Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country

OBJECTIVE: To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of beta-cell autoimmunity among three geographical regions in Finland. RESEARCH DESIGN AND METHODS: The series comprised 4,642 children with increased HLA-DQB1-defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of beta-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A). RESULTS: The high- and moderate-risk genotypes were unevenly distributed among the three areas (P<0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P<0.001) or Tampere regions (27.2%; P<0.001). This genotype was associated with an increased frequency of ICA seroconversion relative to the moderate risk genotypes (hazard ratio 1.89, 95% CI 1.36-2.62). Seroconversions to ICA positivity occurred less commonly in Tampere than in Turku (0.47, 0.28-0.75), whereas the seroconversion rate in Oulu did not differ from that in Turku (0.72, 0.51-1.03). The Tampere-Turku difference persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere than in Turku (0.39, 0.16-0.82). CONCLUSIONS: These data show that in Finland, the country with the highest incidence of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the risk of seroconversion to autoantibody positivity show geographical variation. The difference in seroconversion rate could not be explained by the difference in HLA-DQB1-defined disease susceptibility, implying that the impact of environmental triggers of diabetes-associated autoimmunity may differ between the three regions studied.     

Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey

OBJECTIVE: To investigate thyroid autoimmunity in a very large nationwide cohort of children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data were analyzed from 17,749 patients with type 1 diabetes aged 0.1-20 years who were treated in 118 pediatric diabetes centers in Germany and Austria. Antibodies to thyroglobulin (anti-TG) and thyroperoxidase (anti-TPO) were measured and documented at least once in 7,097 patients. A total of 49.5% of these patients were boys, the mean age was 12.4 years (range 0.3-20.0 years), and the mean duration of diabetes was 4.5 years (range 0.0-19.5 years). A titer exceeding 100 units/ml or 1:100 was considered significantly elevated. RESULTS: In 1,530 patients, thyroid antibody levels were elevated on at least one occasion, whereas 5,567 were antibody-negative during the observation period. Patients with thyroid antibodies were significantly older (P < 0.001), had a longer duration of diabetes (P < 0.001), and developed diabetes later in life (P < 0.001) than those without antibodies. A total of 63% of patients with positive antibodies were girls, compared with 45% of patients without antibodies (P < 0.001). The prevalence of significant thyroid antibody titers increased with increasing age; the highest prevalence was in the 15- to 20-year age group (anti-TPO: 16.9%, P < 0.001; anti-TG: 12.8%, P < 0.001). Thyroid-stimulating hormone (TSH) levels were higher in patients with thyroid autoimmunity (3.34 microU/ml, range 0.0-615.0 microU/ml) than in control subjects (1.84 microU/ml, range 0.0-149.0 microU/ml) (P < 0.001). Even higher TSH levels were observed in patients with both anti-TPO and anti-TG (4.55 microU/ml, range 0.0-197.0 microU/ml). CONCLUSIONS: Thyroid autoimmunity seems to be particularly common in girls with diabetes during the second decade of life and may be associated with elevated TSH levels, indicating subclinical hypothyroidism.     

Bacteremia in diabetic patients: comparison of incidence and mortality with nondiabetic patients

We determined the incidence of bacteremia and associated mortality in diabetic and nondiabetic patients in the four major hospitals of one metropolitan area over the 5-yr period 1977-1981. Mortality rates, based on episodes of bacteremia, were similar in diabetic and nondiabetic patients in most instances. Diabetic patients experienced lower mortality rates from Enterobacteriaceae bacteremia compared with nondiabetic patients; this finding was explained by a greater tendency for diabetic patients to have Escherichia coli bacteremia due to community-acquired urinary tract infection. However, the incidence of bacteremia due to all microorganisms was increased twofold in diabetic patients and the incidence of Enterobacteriaceae bacteremia was increased threefold. Because of their increased incidence of bacteremia, diabetic patients in this population were nearly twice as likely to die as a result of bacteremia compared with nondiabetic patients. Thus, the frequent occurrence of bacteremia among patients with diabetes mellitus represents a significant problem.     

