Levels Of Insulin Autoantibodies Research Articles

Metabolically inactive insulin analogue does not prevent autoimmune diabetes in NOD mice.

Insulin is widely considered to be a driver antigen in type 1 diabetes in humans and in mouse models of the disease. Therefore, insulin or insulin analogues are candidates for tolerogenic drugs to prevent disease onset in individuals with risk of diabetes. Previous experiments have shown that autoimmune diabetes can be prevented in NOD mice by repeated doses of insulin administered via an oral, nasal or parenteral route, but clinical trials in humans have not succeeded. The hypoglycaemic activity of insulin is dose-limiting in clinical studies attempting tolerance and disease prevention. Here, we aimed to investigate the therapeutic potential of metabolically inactive insulin analogue (MII) in NOD mice. The tolerogenic potential of MII to prevent autoimmune diabetes was studied by administering multiple i.v. or s.c. injections of MII to non-diabetic 7-12-week-old female NOD mice in three geographical colony locations. The incidence of diabetes was assessed from daily or weekly blood glucose measurements. The effect of MII on insulin autoantibody levels was studied using an electrochemiluminescence-based insulin autoantibody assay. The effect on the number of insulin-reactive CD8+ and CD4+ T lymphocytes in peripheral lymphoid tissue was studied with MHC class I and MHC class II tetramers, respectively. We found that twice-weekly s.c. administration of MII accelerates rather than prevents diabetes. High-dose i.v. treatment did not prevent disease or affect insulin autoantibody levels, but it increased the amount of insulin-reactive CD4+ T lymphocytes in peripheral lymphoid tissue. Our data suggest that parenteral MII, even when used in high doses, has little or no therapeutic potential in NOD mice and may exacerbate disease.

Effects of TRPM7/miR-34a Gene Silencing on Spatial Cognitive Function and Hippocampal Neurogenesis in Mice with Type 1 Diabetes Mellitus.

This study aimed to explore the effects of transient receptor potential melastatin 7 (TRPM7)/microRNA-34a (miR-34a) gene silencing on spatial cognitive function and hippocampal neurogenesis in mice with type 1 diabetes mellitus (T1DM). BALB/c mice were chosen to establish T1DM models and divided into five groups respectively: the negative control (NC), T1DM, T1DM+si-TRPM7, T1DM+si-miR-34a, and T1DM+si-TRPM7+si-miR-34a groups. Morris water maze (MWM) test was adopted to observe behavioral alterations in mice. In all groups, changes in weight, fasting insulin, blood glucose, and insulin-related antibodies: insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GAD-Ab) were monitored. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to test TRPM7 and miR-34a expressions. Nissl staining was performed to detect neuron numbers in hippocampal tissues. Ultrastructure of hippocampal neurons was observed by transmission electron microscopy. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to assess cell apoptosis, and Western blotting was applied to examine expressions of apoptosis-related proteins. Compared to the NC group, the mice in the T1DM group had increased expressions of TRPM7 and miR-34a; decreased weight and fasting insulin; increased blood glucose and levels of ICA, IAA, and GAD-Ab; prolonged escape latency; less time spent in the target quadrant; incomplete neuronal structure; reduced neuron numbers; increased cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but reduced Bcl-2 expression. In comparison to the T1DM group, the T1DM+si-TRPM7, T1DM+si-miR-34a, and T1DM+si-TRPM7+si-miR-34a groups showed increased weight and fasting insulin; reduced blood glucose and levels of ICA, IAA, and GAD-Ab; shortened escape latency; prolonged time spent in the target quadrant platform; intact neuronal structure; increased neuron numbers; repaired neurons; reduced cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but increased Bcl-2 expression. The T1DM+si-TRPM7+si-miR-34a group underwent more obvious changes than the T1DM+si-TRPM7 and T1DM+si-miR-34a groups. Our results demonstrated that TRPM7/miR-34a gene silencing could improve spatial cognitive function and protect hippocampal neurogenesis in mice with T1DM.

