A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes

OBJECTIVE: The association of antioxidant nutrients and risk of nuclear opacification was evaluated in the Longitudinal Study of Cataract. DESIGN: Nutritional data were collected at baseline on the 764 participants, which included assessment of dietary intake, use of vitamin supplements, and plasma levels of vitamin E. Ophthalmologic and other data were collected at baseline and at yearly follow-up visits, including lens photographs, which were graded using the Lens Opacities Classification System III protocol. MAIN OUTCOME MEASURES: Analyses examined whether the nutritional factors at baseline were related to increases in nuclear opacification at follow-up. The MULCOX2 approach, an extension of the Cox regression model, was used. Results are presented as relative risks (RRs) and 95% confidence intervals. INTERVENTION: Intervention was not applicable. RESULTS: The risk of nuclear opacification at follow-up was decreased in regular users of multivitamin supplements (RR = 0.69; 0.48-0.99), vitamin E supplements (RR = 0.43; 0.19-0.99), and in persons with higher plasma levels of vitamin E (RR = 0.58; 0.36-0.94). CONCLUSIONS: In regular users of multivitamin supplements, the risk of nuclear opacification was reduced by one third; in regular users of vitamin E supplements and persons with higher plasma levels of vitamin E, the risk was reduced by approximately half. These results are similar to those obtained in our earlier case-control study. Because these data are based on observational studies only, the results are suggestive but inconclusive. The possible effect of nutritional supplements on the lens requires confirmation by ongoing clinical trials.     

Descriptive epidemiology of IDDM in Hokkaido, Japan: the Childhood IDDM Hokkaido Registry

OBJECTIVE: To identify the incidence of IDDM with regard to sex, age, family history of diabetes, season, and 5-year period of childhood IDDM among children ages 0-14 years from a population-based epidemiological study in Hokkaido, Japan, from 1973 to 1992. RESEARCH DESIGN AND METHODS: Registration of all new IDDM cases in Hokkaido was conducted by the Childhood IDDM Hokkaido Registry Study Group from 1973 to 1992. The cases were selected from among 1) patients who were admitted to the member hospitals of the study group, 2) patients who answered a questionnaire distributed to hospitals and diabetic clinics throughout Hokkaido, and 3) patients whose cases were recorded in free-treatment medical records of urban and rural districts. The case ascertainment rate was estimated to be 100%. Differences in incidence with regard to sex, age, family history of diabetes, season, and year period were analyzed by the Poisson regression analysis by GENMOD. RESULTS: During the 20-year period studied, 396 cases (181 boys, 215 girls) of abrupt-onset IDDM were registered. Statistically significant differences in annual incidence were found according to sex (female), age (8-14 years), history (having no diabetes in family), season (spring), and 5-year period. CONCLUSIONS: This is the first population-based, long-term epidemiological study of childhood IDDM from Japan. We observed a significantly higher annual incidence (per 100,000/year) of IDDM in female subjects (1.81), older age-groups (2.25 for 8-14 years), subjects with no family history of diabetes (1.26), diabetes onset in the spring (2.20), and an increased trend over the 20 years. In addition, the heterogeneity of IDDM among Japanese children needs to be elucidated.     

Linkage and association between a CD4 gene polymorphism and IDDM in Danish IDDM patients. The Danish IDDM Epidemiology and Genetics Group, and The Danish Study Group of Diabetes in Childhood

PURPOSE: Our purpose was to determine the neuroradiologic findings of Marinesco-Sj?gren syndrome on plain skull radiographs, CT, and MR images. METHODS: Eight patients with proved Marinesco-Sj?gren syndrome (age range, 4 to 56 years) had a total of nine CT scans, seven MR imaging studies, and two plain radiographic examinations of the skull. The findings were reviewed retrospectively, with particular attention to the size of the posterior fossa and cerebellum. RESULTS: All patients had hypoplastic cerebellar hemispheres and a hypoplastic vermis in a small posterior fossa. One patient had a midline posterior fossa cyst and another had agenesis of the corpus callosum. CONCLUSION: Hypoplasia of the cerebellar hemispheres and the vermis and a small posterior fossa are the most prominent neuroradiologic findings in Marinesco-Sj?gren syndrome.     

