Zhiguo Xie

Persistence of glutamic acid decarboxylase antibody (GADA) is associated with clinical characteristics of latent autoimmune diabetes in adults: a prospective study with 3-year follow-up.

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.

HLA Genetic Discrepancy Between Latent Autoimmune Diabetes in Adults and Type 1 Diabetes: LADA China Study No. 6

CONTEXT The discrepancies in terms of human leukocyte antigen (HLA)-DRB1-DQA1-DQB1 conferred risks between latent autoimmune diabetes in adults (LADA) and type 1 diabetes (T1D) patients remained almost completely unknown. The goal of the current study is to determine and compare HLA-conferred risks between LADA and T1D. DESIGN A case-control study was conducted in a representative Chinese data set containing 520 T1D patients, 562 LADA patients, and 1065 controls. The frequencies and odds ratios for HLA susceptible haplotypes and genotypes and for arginine at residue 52 in the DQ-α chain or aspartic acid at residue 57 in the DQ-β chain were analyzed. RESULTS DRB1*0405-DQA1*03-DQB1*0401 and DRB1*0901-DQA1*03-DQB1*0303 are the major LADA susceptible haplotypes, which also confer comparable risks for T1D (odds ratio 2.02 vs 2.20 and 1.61 vs 2.30, respectively). The strongly associated T1D haplotype DRB1*0301-DQA1*05-DQB1*0201 is also associated with LADA but confers only half of the T1D risk (odds ratio 2.65 vs 4.84). Interestingly, the most susceptible T1D haplotypes, DRB1*0901-DQA1*05-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0201, and DRB1*0301-DQA1*03-DQB1*0303, are not associated with LADA. Genotypes for DR3/DR3, DR3/DR9, and DR9/DR9 are highly associated with T1D susceptibility, whereas only DR9/DR9 confers risk for LADA. DR3/DR3 is the high-risk genotype in Chinese T1D patients, which manifests similar risk as the DR3/DR4 genotype in Caucasians but with a lower frequency. DR9/DR9 is the high risk LADA genotype in Chinese. Alleles with DQ-α arginine at residue 52-positive, DQ-β aspartic acid at residue 57-negative, and their combination formed in cis or trans confer susceptibility to T1D but not to LADA. CONCLUSION Our results suggest that LADA risk conferred by HLA-DRB1-DQA1-DQB1 loci in Chinese differs significantly from that of T1D risk. This information would be useful for classifying Asian LADA patients, which should provides novel insight into the understanding of its pathoetiology as well.

Effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in mice.

OBJECTIVE To investigate the effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in C57BL/6 mice. METHODS Four-week-old C57BL/6 mice were allocated into normal diet group,high-fat diet group,and high-glucose diet group according to the random number table until 20 weeks old. Body weight,epididymal adipose tissue weight,blood leptin,fat infiltration in liver,M1/M2 macrophage subtypes,and monocyte chemoattractant protein-1 mRNA in epididymal adipose tissues were measured. RESULTS Compared with normal diet group,body weight,epididymal adipose tissue weight,and leptin concentration in high fat diet group at 20 weeks were significantly increased (P < 0.05),and oil red O staining showed more prominent adipocyte infiltration in liver in high-fat diet group than those in normal diet and high-glucose diet group. However,no apparent differences were seen in high-glucose diet group at 20 weeks in terms of body weight,epididymal adipose tissue weight and leptin concentration. In high-fat diet group,the macrophages infiltration in epididymal adipose tissue increased with time and the percentage of M2 macrophage decreased in high-fat diet group than that in high-glucose diet group(P<0.05). Compared with normal diet group,monocyte chemoattractant protein-1 mRNA expression increased significantly in high-fat diet group(P<0.05). In high-glucose group,however,no significant differences were discerned (P > 0.05). CONCLUSION High-fat diet,rather than 60% high glucose diet,will lead to obesity and macrophage infiltration in adipose tissues.