NOD mice with high incidence of type 1 diabetes are not T lymphocytopenic

An autoimmune pathogenesis has been indicated in insulin-dependent (type 1) diabetes mellitus (IDDM). Previously we reported that non-obese diabetic (NOD) mice as an animal model of spontaneously developing IDDM were immunologically characterized by T lymphocytopenia and impaired cellular immunities. The cumulative incidence of diabetes in the T lymphocytopenic female NOD mice was 10-20% by 24 weeks of age. On the other hand, the incidence of diabetes are 80-90% in the female NOD/Shi-Sendai (S), in whom proportion of lymophocyte subsets has not been known yet. Therefore, we examined the spleen cells of female NOD/Shi-S and female NOD/Shi with high incidence of diabetes, and of female Jcl:ICR as a control. Cell numbers, populations of T cells (Thy 1.2+, Lyt-1+ and Lyt-2+), B cells (surface-Ig+), NK cells (acialo GM1+) and responsiveness to Concanavalin A were analyzed as immunological parameters. In contrast to the T lymphocytopenic NOD, these immunological parameters were not impaired in the NOD/Shi-S and NOD/Shi in comparison to those of Jcl:ICR. The results indicate that there may be a positive association between the incidence of diabetes and T cell number and functions in female NOD mice.     

A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland

OBJECTIVE: Type 1 diabetes results from gene-environment interactions in subjects with genetic susceptibility to the disease. We assessed the contribution of environmental and genetic factors to type 1 diabetes by comparing the incidence in two neighboring populations living in conspicuously different socioeconomic circumstances. RESEARCH DESIGN AND METHODS: We compared the incidence over a 10-year period (1990-99) in children younger than 15 years of age living in the Karelian Republic of Russia and in Finland. The frequency of susceptible and protective human leukocyte antigen (HLA)-DQ alleles was analyzed in 400 non-diabetic schoolchildren from Russian Karelia and 1000 Finnish subjects. RESULTS: The average annual age-adjusted incidence of type 1 diabetes was lower in Russian Karelia than in Finland: 7.4 per 100000 (95% confidence interval 3.5-11.3) versus 41.4 per 100000 (37.3-45.5), while there were no differences in the frequency of the HLA DQ genotypes predisposing to type 1 diabetes in the background populations. The incidence rate did not differ significantly between different ethnic groups in Russian Karelia (Finns/Karelians, Russians, others). CONCLUSIONS: There is a close to six-fold gradient in the incidence of type 1 diabetes between Russian Karelia and Finland, although the predisposing HLA DQ genotypes are equally frequent in the two populations. This suggests that environmental factors contribute to this steep difference in the incidence rate between these adjacent regions.     

Prediction and diagnosis of type 1 diabetes using beta-cell autoantibodies

The clinical manifestation of type 1 diabetes is the endpoint of a long-lasting immune-mediated destruction process of the B-cells. Autoantibodies originating from this process can be applied in the diagnosis and clinical discrimination of autoimmune diabetes as well as in the prediction of this disease. At clinical diagnosis between 80-90% of patients with type 1 diabetes are positive for antibodies to B-cell antigens, such as ICA and antibodies to glutamic acid decarboxylase or IA2. These antibodies can also be detected in the presymptomatic period before onset of the disease, and can thus be used to predict type 1 diabetes. Using a combination of antibodies, diabetes can be predicted in 70-80% of future cases of diabetes, with a positive predictive value between 30-80%, depending on the type of antibody tested for and the population studied. Between 5 and 30% of patients initially diagnosed with type 2 diabetes will show progression to insulin dependency and turn out to have type 1 within three years of diagnosis. It is clinically relevant to identify these patients early in the course of disease, as deterioration of metabolic control results in an increased risk for macro- and micro-vascular complications. Autoantibodies to glutamic acid decarboxylase or ICA are of high diagnostic sensitivity in these cases and are better predictors for future insulin dependency than biochemical or clinical parameters. Increasing knowledge on the applicability of antibodies for diabetes prediction and diagnosis and the development of commercial assays for antibodies to glutamic acid decarboxylase and IA2 antibodies has enabled the implementation of B-cell autoantibodies in routine diagnostic settings.     