Incidence of IDDM in children living in Puerto Rico. Puerto Rican IDDM Coalition

OBJECTIVE: To determine incidence, geographic distribution, and seasonal variation of IDDM in children 0-14 years of age living in Puerto Rico. Because these data have been collected through the infrastructure of the World Health Organization's DiaMond project, these results are directly comparable with incidence data from other population worldwide involved in this study. RESEARCH DESIGN AND METHODS: Beginning in 1990, new cases of IDDM were registered retrospectively from 1985 and prospectively to 1994 by review of medical records from island hospitals. Included in the hospital registry are 1,527 cases of IDDM. Validation of the primary source was by three secondary lists of cases obtained through diabetic camps, surveys of schools, and a government registry. Long linear modeling (capture-recapture) was used to correct incidence. RESULTS: Mean incidence of IDDM from 1985-1994 was 18.0 cases/100,000 children per year (95% CI 17.6-18.3). There was a slight female rather than male predominance: 51% of the cases were girls, and 49% were boys. Although Puerto Rico has marked variation in rainfall, altitude, and genetic markers, no significant differences are found in the incidence rates of different areas or seasons of the island. CONCLUSIONS: This registry of Puerto Rican children is the largest IDDM registry of minority children in the U.S. The results of this study indicate that the annual incidence of IDDM of children living in Puerto Rico is higher than the incidence of other multiracial ethnic groups living in the U.S.     

Non-insulin-mediated glucose disappearance in subjects with IDDM. Discordance between experimental results and minimal model analysis

Both insulin and glucose contribute to the regulation of glucose metabolism in vivo. We directly measured the ability of glucose per se to promote glucose disposal in subjects with insulin-dependent diabetes mellitus (IDDM). We compared our results with predictions of the minimal model of glucose metabolism. To identify minimal model parameters, a frequently sampled intravenous glucose tolerance test (FSIVGTT) was administered to each subject while they were connected to a Biostator (a device that monitors blood glucose and gives insulin to mimic normal insulin secretion). Data from this test reflected normal glucose tolerance and were in excellent agreement with minimal model predictions. The FSIVGTT was then repeated without the Biostator in the same diabetic subjects in order to directly measure the effect of glucose per se to promote glucose disposal in the absence of an incremental insulin effect (a basal insulin drip was maintained). To compare these results with minimal model predictions, the equations describing glucose disappearance in the absence of an incremental insulin effect were solved using parameters identified from the Biostator experiment. The glucose disappearance measured in the absence of an incremental insulin response was much slower than the minimal model predictions. Thus, the minimal model appears to overestimate the effect of glucose per se on glucose uptake and underestimate the contribution of incremental insulin.     

Puberty, IDDM, and death in Japan. Diabetes Epidemiology Research International Study Group

OBJECTIVE: To investigate the impact of age at onset on the prognosis of childhood IDDM in Japan. RESEARCH DESIGN AND METHODS: The study population consisted of 987 prepubertal-onset and 345 pubertal-onset IDDM cases who were registered by two nationwide surveys and who were diagnosed between 1965 and 1979. The living status was identified as of 1 January 1990 with the ascertainment rate of 96.5%. Prognosis was evaluated by cause- and age-specific mortality rates and life-table analyses; in addition, an attained-age-matched case-control study was analyzed by conditional logistic regression. RESULTS: The adjusted mortality rates per 100,000 person-years for the pubertal-onset cases were significantly higher than those of the prepubertal-onset cases (835 [95% CI 573-1,168] vs. 391 [283-526]). Life-table analyses revealed that the survival rate of the pubertal-onset cases was lower than that of the prepubertal-onset cases for each observation period. Life-table analyses after the age of 15 years indicated that the prognosis of pubertal cases was almost the same as that of the prepubertal cases despite having a shorter duration of diabetes. The attained-age-matched case-control study indicated that the pubertal onset was a potent determinant of death. CONCLUSIONS: The prognosis of pubertal-onset IDDM was considerably poorer than that of prepubertal-onset IDDM.     

Cases 1, 2, and 3

A quantitative analysis of amino acids in microsamples of dried blood spots by chemical ionization mass spectrometry has been developed. Isotope ratio determination was used as the quantitating technique via multiple labelled internal standards. This procedure yields excellent precision and accuracy as demonstrated by the analysis of known amino acid mixtures and of phenylalanine in the blood from newborns.     

