidyl peptidase 4 inhibitor sitagliptin maintains β cell function in patients with recent onset latent Autoimmune Diabetes in adults one year prospective study
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Yunjuan Zhao, Gan Huang, Yufei Xiang, David R G Leslie, Lin Yang, Lingjiao Liu, Zhaofeng Long, Xiangbing Wang, Zhiguang ZhouAbstract: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: The objective of the study was to investigate the effects of the 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/d 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, glycosylated hemoglobin, and C-peptide levels. Results: There were no dif...
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frequency immunogenetics and clinical characteristics of latent Autoimmune Diabetes in china lada china study a nationwide multicenter clinic based cross sectional study
Diabetes, 2013Co-Authors: Zhiguang Zhou, Gan Huang, Yufei Xiang, Lin Yang, Weiping Jia, Guang Ning, Jian Lin, Zhenqi Liu, William Hagopian, David R G LeslieAbstract: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 ( 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.
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protective effects of 1 α hydroxyvitamin d3 on residual β cell function in patients with adult onset latent Autoimmune Diabetes lada
Diabetes-metabolism Research and Reviews, 2009Co-Authors: Lan Liao, Gan Huang, Xiangbing Wang, Jian Lin, Xiang Yan, Minxiang Lei, Zhiguang ZhouAbstract:Background Previous in vitro and in vivo studies have demonstrated that vitamin D could prevent pancreatic β-cell destruction and reduce the incidence of Autoimmune Diabetes. In children with type 1 Diabetes, vitamin D treatment produces moderate protective effects on residual β-cell function and has proven to be safe. Therefore, we hypothesized that vitamin D might have protective effects on β-cell function in patients with latent Autoimmune Diabetes in adults (LADA), a form of slowly progressive Autoimmune type 1 Diabetes. Methods Thirty-five patients with LADA were randomly assigned to receive subcutaneous insulin alone (n = 18) or insulin plus 1-α-hydroxyvitamin D3 (1-α(OH)D3; 0.5 µg per day) (n = 17) for 1 year. Plasma C-peptide levels in fasting state (FCP) and 2 h after 75-g glucose load (PCP) were measured every 6 months with radioimmunoassay. Results Both FCP and PCP levels stayed steady in the insulin plus 1-α(OH)D3 group, while FCP decreased in insulin-alone group (P = 0.006) during the 12-month intervention. Seventy percent of patients treated with 1-α(OH)D3 maintained or increased their FCP concentrations after 1 year of treatment, while only 22% of patients treated with insulin alone maintained stable FCP levels (P < 0.01). Further analysis on LADA subgroups with different durations of Diabetes demonstrated that islet β-cell function was better preserved (as reflected by significantly higher FCP and PCP levels) in the 1-α(OH)D3 plus insulin group only in patients with Diabetes duration no longer than 1 year. No severe side effects were observed in any group. Conclusion Our data suggest that 1-alpha(OH)D3 plus insulin therapy can preserve pancreatic β-cell function in patients with LADA. Copyright © 2009 John Wiley & Sons, Ltd.
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optimal cutoff point of glutamate decarboxylase antibody titers in differentiating two subtypes of adult onset latent Autoimmune Diabetes
Annals of the New York Academy of Sciences, 2004Co-Authors: Xiayu Li, Gan Huang, Liting Yang, Zhiguang Zhou, Xiang Chen, Joseph WangAbstract:: The optimal cutoff point of glutamate decarboxylase antibody (GAD-Ab) titers for differentiating two latent Autoimmune Diabetes (LADA) subtypes remains unclear. One hundred and forty-five GAD-Ab-positive patients screened from phenotypic type 2 Diabetes were diagnosed as LADA. The clinical features were compared among LADA patients with different GAD-Ab titers. The receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic value of GAD-Ab titers and to define the optimal cutoff point. The heterogeneity of clinical features in LADA could be discriminated by five GAD-Ab titers, with maximal differences at the titer of 175 U/mL. The ROC curve analysis showed that the optimal cutoff point for discriminating two LADA subtypes was at the titer of 175 U/mL, with sensitivity and specificity of 54.5% and 92.1%, respectively. These findings demonstrated that the two clinically distinct subtypes of LADA can be optimally discriminated by the GAD-Ab titers.
Danny Zipris - One of the best experts on this subject based on the ideXlab platform.
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brief dexamethasone treatment during acute infection prevents virus induced Autoimmune Diabetes
Clinical Immunology, 2010Co-Authors: Pilar Londono, Akiko Komura, Naoko Hara, Danny ZiprisAbstract:Abstract We used the LEW1.WR1 rat to test the hypothesis that Kilham rat virus-induced innate immune activation is involved in the mechanism of Autoimmune Diabetes. Animals were treated with dexamethasone, an anti-inflammatory glucocorticoid, beginning on the day of infection. Administering dexamethasone on five consecutive days completely blocked the disease. Strikingly, a single dose of dexamethasone was sufficient to prevent islet destruction. Dexamethasone downmodulated inflammation and restored normal ratios between CD8+ and CD4+CD25+Foxp3+ cells in the spleen. Finally, dexamethasone therapy lowered the frequency of splenic anti-virus CD8+ T cells, but did not interfere with the ability of the host to generate anti-KRV antibodies and eliminate the virus from the spleen. Our data demonstrate a strong association between early virus-induced proinflammatory responses and islet destruction and raise the possibility that targeting innate immune pathways in the early stages of Diabetes may be a useful strategy for disease prevention.
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tlr9 signaling pathways are involved in kilham rat virus induced Autoimmune Diabetes in the biobreeding Diabetes resistant rat
Journal of Immunology, 2007Co-Authors: Danny Zipris, Egil Lien, Anjali Nair, Dale L Greiner, John P Mordes, Aldo A RossiniAbstract:Viral infections are associated epidemiologically with the expression of type 1 Diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in Diabetes, we used a model of viral induction of Autoimmune Diabetes in genetically susceptible biobreeding Diabetes-resistant (BBDR) rats. BBDR rats do not develop Diabetes in viral-Ab-free environments, but ∼25% of animals infected with the parvovirus Kilham rat virus (KRV) develop Autoimmune Diabetes via a mechanism that does not involve β cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-α. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-κB. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of Diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and Autoimmune Diabetes in the BBDR rat.
