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Objective: It is often difficult to determine the pathophysiology of childhood diabetes at onset, particularly in overweight children, because obesity has been associated with both type 1 and type 2 diabetes. We compared children at the diagnosis of diabetes in a multiethnic population-based registry to understand the epidemiology of the disease during a time of rapidly changing diagnostic and treatment norms., Methods: Incident diabetes was ascertained in Chicagoans who were aged 0 to 17 years from 1985 to 2001. We classified as type 2 those with polycystic ovary syndrome, acanthosis, or a physician's note indicating type 2 or those who reported subsequent use of oral agents (n = 203); 73% of them were also obese. Patients with obesity at onset but no other indicator of possible type 2 (n = 197) were classified as having obesity-related/undetermined type. The remaining 842 cases were classified as type 1. Logistic regression analyses were conducted., Results: Fully 32% of cases were classified as non-type 1, including 37% of non-Hispanic blacks, 30% of Latinos, and 14% of non-Hispanic whites. The proportion of obesity-undetermined and type 2 increased over the 17 years. Comparing the 3 patient groups, type 2 cases were more often female, non-Hispanic black, and older and had a first-degree diabetic relative, whereas Latino boys were overrepresented among the obese/undetermined., Conclusion: Obesity is prevalent in youths with newly diagnosed diabetes, particularly during recent years. The growth in non-type 1 diabetes in children since 1985 likely reflects both a true increase and greater physician awareness of the possibility that type 2 diabetes may occur in children.

The aim of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genes that predispose to type 2 diabetes or are responsible for variability in diabetes-related traits via a positional cloning and positional candidate gene approach. In a previously published genome-wide scan of 478 Finnish affected sibling pair (ASP) families (FUSION 1), the strongest linkage results were on chromosomes 20 and 11. We now report a second genome-wide scan using an independent set of 242 Finnish ASP families (FUSION 2), a detailed analysis of the combined set of 737 FUSION 1 + 2 families (495 updated FUSION 1 families), and fine mapping of the regions of chromosomes 11 and 20. The strongest FUSION 2 linkage results were on chromosomes 6 (maximum logarithm of odds score [MLS] = 2.30 at 95 cM) and 14 (MLS = 1.80 at 57 cM). For the combined FUSION 1 + 2 families, three results were particularly notable: chromosome 11 (MLS = 2.98 at 82 cM), chromosome 14 (MLS = 2.74 at 58 cM), and chromosome 6 (MLS = 2.66 at 96 cM). We obtained smaller FUSION 1 + 2 MLSs on chromosomes X (MLS = 1.27 at 152 cM) and 20p (MLS = 1.21 at 20 cM). Among the 10 regions that showed nominally significant evidence for linkage in FUSION 1, four (on chromosomes 6, 11, 14, and X) also showed evidence for linkage in FUSION 2 and stronger evidence for linkage in the combined FUSION 1 + 2 sample.

Type 1 diabetes, a chronic autoimmune disease, causes destruction of insulin-producing beta-cells over a period of years. Although many markers of the autoimmune process have been described, none can convincingly predict the rate of disease progression. Moreover, there is relatively little information about changes in insulin secretion in individuals with type 1 diabetes over time. Previous studies document C-peptide at a limited number of time points, often after a nonphysiologic stimulus, and under non-steady-state conditions. Such methods do not provide qualitative information and may not reflect physiologic responses. We have studied qualitative and quantitative insulin secretion to a 4-h mixed meal in 41 patients with newly diagnosed type 1 diabetes and followed the course of this response for 24 months in 20 patients. Newly diagnosed diabetic patients had an average total insulin secretion in response to a mixed meal that was 52% of that in nondiabetic control subjects, considerably higher than has been described previously. In diabetic patients there was a decline of beta-cell function at an average rate of 756 +/- 132 pmol/month to a final value of 28 +/- 8.4% of initial levels after 2 years. There was a significant correlation between the total insulin secretory response and control of glucose, measured by HbA(1c) (P = 0.003). Two persistent patterns of insulin response were seen depending on the peak insulin response following the oral meal. Patients with an early insulin response (i.e., within the first 45 min after ingestion) to a mixed meal, which was also seen in 37 of 38 nondiabetic control subjects, had a significantly accelerated loss of insulin secretion, as compared with those in whom the insulin response occurred after this time (P < 0.05), and significantly greater insulin secretory responses at 18 and 24 months (P < 0.02). These results, which are the first qualitative studies of insulin secretion in type 1 diabetes, indicate that the physiologic metabolic response is greater at diagnosis than has previously been appreciated, and that the qualitative insulin secretory response is an important determinant of the rate of metabolic decompensation from autoimmune destruction.

The frequency of type 1 diabetes mellitus (T1DM)-associated HLA DQ alleles in the U.S. Pacific Northwest is as high as in Scandinavia, which has the highest T1DM incidence in the world. The high regional rate of islet autoimmunity observed among DPT-1 relatives supports this notion. Fortunately, Washington State archives dried blood spots after legislature-mandated newborn screening. The Diabetes Evaluation in Washington (DEW-IT) study aims to show that population-based prospective prediction of T1DM by HLA genotype screening followed by autoantibody surveillance can be performed within the public health infrastructure.

Background: Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease., Methods: We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease., Results: Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment., Conclusions: Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.

Objective: Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population., Research Design and Methods: Autoantibodies to pancreatic islets (islet cell antibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test >99th percentile., Results: Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25-75%) and 100% sensitivity (58-100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86-99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers., Conclusions: Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years.

The aim of the study was to describe 5-year changes in meal-stimulated pancreatic insulin reserve in adults with normal and impaired glucose tolerance (NGT, IGT) and diabetes, with or without islet-related antibodies. This was a 5-year follow-up of 270 residents of Wadena, MN, of northern European origin, with good kidney function, defined as creatinine clearance greater than 60 mL/min/1.73 m(2). The subjects comprised a population-based sample originally studied in 1986 to 1987. Urine C-peptide (CP), in a 260-minute collection, was the integrated measure of insulin secretion; Ensure-Plus (Ross, Columbus, OH) was the liquid meal. Islet cytoplasmic antibodies (ICA), insulin autoantibodies (IAA), and glutamate decarboxylase antibodies (GAD65ab) were measured. In 182 subjects with NGT, there was no mean within-subject change in urine CP over 5 years (P =.34). In 41 subjects with impaired GT (IGT), there was a moderate, but nonsignificant, increase in mean CP, and 6 (15%) subjects increased. In 37 type 2 diabetic subjects not taking insulin (type 2-No Ins), who had a mean diabetes duration at the 5-year examination of 9.6 +/- 6.3 years, there was a 21% decrease in mean urine CP (P =.012), attributable mostly to a major drop in 8 of the 37 subjects (22%). Islet-related antibody tests were mostly negative; GAD65ab positivity was related to CP decline only among insulin-taking subjects. In summary, in Wadena adults, meal-stimulated urine CP was stable or increased over 5 years in subjects with NGT and IGT, but CP decreased significantly in about one fifth of type 2-No Ins subjects, with no relation to antibody test results., (Copyright 2002 by W.B. Saunders Company)