Adult ; Diabetes Mellitus, Type 1 ; classification ; immunology ; Diabetes Mellitus, Type 2 ; classification ; immunology ; Humans

The review is aimed to explore the clinical and pathogenic spectrum of autoimmune diabetes including Type 1 diabetes and latent autoimmune diabetes in adults (LADA). Genetic susceptibility modifies age at onset in autoimmune diabetes. The most important genetic susceptibility to Type 1 diabetes and LADA is in the HLA region. Because of the age-related genetic factors, LADA can not be distinguished from classic Type 1 diabetes by genetics. Non-genetic factors contribute much to Type 1 diabetes, but little is known in LADA. Diabetes-associated immune process can occur in early childhood and can be predictive of an ongoing beta cell destruction. The management and prevention of LADA need to be investigated in order to define the best therapeutic strategy.
Diabetes Mellitus, Type 1 ; etiology ; genetics ; immunology ; therapy ; Humans

The importance of innate immunity in host defense is becoming clear after discovery of innate immune receptors such as Toll-like receptor or Nod-like receptor. Innate immune system plays an important role in diverse pathological situations such as autoimmune diseases. Role of innate immunity in the pathogenesis of metabolic disorders such as type 2 diabetes, metabolic syndrome or atherosclerosis that has not been previously considered as inflammatory disorders, is also being appreciated. Here, the role of innate immunity in the development of type 1 diabetes, a classical organ-specific autoimmune disease, and type 2 diabetes will be discussed, focusing on the role of specific innate immune receptors involved in these disease processes.
Animals ; Cytokines/*immunology ; Diabetes Mellitus, Type 1/*immunology ; Diabetes Mellitus, Type 2/*immunology ; Humans ; Immunity, Innate/*immunology ; Inflammasomes/*immunology ; *Models, Immunological ; Pancreas/immunology

OBJECTIVETo 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 SOURCESA 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 SELECTIONEnglish-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed.

RESULTSThe 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.

CONCLUSIONSZnT8 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.

Animals ; Autoantibodies ; immunology ; Autoantigens ; immunology ; Cation Transport Proteins ; immunology ; metabolism ; Diabetes Mellitus, Type 1 ; immunology ; metabolism ; Humans

Autoimmune diabetes is a T cell-mediated disease characterized by the autoimmune destruction of pancreatic β-cells and insulin deficiency. It is related to multiple genes. The IDDM1 locus, which lies within the human leukocyte antigen (HLA) and the IDDM2 locus, which is located to the insulin gene region, are two major genetic contributors of susceptibility. Many other loci conferring susceptibility to autoimmune diabetes are being discovered, including PTPN22, CTLA4, IL2RA and IFIH1. In this article, these loci and their possible immunologic mechanisms involved in the pathogenesis of this disease will be reviewed.
Animals ; Diabetes Mellitus, Type 1 ; genetics ; immunology ; pathology ; Genetic Predisposition to Disease ; Humans

OBJECTIVETo measure levels of cytokines including IL-1β, IL-12, IL-18 and TNF-α in children with newly diagnosed type 1 diabetes and to analyze their correlation with clinical indices such as infection and onset time.

METHODSA total of 33 children with newly diagnosed type 1 diabetes were assigned to the case group, and 27 healthy children to the control group. The case group was further divided into increased white blood cell (WBC) and normal WBC subgroups according to peripheral WBC level. The serum levels of cytokines including IL-1β, IL-12, IL-18 and TNF-α were measured by enzyme-linked immunosorbent assay. Blood pH, blood sugar, blood lactate, fructosamine, peripheral leukocytes and neutrophils and some other clinical indices were also measured.

RESULTSThe level of IL-12 in the case group was higher than in the control group (P<0.001). In the case group, the level of IL-18 was negatively correlated with onset time (r=0.413, P=0.015), the neutrophil count was positively correlated with IL-1β level (r=0.413, P=0.023) and the WBC count was positively correlated with IL-18 level (r=0.352, P=0.038). IL-1β, IL-12 and IL-18 levels in the increased WBC subgroup were higher than in the normal WBC subgroup (P<0.05 for all comparisons).

