Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.     

Heterogeneity of human red cell autoantibodies assessed by isoelectric focusing

Human red cell (RBC) autoantibodies may be the products of a single lymphocyte clone or of a restricted number of clones. For insight into the clonal distribution of human RBC autoantibodies, serum fractions from 28 individuals with various forms of autoimmune hemolytic anemia (AHA) and two nonanemic individuals with positive direct antiglobulin tests were separated by isoelectric focusing (IEF), and RBC binding in each fraction was quantitated with a solid-phase radioimmunoassay. IEF fractions of serum from normal volunteers and patients with nonimmune hemolytic anemia served as controls. These studies indicate that RBC antibodies are found in a restricted number of IEF fractions in sera from some patients with immune hemolytic anemia. IEF fractions containing RBC-binding activity vary among patients with idiopathic AHA, and distinct patterns of binding activity are found in serum from some patients with AHA associated with alphamethyldopa and procainamide or with B-cell immunoproliferative diseases. These findings suggest that the mechanism leading to autoantibody production may differ among patients with the various forms of immune hemolytic anemia.     

Both insulin sensitivity and insulin clearance in children and young adults with Type I (insulin-dependent) diabetes vary with growth hormone concentrations and with age

Aims/hypothesis. We measured insulin clearance rates in children and young adults with Type I (insulin-dependent) diabetes mellitus to establish their relation with insulin sensitivity and with factors such as growth hormone secretion and body mass index.¶Methods. We studied 46 subjects [mean (range) age 14.4 (9.8–24.6) years), body mass index 21.1 (15.8–29.6)Kgm²] using an overnight (1800–0800 hours) variable rate insulin infusion euglycaemic clamp protocol (5 mmol/l). Plasma free insulin concentrations during steady-state euglycaemia were used as an index of insulin sensitivity and insulin clearance determined as a ratio of insulin infusion rate to plasma free insulin.¶Results. During steady-state euglycaemia (0500–0730 hours), insulin sensitivity [mean (SEM) plasma insulin 0.020 (0.002) mU/l] and insulin clearance rates [19.1 (1.8) ml · kg^–1· min] varied with age non-linearly and in a reciprocal fashion to each other (cubic regression F = 4.09, p = 0.01; F = 3.55, p = 0.02, respectively). Insulin sensitivity was negatively related to BMI (r = –0.37, p = 0.011) and mean overnight growth hormone concentrations (r = –0.40, p = 0.007). Insulin clearance was only related to growth hormone concentrations (r = –0.37, p = 0.014). These relations were still evident after stepwise multiple regression analysis (potential determinants: C peptide, sex, age, puberty stage, HbA_{1 c}, duration of diabetes): insulin sensitivity r = 0.55, p < 0.001; insulin clearance r = 0.37, p < 0.02.¶Conclusions/interpretation. Insulin clearance rates vary with age in young subjects with Type I diabetes and are highest during mid-adolescence when insulin sensitivity is at its lowest. Both insulin sensitivity and insulin clearance are related to circulating growth hormone concentrations. [Diabetologia (2000) 43: 61–68]     

Fasting and post-glucose ghrelin levels in SGA infants: relationships with size and weight gain at one year of age

Wide ranges in postnatal weight gain are seen in infants born small for gestational age (SGA); most show some catch-up growth and this may be driven by increased appetite. Ghrelin, the natural ligand of the GH secretagogue receptor, has potent orexigenic effects. In adults circulating ghrelin levels are increased in anorexia, decreased in obesity and show post prandial suppression. The aim of the present study was to test the hypothesis that rate of weight gain over the first year in SGA infants may relate to variable suppression of circulating ghrelin levels. Serum ghrelin levels were measured in 1 y old infants born SGA (n = 85) and in control infants born adequate for gestatitional age (AGA) (n = 22) fasting and 10 minutes after intravenous (iv) glucose (0.5 g/Kg of 25% dextrose). Sex- and gestational age-adjusted SD scores (SDS) for body weight were calculated at birth and at 1 y, and delta weight SDS between 0-1 y was calculated as an index of postnatal weight gain. In both SGA and AGA groups, ghrelin levels reduced from fasting (mean +/- SE: 104.4 +/- 6.4 fmol/ml) to 10 minutes post-iv glucose (82.7 +/- 5.3, p < 0.005). There were no differences in ghrelin levels between SGA and AGA infants (fasting or post-iv glucose). However, in SGA infants ghrelin levels post-glucose, but not fasting, were psitively related to current length (r = 0.28, p < 0.05), weight (r = 0.23, p < 0.05) and to change in weight SDS 0-1 y (r = 0.22, p < 0.05). SGA infants who showed poor catch-up growth showed a larger decline in ghrelin concentrations post-iv glucose. In conclusion, circulating ghrelin levels rapidly decreased after iv glucose. Higher ghrelin levels or lower reductions in circulating levels following iv glucose were seen in SGA infants who showed greater infancy weight gain, suggesting that sustained orexigenic drive could contribute to postnatal catch-up growth.     

A longitudinal study of total and free thyroid hormones and thyroxine binding globulin during normal puberty

Thyroid hormones are essential for normal pubertal growth, yet the changes in total and, especially, free thyroid hormones and thyroxine-binding globulin during puberty have not been adequately defined. Serum from 39 normal children (20 girls, 19 boys) between the ages of 10 and 15 years were assayed for total T4, free T4, free T3 and thyroxine-binding globulin at 6-monthly intervals; the free hormone assays were valid, non-analogue methodologies. In the girls, free T4 levels fell from 15.7 +/- 0.6 pmol/l at 10 years to 13.0 +/- 0.6 (p less than 0.001) at 12.5 years before rising to 15.9 +/- 0.7 at 15 years; this nadir occurred at puberty stages 3-4. Changes in total T4 followed a similar pattern with a slight delay in the nadir (13 years, puberty stage 4). In the boys, free T4 fell from 16.3 +/- 0.6 pmol/l at 10 years to 14.3 +/- 0.3 at 13.5 years, then rising to 15.4 +/- 0.5 at 15 years; the nadir again occurred at puberty stages 3-4. The corresponding nadir in total T4 which occurred at puberty stages 4-5 was not apparent by age analysis. Thyroxine-binding globulin concentrations remained unchanged in the girls, but fell slightly in the boys during later puberty. Free T3 concentrations in the girls showed a progressive fall after 12.5 years which was significant by the age of 14 when most had been in puberty stage 5 for more than 1 year. The boys showed no change of free T3 concentration throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)