Gliclazide-Induced Insulin Autoimmune Syndrome: A Rare Case Report and Review on Literature

Insulin Autoimmune Syndrome (IAS) is a rare condition characterized by the combination of recurrent severely spontaneous hypoglycemia without evidence of exogenous insulin administration, high concentration of total serum insulin, and the presence of a high titer of insulin autoantibody (IAA). But now we describe a case with IAS caused by gliclazide and hardly occuring hypoglycemia. A 70-year-old man with type 2 diabetes presented to our department with poor glycemic control without evidence of hypoglycemia, but the levels of serum insulin and IAA were very high. He had no exogenous insulin administration history. Switching antidiabetic therapy from gliclazide to acarbose and metformin, the patient's serum insulin level and IAA decreased gradually. Accordingly, the glycemic control improved and there was no episode of hypoglycemia. Hence, clinicians should pay more attention to type 2 diabetic patients treated with gliclazide and detect their serum insulin concentration and IAA to exclude or diagnose IAS and perform the best therapeutic regimen to these patients.

Factors associated with increased irisin levels in the type 1 diabetes mellitus.

The aim of the present study was to determine the irisin levels in patients with the type 1 diabetes mellitus (T1DM) and to examine the relation of irisin levels with the inflammation and autoimmunity. This study included 35 cases diagnosed with T1DM and 36 healthy volunteers. Antiglutamic acid decarboxylase (anti-GAD), islet cell antibody (ICA), and insulin autoantibody levels were measured in patients at the time when they were included into the study and recorded from the patient files. Serum irisin levels were measured by ELISA kit. The median irisin levels were determined higher in T1DM group compared to the control one (6.8 ng/ml vs. 4.8 ng/ml, p=0.022; respectively). Median irisin levels were higher in anti-GAD (p=0.022) and ICA (p=0.044) positive groups compared to negative groups. In T1DM group, irisin levels displayed positive correlation with glycosylated hemoglobin (HbA1c) (r=0.377, p<0.001) and anti-GAD (r=0.392, p=0.020) and negative correlation with creatinine (r=-0390, p=0.021). In multivariate regression model, HbA1c (B±SE: 2.76±17683, p<0.001), and anti-GAD (B±SE: 2.311±0.610, p=0.001) were determined as independent predictors for predicting the irisin levels. In patients with T1DM, which chronic inflammation and autoimmunity take part in their etiopathogenesis, anti-GAD levels were an independent risk factor for the irisin. Th is may suggest that factors such as inflammation and autoimmunity can be effective in the synthesis of irisin.

Insulin-induced autoimmune syndrome: A case report.

Insulin autoimmune syndrome (IAS) is a disease characterized by hyperinsulinemic hypoglycemia associated with autoantibodies against endogenous insulin. A 56-year-old man was admitted to Ningbo First Hospital for the treatment of spontaneous hypoglycemia. He was found to have elevated fasting insulin level (>1,000 mIU/l) and presence of insulin autoantibodies, and after appropriate workup, was diagnosed with IAS. After treating with prednisone for 2 months, his insulin level started decreasing. In patients with repeated hypoglycemia, IAS should be considered in the differential diagnosis. Prednisone may be effective for the treatment of hypoglycemia in patients with IAS.

Predictors of slow progression to diabetes in children with multiple islet autoantibodies

Although most children with multiple islet autoantibodies develop type 1 diabetes, rate of progression is highly variable. The goal of this study was to explore potential factors involved in rate of progression to diabetes in children with multiple islet autoantibodies. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 118 children with multiple islet autoantibodies for progression to diabetes. After excluding 27 children currently diabetes-free but followed for <10 years, the study population was grouped into: rapid progressors (N = 39) who developed diabetes in <5 years; moderate progressors (N = 25), diagnosed with diabetes within 5–10 years; and slow progressors (N = 27), diabetes-free for >10 years. Islet autoimmunity appeared at 4.0 ± 3.5, 3.2 ± 1.8 and 5.8 ± 3.1 years of age in rapid, moderate and slow progressors, respectively (p = 0.006). Insulin autoantibody levels were lower in slow progressors compared to moderate and rapid progressors. The groups did not differ by gender, ethnicity, family history, susceptibility HLA and non-HLA genes. The rate of development of individual islet autoantibodies including mIAA, GADA, IA-2A and ZnT8A were all slower in the slow versus moderate/rapid progressors. In multivariate analyses, older age at seroconversion and lower initial mIAA levels independently predicted slower progression to diabetes. Later onset of islet autoimmunity and lower autoantibody levels predicted slower progression to diabetes among children with multiple islet autoantibodies. These factors may need to be considered in the design of trials to prevent type 1 diabetes.