CONCLUSIONSCytokine secretion disorders of Th1 cells exist in children with type 1 diabetes. Infections may induce cytokine secretion and might contribute to the early onset of diabetes.

Adolescent ; Child ; Child, Preschool ; Cytokines ; blood ; Diabetes Mellitus, Type 1 ; immunology ; Female ; Humans ; Infant ; Male ; Th1 Cells ; immunology

Type 1 diabetes is considered as Th1 cell mediated autoimmune disease and the suppression of Th1 cells or the activation of Th2 cells has been regarded as a plausible immunologic intervention for the prevention of type 1 diabetogenesis in a rodent model. CpG ODN is an immunostimulatory sequence primarily present in bacterial DNA, viral DNA and BCG. CpG ODN is conventionally classified as a Th1 cell activator, which has been clinically applied to cancer, allergy and infectious disease. Recently, there was a promising report of that CpG ODN administration suppressed the development of type 1 diabetes in NOD mice by inducing Th2 cell mediated cytokine. However, the antidiabetogenic effect of CpG ODN on NOD mice is controversial. Thus, two studies were serially undertaken with various kinds of CpG motif to find a more optimal sequence and administration method. In the first study, CpG ODN was vaccinated four times and pancreatic inflammation and the quantity of serum insulin subsequently evaluated. In the second study, the amounts of IFN gamma and IL-4 in sera were measured as representative cytokines of Th1 and Th2 cells, respectively. As a result, vaccination or continuous injection of CpG ODN failed to show a preventive effect on type 1 diabetogenesis in NOD mice. Structural differences of CpG ODN also had no affect on the result. CpG ODN also consistently showed affect on the pancreatic pathology. The productions of IFN gamma and IL-4 were detected only in the K and D type CpG ODN administration groups. Comparison of the two cytokines leads to the conclusion that CpG ODN generated a Th1-weighted response in both study groups. It was assumed that CpG ODN failed to produce Th2-weighted cytokine milieu, which can overcome the genetically determined phenotype of NOD mice. Given these results, it was concluded that the immunotherapeutic application of CpG ODN on Type 1 diabetes had clear limitations.
Animals ; DNA/*pharmacology ; Diabetes Mellitus, Type 1/*immunology/*prevention & control ; Female ; Mice ; Mice, Inbred NOD ; Th1 Cells/*immunology

OBJECTIVETo investigate the prevalence of metabolic syndrome (MS) in latent autoimmune diabetes in adults (LADA) and to study the positivity of glutamic acid decarboxylase autoantibody (GADA) in diabetic patients with MS.

METHODSSera of 598 patients with an initial diagnosis of type 2 diabetes (T2DM) were screened for GADA with radioligand assay. These patients were divided into LADA and T2DM groups according to the titers of GADA to compare the prevalence of MS; the proportions of LADA in diabetic patients with and without MS were studied. We also compared the clinical characteristics of LADA patients with and without MS.

RESULTSAbout 23.7% of the LADA patients had MS. In patients with MS, the prevalence of LADA was 10.0%, of which approximately 95% had low GADA titers, that was, belonging to LADA-type 2. Compared with LADA patients with MS, LADA without MS were similar to classical type 1 diabetes and had features of low body weight, tendency to develop ketosis and impaired islet cell function.

CONCLUSIONAbout 23.7% patients with MS are found in LADA patients. The GADA levels in LADA patients with and without MS are significantly different, which may need different therapeutic strategies.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Autoantibodies ; immunology ; China ; epidemiology ; Diabetes Mellitus, Type 1 ; epidemiology ; immunology ; Diabetes Mellitus, Type 2 ; immunology ; Female ; Glutamate Decarboxylase ; immunology ; Humans ; Male ; Metabolic Syndrome ; epidemiology ; immunology ; Middle Aged ; Prevalence

OBJECTIVETo compare the clinical characteristics between type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA) with different titers of glutamic acid decarboxylase autoantibody (GADA) and to define the two distinct subtypes of LADA.