Delayed gastric emptying and gastric autoimmunity in type 1 diabetes

OBJECTIVE: Delayed gastric emptying and/or gastrointestinal symptoms occur in 30-50% of diabetic patients. Known contributing factors are autonomic neuropathy and acute hyperglycemia, but the role of gastric autoimmunity has never been investigated, although 15-20% of type 1 diabetic patients exhibit parietal cell antibodies (PCAs). We studied gastric motility in diabetes in relation to PCA status, autonomic nerve function, HbA(1c), thyroid-stimulating hormone (TSH), Helicobacter pylori (HP), acid production, and gastric histology. RESEARCH DESIGN AND METHODS: Gastric emptying of solids and liquids (measured by (13)C-octanoic acid and (13)C-glycine breath tests, respectively) was tested in euglycemic conditions in 42 type 1 diabetic patients (male/female: 29/13; 15 PCA+; mean age 40 +/- 15 years; mean HbA(1c) 7.8 +/- 0.9%). Gastrointestinal symptoms, autonomic nerve function (Ewing tests), PCA status (indirect immunofluorescence), gastric histology, and acid secretion (pentagastrin) were assessed. RESULTS: Solid gastric emptying was delayed in 40% and liquid emptying in 36% of patients. Gastric motility did not correlate with symptoms. PCA status, gastric morphology, and acid secretion were similar in those with and without gastroparesis. HbA(1c) level (beta = 1.34, P = 0.011) was the only risk factor for delayed solid emptying in a logistic regression model testing HbA(1c), autonomic nerve function, PCA, HP status, age, sex, diabetes duration, and TSH. Half-emptying time for liquids correlated with TSH level (r = 0.83, P < 0.0001) and autonomic neuropathy score (r = -0.79, P = 0.001). CONCLUSIONS: We found that approximately 50% of type 1 diabetic patients studied had delayed gastric emptying that did not correlate with symptoms. Gastric autoimmunity did not contribute to diabetic gastroparesis. Metabolic control was worse in patients with delayed solid emptying.     

Deteriorating beta-cell function in type 2 diabetes: a long-term model

BACKGROUND: Type 2 diabetes is characterized by insulin resistance and the progressive loss of islet beta-cell function. Although the former is already established at diagnosis and changes little thereafter, beta-cell function continues to decline, leading to secondary failure of anti-hyperglycaemic therapies. AIM: To develop a quantitative model of the process of beta-cell function decay over time, using trial data. DESIGN: Re-analysis of published data. METHODS: The results of the Belfast Diet Study were re-analysed. Assuming patients are diagnosed at different stages in the disease process, time displacement of data was used to obtain a bi-partite spline model describing loss of insulin secretion over a 6-year period. RESULTS: The model was developed combining two phases, in which a long slow gradual loss of beta-cell function leads to a crisis in metabolic regulation, precipitating a much more rapid decay phase. This paradigm was consistent with a previous non-linear model of beta-cell mass regulation. DISCUSSION: This model may have important implications for targeting appropriate therapy to patients in each phase: delaying or avoiding full clinical type 2 diabetes in the first phase; and preventing the development of diabetic complications in the second phase.     

Gene therapy for type 1 diabetes: a novel approach for targeted treatment of autoimmunity

It has been difficult to develop therapies that target those T cells initiating and mediating the pathogenesis of autoimmune disease. Indeed, most current treatments indiscriminately affect both the autoreactive T cells and the "good" T cells, putting the patient at risk of compromised immune function. A new approach raises the possibility of targeted therapy for autoimmunity. Transplantation of hematopoietic stem cells modified to express a protective form of MHC class II corrects a defect in central tolerance. This method contrasts with other targeted therapies that attempt to modify peripheral tolerance, which is also defective in type 1 diabetes mellitus.     

新诊断2型糖尿病患者血糖波动与胰岛细胞功能的关系

目的：探讨新诊断2型糖尿病患者血糖波动与胰岛细胞功能的关系。方法分析51例新诊断2型糖尿病患者的临床资料,血糖波动采用OGTT 1 h与OGTT 0 h差值（GLU1）、OGTT 2 h与OGTT 0 h差值（GLU2）表示。胰岛细胞功能采用空腹血清胰岛素、空腹血清C肽、稳态模式评估法的胰岛素分泌指数（HOMA-β）及胰岛素抵抗指数（HOMA-IR）表示。分析患者血糖波动情况,即GLU1、GLU2与空腹血清胰岛素、空腹血清C肽、HOMA-β、HOMA-IR的相关性。结果该组患者的GLU1为（7.84±2.31）mmol/L,GLU2为（7.4±2.7）mmol/L,空腹血清胰岛素为（13.8±6.0）mU/L,空腹血清C肽为（0.85±0.26）nmol/L,HOMA-β的对数值为4.10±0.64,HOMA-IR的对数值为1.43±0.54。GLU1、GLU2与空腹血清胰岛素、空腹血清C肽、HOMA-IR的对数无相关性（P均＞0.05）,但与HOMA-β的对数值呈负相关（r值分别为-0.344、-0.498,P均＜0.05）。结论新诊断2型糖尿病患者血糖波动可能与胰岛素分泌缺陷密切相关。