Insulin autoimmune syndrome – a rare cause of hypoglycaemia: a report on 2 cases

Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of hypoglycaemia in countries other than Japan and Korea. It is a syndrome of hypoglycaemia with elevated insulin and insulin antibody levels. Although there is a genetic basis to the disease, many drugs and autoimmune conditions such as Graves’ disease have been implicated in the pathogenesis. Here we report two cases of IAS identified in Sri Lanka. Case 1: A 47-year-old previously healthy male patient presented with neuroglycopenic symptoms and seizures with low blood glucose levels in a background of high insulin levels. Conventional imaging was negative for a pancreatic tumour.Calcium stimulation testing revealed very high basal insulin levels from all regions of the pancreas. Insulin antibodies were above the normal levels. A diagnosis of IAS was made and steroids and frequent small meals containing complex carbohydrates was started as treatment. In spite of treatment, the patient continued to have high insulin levels, but free of symptoms. Case 2 : A 37-year-old female with Graves’ disease who was treated with carbimazole, presented with hypoglycaemic episodes that occur 4 to 6 hours after meals. Investigations revealed high insulin levels in the presence of hypoglycaemia, which occurred 6 hours into the prolonged fasting test. Imaging by CT, MRI and endoscopic ultrasonography yielded negative results. She had very high insulin autoantibody levels. A diagnosis of IAS secondary to carbimazole was made and the anti-thyroid drugs were withdrawn. Her symptoms resolved and her biochemistry got normalized with drug withdrawal.

Mesenchymal Stem Cell Modulates T Follicular Helper Cell to Induce Immunotolerance of Islet Allograft

ObjectiveTo verify whether mesenchymal stem cells protected the islet allograft via modulating follicular B helper T cells (Tfh) cells. MethodsThe recipient mice were divided into 5 groups. Group A: the diabetic group (n = 12); Group B: islets alone group (n = 12); Group C: MSCs and islets co-transplanted group (n = 12, MSCs = 0.5 × 106); Group D: MSCs and islets co-transplanted group (n = 12, MSCs = 1 × 106); Group E: MSCs and islets co-transplanted group (n = 12, MSCs = 2 × 106); One control group of normal NOD mice was set as well. ELISA was used to examine the autoantibody level of GAD65 Ab, insulin autoantibodies, and insulin. The Tfh count was determined by fluorescence-activated cell sorting. The insulin expression of islet grafts, the infiltration of lymphocytes, and the Tfh cells were observed via hematoxylin and eosin staining and immunohistochemical staining. ResultsThere was significant prolonged graft survival and more insulin expression of islet grafts observed in the co-transplant group. A lower level of the Tfh cells and autoantibody GAD65 Ab, insulin autoantibodies were also presented in the co-transplant group (P < .01). The infiltration of lymphocytes in the co-transplant group was notably less than in the islet-alone group (P < .01). ConclusionsMesenchymal stem cells were able to protect the islet allograft by regulating the follicular helper T cells.

Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY).

While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]). The mean GADA level did not significantly affect the risk of diabetes. In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive.

Clinical features and causes of endogenous hyperinsulinemic hypoglycemia in Korea.

BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH) is characterized by an inappropriately high plasma insulin level, despite a low plasma glucose level. Most of the EHH cases are caused by insulinoma, whereas nesidioblastosis and insulin autoimmune syndrome (IAS) are relatively rare.MethodsTo evaluate the relative frequencies of various causes of EHH in Korea, we retrospectively analyzed 84 patients who were diagnosed with EHH from 1998 to 2012 in a university hospital.ResultsAmong the 84 EHH patients, 74 patients (88%), five (6%), and five (6%) were diagnosed with insulinoma, nesidioblastosis or IAS, respectively. The most common clinical manifestation of EHH was neuroglycopenic symptoms. Symptom duration before diagnosis was 14.5 months (range, 1 to 120 months) for insulinoma, 1.0 months (range, 6 days to 7 months) for nesidioblastosis, and 2.0 months (range, 1 to 12 months) for IAS. One patient, who was diagnosed with nesidioblastosis in 2006, underwent distal pancreatectomy but was later determined to be positive for insulin autoantibodies. Except for one patient who was diagnosed in 2007, the remaining three patients with nesidioblastosis demonstrated severe hyperinsulinemia (157 to 2,719 µIU/mL), which suggests that these patients might have had IAS, rather than nesidioblastosis.ConclusionThe results of this study suggest that the prevalence of IAS may be higher in Korea than previously thought. Therefore, measurement of insulin autoantibody levels is warranted for EHH patients, especially in patients with very high plasma insulin levels.