METHODSSera of 750 patients with an initial diagnosis of T2DM from central south of China were screened for GADA using a radioligand assay. The distribution and frequency of GADA levels were described. Two hundred and ninety-five patients were divided into the T2DM group (n = 233) and the LADA group (n = 62) to compare the age of onset, body mass index, HbA(1c), C-peptide, hypertension, dyslipidemia and chronic diabetic complications. Furthermore, LADA patients with different GADA titers were subdivided to analyze the same indexes as the above.

RESULTSThe prevalence of LADA (defined as GADA > or = 0.05, namely GADA positive) was 9.7% in the 750 initially diagnosed type 2 diabetic patients. Compared with T2DM, LADA patients were younger at their ages of onset, had lower C-peptide and body mass index, and also had less cases with hypertension and with dyslipidemia. However, only patients with high titer of GADA had poorer beta cell functions and less diabetic complications compared to T2DM and low GADA titer of LADA patients. Patients with low GADA titer were similar to T2DM patients, except that they were prone to develop ketosis more frequently.

CONCLUSIONSTwo clinically distinct subtypes of LADA can be identified by GADA levels in patients initially-diagnosed as type 2 diabetes. Patients with high titer of GADA (GADA > or = 0.5) subsequently develop more insulin dependency, which are classified as LADA-type 1; while those with lower GADA titer (0.05 < or = GADA < 0.5) and having clinical and metabolic phenotypes of type 2 diabetes are classified as LADA-type 2.

Adult ; Aged ; Aged, 80 and over ; Autoantibodies ; analysis ; Autoimmune Diseases ; classification ; immunology ; Diabetes Mellitus, Type 1 ; classification ; immunology ; Diabetes Mellitus, Type 2 ; classification ; immunology ; Female ; Glutamate Decarboxylase ; immunology ; Humans ; Male ; Middle Aged

INTRODUCTIONWith advancement in the understanding of the pathogenesis underlying diabetes mellitus (DM), the boundary between type 1 and type 2 DM (T1DM and T2DM) does not seem to be as clear cut as previously thought. This study was designed to test the possibility of overlap between the spectra of immune-mediated DM and insulin resistance.

METHODSTo test for the possibility of overlap, we looked for autoantibodies typical of T1DM in patients with classical T2DM, and insulin resistance in patients with T1DM. Autoantibodies against islet cell antigen, glutamic acid decarboxylase-65 and insulinoma-associated antigen-2 were tested in 82 patients with T2DM and 27 patients with T1DM. The patients had been diagnosed on clinical criteria using standard laboratory techniques. Clinical parameters of diagnostic importance were noted, and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using fasting insulin and fasting blood glucose ratio.

RESULTSAutoantibodies against one or more beta cell antigens were detected in 12.19% of patients clinically diagnosed to have T2DM, and insulin resistance (HOMA-IR > 2.5) was diagnosed in 37.03% of patients with T1DM. It was not possible to identify any combination of clinical or biochemical markers that could predict autoantibody positivity in T2DM patients. T1DM patients with insulin resistance had a significantly higher body mass index than their insulin-sensitive counterparts (p = 0.02).

CONCLUSIONAutoantibodies against beta cell antigens are detectable in insulin-resistant T2DM patients, and insulin resistance may be present in relatively overweight T1DM patients. No differentiating clinical features that might predict autoantibody positivity in T2DM patients were found.

Adolescent ; Adult ; Autoantibodies ; blood ; immunology ; Biomarkers ; blood ; Blood Glucose ; analysis ; Body Mass Index ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1 ; classification ; immunology ; Diabetes Mellitus, Type 2 ; classification ; immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Insulin Resistance ; immunology ; Male