Age and family relationship accentuate the risk of insulin-dependent diabetes mellitus (IDDM) in relatives of patients with IDDM

The international community of diabetologists is rapidly becoming involved in intervention trials aimed at preventing insulin-dependent diabetes in high risk relatives. Whereas age and relationship to a proband with insulin-dependent diabetes mellitus interacting with detected islet cell autoantibodies (ICA) are risk factors, their independent contribution to that risk remains unclear. In a prospective study of 6851 nondiabetic relatives of 2742 probands conducted between 1979-1993, we found age, but not relationship, to be a dramatic risk variable in ICA-positive persons as estimated by the Cox regression model. The 5-yr risk of insulin-dependent diabetes mellitus was 66% for those found to have ICA detectable before age 10 yr, falling progressively to less than 16% for ICA-positive relatives over age 40 yr. In ICA-negative relatives, age and relationship are independent prognostic variables.     

Stereoselective conjugation of prostaglandin A2 and prostaglandin J2 with glutathione, catalyzed by the human glutathione S-transferases A1-1, A2-2, M1a-1a, and P1-1

Prostaglandins containing an alpha,beta-unsaturated keto group, such as prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2), inhibit cell proliferation. These cyclopentenone prostaglandins may be conjugated with GSH chemically or enzymatically via glutathione S-transferases, and this has been suggested to result in inhibition of the antiproliferative mode of action. In the present study, the role of the major human GSTs in the conjugation of PGA2 and PGJ2 with GSH was investigated with purified enzymes, i.e., the Alpha-class enzymes GST A1-1 and GST A2-2, the Mu-class enzyme GST M1a-1a, and the Pi-class enzyme GST P1-1. The GSH conjugates were separated from the parent compound by HPLC and identified by fast atom bombardment mass spectrometry and 1H-NMR. Two GSH conjugates were found for both PGA2 and PGJ2, the R- and S-GSH conjugates of both prostaglandins. Incubation experiments with PGA2 and PGJ2 (70-600 microM) clearly showed the role of individual GSTs in the conjugation of PGA2 and PGJ2. Compared to the chemical reaction, enzyme activities towards PGA2 were up to 5.4 times as high (GSTA1-1) at the lowest concentration (70 microM), while at the highest concentration (600 microM) enzyme activities were up to 3.0 times as high (GST P1-1). For PGJ2, enzyme activities were up to 4.3 (GSTM1a-1a, 70 microM) and up to 3.1 (GSTM1a-1a, 600 microM) times as high. As expected, similar amounts of the R- and S-conjugates of both prostaglandins were found in the chemical reaction. Striking stereoselectivities in conjugating activities were observed for GST A1-1 and GST P1-1. GST A1-1 favors the formation of the R-GSH conjugates of both prostaglandins. GST P1-1 showed a clear selectivity with regard to the formation of the S-GSH conjugate of PGA2. However, this selectivity was not found for the formation of the S-GSH conjugate of PGJ2. GSTM1a-1a showed no stereoselectivity with regard to the GSH conjugation of both PGA2 and PGJ2. GSTA2-2 only showed some minor formation of the R-GSH conjugate of PGJ2. The possible implications of the observed stereoselectivity on the effects of PGA2 and PGJ2 are discussed.     

Burden of illness, metabolic control, and complications in relation to depressive symptoms in IDDM patients

Relationships between demographic-, treatment-, and sickness-related factors, metabolic control (HbA1c), perceived burden of illness, and degree of depressive symptoms were examined in a group of 155 insulin-dependent diabetic patients, aged 35.3 +/- 8.9 years. The patients completed a questionnaire measuring depressive symptoms and three aspects of perceived burden of illness. No gender differences in HbA1c level or occurrence of late diabetic complications were found. Both men and women showed a modestly elevated degree of depression compared with norm groups. Self-reported burden of illness was strongly related to depression but was largely unrelated to objective disease-related measures. Level of depression was correlated neither with degree of metabolic control nor with the presence of such late diabetic complications as retinopathy and nephropathy. Some 44% of the variance in depression could be explained by worries about complications in those patients with the lowest HbA1c levels, by perceived restrictions in everyday life in patients with intermediate metabolic control, and by problems of glycaemic regulation in patients with poor metabolic control. Degree of depression was largely unrelated to disease severity, but was found to be related to the perceived daily burden of living with the disease, the specific worries and concerns associated with a depressed mood varying with degree of metabolic control.