The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A−/− nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A−/− NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I∶C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I∶C). In addition, injection of high-dose poly(I∶C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A−/− NOD mice compared with untreated SR-A−/− NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A−/− NOD mice treated with poly(I∶C) than in untreated SR-A−/− NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A−/− NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I∶C) treatment even in SR-A−/− NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

Hypoglycemic coma due to insulin autoimmune syndrome induced by methimazole: A rare case report.

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin-binding autoantibodies and fasting or late postprandial hypoglycemia. The number of reports on the association of human leukocyte antigen (HLA) genotype with this disease in adolescents in China is limited. This is the case report of a 17-year-old female patient with Graves’ disease who was treated with methimazole (MTZ). After 4 weeks of continuous MTZ treatment, the patient suffered an episode of unconsciousness during the late postprandial phase and was admitted to the hospital, where the blood glucose level was found to be 2.88 mmol/l. The symptoms were relieved following intravenous glucose administration. Imaging studies of the pancreas were unremarkable, but the laboratory investigations on admission revealed high serum levels of total insulin, associated with relatively low levels of free insulin and markedly elevated insulin autoantibody (IAB) levels. HLA testing revealed DRB1*0406/0901 and the patient discontinued MTZ and was prescribed propylthiouracil. During the long-term follow-up, the total insulin and IAB levels gradually declined. There was no other episode of hypoglycemia. Therefore, in adolescents with Graves’ disease receiving antithyroid treatment with MTZ who experience hypoglycemia, the IAB levels should be assessed to exclude or confirm IAS as the underlying cause.

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. Children developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

Immunotherapy trials for type 1 diabetes: the contribution of George Eisenbarth.

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β-cells, and as such it should respond to immunotherapy. George Eisenbarth gave many significant contributions to this field. He has been involved at some level in most immunotherapy trials during the past three decades. He was among the pioneers who attempted immunotherapy approaches in patients with recent-onset T1D. In the early 1980s he began studying relatives of those with the disease, leading to the concept that T1D was a chronic autoimmune disease, in which islet autoimmune responses would silently destroy β-cells and cause progressive impairment of insulin secretion, years to months before a diagnosis was made. Consequently, he was one of the first to attempt immune intervention in people at high risk of T1D. Throughout his career he developed autoantibody assays and predictive models (which included metabolic testing and later genetics) to identify individuals at risk of T1D. He provided seminal intellectual contributions and critical tools for prevention trials. His focus on insulin as a critical autoantigen led to multiple prevention trials, including the Diabetes Prevention Trial-Type 1 (DPT-1), which studied both parenteral and oral insulin. In the DPT-1 Oral Insulin Trial, a cohort with higher levels of insulin autoantibodies was identified that appeared to have delayed disease progression. Type 1 Diabetes TrialNet is conducting a new trial to verify or refute this observation. Moreover, George identified and tested in the mouse small molecules that block or modulate presentation of a key insulin peptide and in turn prevent the activation of insulin-specific T-lymphocytes. Thus, we believe his greatest contribution is yet to come, as in the near future we should see this most recent work translate into clinical trials.

Reducing the Risk of Developing Diabetes

Reducing the Risk of Developing Diabetes

Nearby Construction Impedes the Progression to Overt Autoimmune Diabetes in NOD Mice

Construction nearby animal houses has sporadically been reported to affect various aspects of animal health. Most of the reports have focussed on the impact on stress hormone levels and the hypersensitivity of animals relative to humans. There has also been an anecdotal report on the impact of construction on autoimmune diabetes in NOD mice. Here, we describe that nearby construction significantly impedes the progression to overt diabetes in female NOD mice offspring. We demonstrate that this was not due to a genetic drift or to particularities associated with our specific mouse colony. Interestingly, although the glycemia levels remained low in mice born from mothers subject to construction stress during gestation, we detected an active autoimmune reaction towards pancreatic islet cells, as measured by both the degree of insulitis and the presence of insulin autoantibody levels in the serum. These results suggest that the external stress imposed during embryonic development does not prevent but significantly delays the autoimmune process. Together, our findings emphasize the impact of surrounding factors during in vivo studies and are in agreement with the hypothesis that both environmental and genetic cues contribute to autoimmune diabetes development.

Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status

BackgroundThe detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable.MethodsWe have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories.ResultsOur ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories.ConclusionsThese novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials.

Age of Islet Autoantibody Appearance and Mean Levels of Insulin, but Not GAD or IA-2 Autoantibodies, Predict Age of Diagnosis of Type 1 Diabetes

OBJECTIVEWe evaluated predictors of progression to diabetes in children with high-risk HLA genotypes and persistent islet autoantibodies.RESEARCH DESIGN AND METHODSThe Diabetes Autoimmunity Study in the Young (DAISY) followed 2,542 children with autoantibodies measured to GAD, IA-2, and insulin.RESULTSPersistent islet autoantibodies developed in 169 subjects, and 55 of those progressed to diabetes. Children expressing three autoantibodies showed a linear progression to diabetes with 74% cumulative incidence by the 10-year follow-up compared with 70% with two antibodies and 15% with one antibody (P < 0.0001). Both age of appearance of first autoantibody and insulin autoantibody (IAA) levels, but not GAD or IA-2 autoantibodies, were major determinants of the age of diabetes diagnosis (r = 0.79, P < 0.0001).CONCLUSIONSIn the DAISY cohort, 89% of children who progressed to diabetes expressed two or more autoantibodies. Age of diagnosis of diabetes is strongly correlated with age of appearance of first autoantibody and IAA levels.

The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages

The nonobese diabetic (NOD) mouse spontaneously develops several autoimmune diseases, including type 1 diabetes and to a lesser extent thyroiditis and sialitis. Imbalance between effector T cells (Teffs) and regulatory T cells (Tregs) has recently been proposed as a mechanism for the disease pathogenesis in NOD mice, but previous studies have shown the various outcomes by different timing and methods of Treg-depletion. This study was, therefore, designed to compare the consequences of Treg-depletion by the same method (anti-CD25 antibody) on the spectrum of organ-specific autoimmune diseases in NOD mice of different ages. Treg-depletion by anti-CD25 antibody at 10 days of age accelerated development of all three diseases we examined (insulitis/diabetes, thyroiditis, and sialitis); Treg-depletion at 4 weeks of age accelerated only diabetes but not thyroiditis or sialitis; and Treg-depletion at 12 weeks of age hastened only development of thyroiditis and exhibited little influence on diabetes or sialitis. Increased levels of insulin autoantibodies (IAA) were, however, observed in mice depleted of Tregs at 10 days of age, not in those at 4 weeks. Thus, the consequences of Treg-depletion on the spectrum of organ-specific autoimmune diseases depend on the timing of anti-CD25 antibody injection in NOD mice. Aging gradually tips balance between Teffs and Tregs toward Teff-dominance for diabetes, but this balance for thyroiditis and sialitis likely alters more intricately. Our data also suggest that the levels of IAA are not necessarily correlated with diabetes development.

Hyperthyroidism-Associated Insulin Resistance Is Not Mediated by Adiponectin Levels

To evaluate the relationship between circulating adiponectin and insulin sensitivity in patients with hyperthyroid Graves' disease, we studied 19 adult patients with this disease and 19 age- and sex-matched euthyroid controls. All hyperthyroid patients were treated with antithyroid drugs and were re-evaluated after thyroid function normalized. Before antithyroid treatment, the adiponectin plasma concentrations were not different comparing with those in control group. The adiponectin levels remained unchanged after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) in hyperthyroid group was higher before treatment than after treatment. There was no significant difference in serum glucose and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. BMI-adjusted adiponectin levels were not different among three groups. On the other hand, BMI-adjusted insulin levels and HOMA-IR values were significantly decreased after management of hyperthyroidism. Pearson's correlation revealed that insulin and HOMA-IR values positively correlated with triiodothyronine (T3) and free thyroxine (FT4) levels. However, adiponectin did not correlate with T3, FT4, insulin, HOMA-IR and thyrotropin receptor autoantibody (TRAb) levels. In conclusion, insulin resistance associated with hyperthyroidism is not mediated by the levels of plasma adiponectin.