Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche.

BACKGROUND: Early postnatal rapid 'catch-up' weight gain has been consistently associated with subsequent higher obesity risk and earlier pubertal development. In many low- and middle-income countries, infancy catch-up weight gain is transient and often followed by growth faltering. We explored the hypothesis that even transient catch-up weight gain during infancy is associated with later obesity risk and earlier puberty. METHODS: A total of 2352 (1151 male, 1201 female) black South African children in the birth to twenty prospective birth cohort study (Johannesburg-Soweto) underwent serial measurements of body size and composition from birth to 18 years of age. At the age of 18 years, whole-body fat mass and fat-free mass were determined using dual-energy X-ray absorptiometry. Pubertal development was assessed by the research team between ages 9 and 10 years, and it was recorded annually from the age of 11 years using a validated self-assessment protocol. RESULTS: Catch-up weight gain from birth to the age of 1 year, despite being followed by growth faltering between ages 1 and 2 years, was associated with greater mid-upper arm circumference (P=0.04) and skinfold thickness (P=0.048) at 8 years of age, and with higher weight (P<0.001) and body mass index (P=0.001) at 18 years of age after adjustment for sex, age, smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status. Infancy catch-up weight gain was also associated with younger age at menarche in girls (P<0.001). This association persisted after adjustment for smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status (P=0.005). CONCLUSION: Transient catch-up weight gain from birth to the age of 1 year among children born in a low-income area of South Africa was associated with earlier menarche and greater adiposity in early adulthood. This observation suggests that modifiable determinants of rapid infancy weight gain may be targeted in order to prevent later obesity and consequences of earlier puberty in girls.

Cell-free carrier system for localized delivery of peripheral blood cell-derived engineered factor signaling: towards development of a one-step device for autologous angiogenic therapy.

Spatiotemporally-controlled delivery of hypoxia-induced angiogenic factor mixtures has been identified by this group as a promising strategy for overcoming the limited ability of chronically ischemic tissues to generate adaptive angiogenesis. We previously developed an implantable, as well as an injectable system for delivering fibroblast-produced factors in vivo. Here, we identify peripheral blood cells (PBCs) as the ideal factor-providing candidates, due to their autologous nature, ease of harvest and ample supply, and investigate wound-simulating biochemical and biophysical environmental parameters that can be controlled to optimize PBC angiogenic activity. It was found that hypoxia (3% O2) significantly affected the expression of a range of angiogenesis-related factors including VEGF, angiogenin and thrombospondin-1, relative to the normoxic baseline. While all three factors underwent down-regulation over time under hypoxia, there was significant variation in the temporal profile of their expression. VEGF expression was also found to be dependent on cell-scaffold material composition, with fibrin stimulating production the most, followed by collagen and polystyrene. Cell-scaffold matrix stiffness was an additional important factor, as shown by higher VEGF protein levels when PBCs were cultured on stiff vs. compliant collagen hydrogel scaffolds. Engineered PBC-derived factor mixtures could be harvested within cell-free gel and microsphere carriers. The angiogenic effectiveness of factor-loaded carriers could be demonstrated by the ability of their releasates to induce endothelial cell tubule formation and directional migration in in vitro Matrigel assays, and microvessel sprouting in the aortic ring assay. To aid the clinical translation of this approach, we propose a device design that integrates this system, and enables one-step harvesting and delivering of angiogenic factor protein mixtures from autologous peripheral blood. This will facilitate the controlled release of these factors both at the bed-side, as an angiogenic therapy in wounds and peripheral ischemic tissue, as well as pre-, intra- and post-operatively as angiogenic support for central ischemic tissue, grafts, flaps and tissue engineered implants.

Structure and Volta potential of lipid multilayers: effect of X-ray irradiation.

The effect of hard X-ray radiation on the structure and electrostatics of solid-supported lipid multilayer membranes is investigated using a scanning Kelvin probe (SKP) integrated with a high-energy synchrotron beamline to enable in situ measurements of the membranes' local Volta potential (V(p)) during X-ray structural characterization. The undulator radiation employed does not induce any detectable structural damage, but the V(p) of both bare and lipid-modified substrates is found to undergo strong radiation-induced shifts, almost immediately after X-ray exposure. Sample regions that are macroscopically distant (~cm) from the irradiated region experience an exponential V(p) growth with a characteristic time constant of several minutes. The V(p) variations occurring upon periodic on/off X-ray beam switching are fully or partially reversible depending on the location and time-scale of the SKP measurement. The general relevance of these findings for synchrotron-based characterization of biomolecular thin films is critically reviewed.