Epigenetic regulation of Toll-like receptors and its roles in type 1 diabetes

The immune system can be divided into adaptive immunity and innate immunity. Adaptive immunity has been confirmed to be involved in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, the role of innate immunity in T1D has only been studied recently. T1D is caused by selective autoimmune destruction of pancreatic islet β cells. A series of studies have suggested that TLRs play a critical role in the pathogenesis of T1D. Aberrant TLR signaling will change immune homeostasis and result in immunopathological conditions such as endotoxin shock and autoimmune responses. Thus, TLR signaling pathways are supposed to be strictly and finely regulated. Epigenetics has recently been proven to be a new regulator of TLR expression. DNA methylation, histone modification, and microRNAs are the three main epigenetic modifications. This review will mainly focus on these epigenetic mechanisms of regulation of TLRs and the role of TLRs in the pathogenesis of T1D.

Elevated histone H3 acetylation is associated with genes involved in T lymphocyte activation and glutamate decarboxylase antibody production in patients with type 1 diabetes

Genetic and epigenetic mechanisms have been implicated in the pathogenesis of type 1 diabetes, and histone acetylation is an epigenetic modification pattern that activates gene transcription. However, the genome‐wide histone H3 acetylation in new‐onset type 1 diabetes patients has not been well described. Accordingly, we aimed to unveil the genome‐wide promoter acetylation profile in CD4+ T lymphocytes from type 1 diabetes patients, especially for those who are glutamate decarboxylase antibody‐positive.

Fulminant type 1 diabetes caused by peginterferon α-2a therapy in hepatitis C: 丙型肝炎患者使用聚乙二醇干扰素α-2a治疗后导致的暴发性1型糖尿病

Interferon therapy can increase the risk of type 1 diabetes (T1D) in patients with hepatitis C. Fulminant T1D (FT1D) is a novel subtype of T1D characterized by extremely rapid progression. However, the relationship between interferon therapy and FT1D remains to be determined. Herein, we report a case of FT1D in a 51-year-old Chinese woman receiving peginterferon α-2a therapy for hepatitis C. This study was approved by the Human Ethics Committee of Central South University and was performed in accordance with ethical standards. Informed consent was obtained from the patient. The patient, with no family or personal history of diabetes, was admitted to the emergency room 1 year after initiation of peginterferon α-2a treatment with a complaint of repeated vomiting for 1 day. Laboratory tests identified severe diabetic ketoacidosis (blood glucose 25.7 mmol/L, pH 7.21, and ketones 6.11 mmol/L); C peptide was undetectable (<5.5 pmol/L) and the patient’s HbA1c level was 6.7% (50 mmol/mol). These findings met the main diagnostic criteria for FT1D proposed by the Japan Diabetes Society. Meanwhile, other immune disorders were identified, specifically: (i) the patient was positive for glutamic acid decarboxylase autoantibody (GADA) and islet antigen 2 autoantibody (IA2A); (ii) hypothyroidism due to Hashimoto thyroiditis with significantly elevated thyroid peroxidase antibody; (iii) megaloblastic anemia (hemoglobin [Hb] 65 g/L, mean corpuscular volume 117.9 fL, mean corpuscular Hb 319 g/L); and (iv) low complement 3 (C3) and complement 4 (C4) levels. Peginterferon α-2a was withdrawn and the patient was reviewed at 3monthly intervals (Table 1). The patient recovered from hypothyroidism and megaloblastic anemia without longterm medication gradually. However, C peptide levels were persistently low. Fortunately, hepatitis C virus (HCV) RNA and liver function were normal during the follow-up period. Human leukocyte antigen (HLA) sequencing identified HLA*DQA1 03, DQB1*0303, and DRB1*0901 alleles. Fulminant T1D is a rare form of T1D that is caused, in particular, by peginterferon α-2a in hepatitis C. A nationwide survey in Japan found that the prevalence of FT1D developing during or shortly after interferon therapy in T1D was 5.5% (5/91). However, the clinical features of FT1D are much worse than classical T1D, such as extremely severe onset, rapid progress, and poor prognosis. So, it is imperative that clinicians identify FT1D and provide treatment. In the present case, the patient was found to be positive for GADA, and HLA sequencing revealed the presence of DQB1*0303 and DRB1*0901 alleles. A national survey in Japan found that frequencies of the DRB1*04:05– DQB1*04:01 and DRB1*09:01–DQB1*03:03 haplotypes were significantly higher in subjects positive for GADA than in control subjects (32.6% vs 14.2% and 25.4% vs 13.7%, respectively). However, in FT1D patients with GADA, the frequency of DRB1*09:01-DQB1*03:03 only (and not DRB1*04:05-DQB1*04:01) was significantly higher than in control subjects (44.0% vs 13.7%; Pcorrected < 0.05, odds ratio 5.0). Therefore, we speculate that the genetic background of HLA DRB1*09:01–DQB1*03:03 may contribute to the production of GADA in some FT1D patients. In addition to autoimmune FT1D, many other wellrecognized negative effects of peginterferon α-2a therapy were found in the present patient. Immediate withdrawal of peginterferon α-2a and proper treatment enabled the patient to recover from hypothyroidism and megaloblastic anemia, but not FT1D. Because of the severity of F1TD and its poor prognosis, we call for extensive assessment and monitoring of glucose tolerance in chronic hepatitis C patients on interferon therapy.

