Diabetes
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The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. ⋯ A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.
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Insulin resistance may be an important cause of a constellation of cardiovascular risk factors in adults, and onset of this syndrome may occur in childhood. However, children normally experience transient insulin resistance at puberty. There were 357 normal children (159 girls, 198 boys) age 10-14 years who underwent euglycemic clamp studies to assess the effects of Tanner stage (T), sex, ethnicity, and BMI on insulin resistance. ⋯ Insulin resistance was strongly related to BMI, triceps skinfold thickness, and waist circumference, and this relationship was independent of Tanner stage or sex. Differences in BMI and adiposity did not, however, entirely explain the insulin resistance of puberty. These results demonstrate that 1) significant differences in insulin resistance are present between boys and girls; 2) insulin resistance increases significantly at T2, T3, and T4, but decreases to near prepubertal levels at T5; and 3) while insulin resistance is related to BMI and anthropometric measures of fatness, these factors do not completely explain the insulin resistance that occurs during the Tanner stages of puberty.
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Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). ⋯ On stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.
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Clinical Trial Controlled Clinical Trial
Cow's milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes.
Insulin autoantibodies (IAAs) often appear as the first sign of islet cell autoimmunity in prediabetic children. Because cow's milk contains bovine insulin, we followed the development of insulin-binding antibodies in children fed with cow's milk formula. Bovine insulin- and human insulin-binding antibodies by enzyme immunoassay and IAA by radioimmunoassay were analyzed in 200 infants carrying HLA-DQB1*0302 but no protective alleles who participated in a Finnish population-based birth-cohort study. ⋯ IgG antibodies correlated with IgG2 antibodies binding to bovine insulin (r = 0.43, P = 0.004) and IAA (r = 0.27, P = 0.02) in diabetic children, but not in healthy children. Cow's milk feeding is an environmental trigger of immunity to insulin in infancy that may explain the epidemiological link between the risk of type 1 diabetes and early exposure to cow's milk formulas. This immune response to insulin may later be diverted into autoaggressive immunity against beta-cells in some individuals, as indicated by our findings in children with diabetes-associated autoantibodies.
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The adipocyte hormone leptin reduces food intake in normal animals. During uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake increases. To test the hypothesis that low leptin levels contribute to diabetic hyperphagia, we investigated the effect on food intake of replacement of leptin at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled diabetes induced by streptozotocin (STZ). ⋯ To determine if sensitivity to leptin-induced anorexia was affected by STZ treatment, a second experiment was performed in which the effect of intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 microg) on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed both 4- and 24-h food intake in the two groups to an equal extent at every dose (by 15, 22, and 35%, respectively). These findings support the hypothesis that the effect of uncontrolled diabetes to lower leptin levels contributes to diabetic hyperphagia and that this effect is not due to altered leptin sensitivity.