The effect of prolonged fasting on levels of growth hormone-binding protein and free growth hormone.

OBJECTIVE: There are limited data on growth hormone-binding protein (GHBP) and free GH levels during the physiological challenge of a prolonged fast. Our aim was to explore the relationships between GHBP, free GH, total GH and non-esterified fatty acid (NEFA) levels during overnight and 24-hour fasts in healthy young adults. DESIGN: We measured nocturnal levels of GHBP at three time-points (22:00, 03:00, 08:00), NEFA every 60 min and ultra-filtered free GH and total GH at 15-minute intervals for 10 h (22:00-08:00) during an overnight and a 24-hour fast in 7 female and 4 male normal-weight subjects aged 24.8 years (range: 22.8-26.9) with BMI 22.5 kg/m² (range: 18-27). RESULTS: Spontaneous free and total GH levels were closely related during the overnight and 24-hour fasts (r=0.99, p<0.0001 and r=0.99, p<0.0001 respectively). 24 h of fasting led to an increase in levels of basal free GH (p=0.03), mean free GH (p=0.04), mean total GH (p=0.04) and NEFA (p<0.0001) whilst GHBP levels remained similar (p=0.8). Percentage free (over total) GH was similar during the overnight and prolonged fasts (p=0.3). There were no associations between levels of NEFA and free (r=0.24, p=0.5) or total GH (r=0.20, p=0.6). CONCLUSIONS: A 24-hour fast led to parallel increases in free and total GH levels whilst there was no discernable change in GHBP levels or the fraction of free GH. This suggests that GHBP plays a role in limiting variations of circulating free GH levels. NEFA levels increased during the prolonged fast but they were not correlated with free or total GH levels.

Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects.

Normal beta-cells adjust their function to compensate for any decrease in insulin sensitivity. Our aim was to explore whether a prolonged fast would allow a study of the effects of changes in circulating free fatty acid (FFA) levels on insulin secretion and insulin sensitivity and whether any potential effects could be reversed by the antilipolytic agent acipimox. Fourteen (8 female, 6 male) healthy young adults (aged 22.8-26.9 yr) without a family history of diabetes and a body mass index of 22.6 +/- 3.2 kg/m(2) were studied on three occasions in random order. Growth hormone and FFA levels were regularly measured overnight (2200-0759), and subjects underwent an intravenous glucose tolerance test in the morning (0800-1100) on each visit. Treatment A was an overnight fast, treatment B was a 24-h fast with regular administrations of a placebo, and treatment C was a 24-h fast with regular ingestions of 250 mg of acipimox. The 24-h fast increased overnight FFA levels (as measured by the area under the curve) 2.8-fold [51.3 (45.6-56.9) vs. 18.4 (14.4-22.5) *10(4) micromol/l*min, P < 0.0001], and it led to decreases in insulin sensitivity [5.7 (3.6-8.9) vs. 2.6 (1.3-4.7) *10(-4) min(-1) per mU/l, P < 0.0001] and the acute insulin response [16.3 (10.9-21.6) vs. 12.7 (8.7-16.6) *10(2) pmol/l*min, P = 0.02], and therefore a reduction in the disposition index [93.1 (64.8-121.4) vs. 35.5 (21.6-49.4) *10(2) pmol/mU, P < 0.0001]. Administration of acipimox during the 24-h fast lowered FFA levels by an average of 20% (range: -62 to +49%; P = 0.03), resulting in a mean increase in the disposition index of 31% (P = 0.03). In conclusion, the 24-h fast was accompanied by substantial increases in fasting FFA levels and induced reductions in the acute glucose-simulated insulin response and insulin sensitivity. The use of acipimox during the prolonged fast increased the disposition index, suggesting a partial reversal of the effects of fasting on the acute insulin response and insulin sensitivity.

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.