Severe insulin resistance due to insulin antibodies: 胰岛素抗体引起的严重胰岛素抵抗

Individual reports have discussed cases of severe insulin resistance (IR) secondary to insulin antibodies (IAs) 1, 2 , and several methods of treatment have shown some success 3-5 . Here, we reported a 58-year-old Chinese woman of a 14-year history of type 2 diabetes with severe diabetic ketoacidosis by IAs. Informed consent was obtained from the patient.

Identification of a distinct phenotype of elderly latent autoimmune diabetes in adults: LADA China Study 8

Latent autoimmune diabetes in adults (LADA) exhibits significant clinical heterogeneity, but the underlying causes remain unclear. The aim of this study was to investigate whether age of onset of LADA contributes to the observed clinical heterogeneity by comparing the clinical, metabolic, and immunogenetic characteristics between elderly and young LADA patients.

Incidence and trend of type 1 diabetes and the underlying environmental determinants

A wealth of epidemiological studies concerning the distribution of type 1 diabetes (T1D) around the world have pointed to the appreciable variation in the incidence of T1D among disparate age groups, ethnicities, and geographical locations. On the whole, the incidence of childhood T1D has been on the rise, and a plausible inverse relationship between the initial incidence rate and the following annual increase in incidence has been raised. Countries that used to exhibit lower incidences tend to have steep annual increase whereas those with already‐established high incidences are more likely to show a modest increase or even stabilization in T1D incidence. Environmental agents considered responsible for the current evolving pattern of T1D incidence will be detailed, mainly including the increasing prevalence of childhood obesity, viral infections in a chronic manner, maternal‐child interaction such as breastfeeding, and latitude‐ultraviolet B‐vitamin D pathway. Certain rationale has been put forward in an attempt to explain the potential association between environmental agents and development of T1D. For instance, accelerator hypothesis regards insulin resistance as the promoter of earlier disease onset in obese children whereas the negative correlation of microbial infections in background populations with incidence of T1D represents the basic component of the hygiene hypothesis. Further investigations are still warranted to verify these theories across multiple ethnic groups and to identify additional contributors to the variation in T1D incidence.

Changes of Regulatory T Cells in the Early Stage of Obesity Mice and Their Modulation on Macrophage Subtypes in Visceral Adipose Tissue.

Objective To investigate the changes of regulatory T cells (Tregs) and whether Tregs can modulate the distribution of macrophage subtypes in visceral adipose tissue in the early stage of obesity.Methods After C57BL/6 mice obesity models were successfully established,metabolic parameters and numbers of Tregs and M1/M2 macrophage were measured at 4,10,and 20 weeks.The changes of metabolic parameters and adipose tissue inflammation in obesity mice after rapamycin intervention were evaluated. Results The early-stage obesity models were successfully established.Compared with normal diet mice,high fat diet mice had significantly higher epididymal adipose tissue mass and serum leptin levels(P<0.05).However,there was no statistical difference in blood glucose and insulin levels between these two groups(All P>0.05). Macrophages infiltration in adipose tissue in high fat diet mice gradually increased with time,coincident with decrease in Treg numbers. Increased numbers of Treg,improved metabolic parameters,and decreased ratio of M1/M2 can be seen after rapamycin intervention in mice.Conclusion The decrease of Tregs in the early stage of obesity may contribute to abnormal distribution of macrophage subtypes in visceral adipose.