Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19–23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-ζ, the two subunits of phosphoinositol 3-kinase (i.e., p85α and p110β) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

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Low birth weight has been associated with an increased incidence of ischaemic heart disease (IHD) and type 2 diabetes. Endocrine regulation of fetal growth by growth hormone (GH) and insulin-like growth factor (IGF)-I is complex. Placental GH is detectable in maternal serum from the 8th to the 12th gestational week, and rises gradually during pregnancy where it replaces pituitary GH in the maternal circulation. The rise in placental GH may explain the pregnancy-induced rise in maternal serum IGF-I levels. In the fetal compartment, IGF-I levels increase significantly in normally growing fetuses from 18 to 40 weeks of gestation, but IGF-I levels are four to five times lower than those in the maternal circulation. Thus IGF-I levels in fetal as well as in maternal circulation are thought to regulate fetal growth. Circulating levels of IGF-I are thought to be genetically controlled and several IGF-I gene polymorphisms have been described. IGF-I gene polymorphisms are associated with birth weight in some studies but not in all. Likewise, IGF-I gene polymorphisms are associated with serum IGF-I in healthy adults in some studies, although some controversy exists. Serum IGF-I decreases with increasing age in healthy adults, and this decline could hypothetically be responsible for the increased risk of IHD with ageing. A recent nested case-control study found that adults without IHD, but with low circulating IGF-I levels and high IGF binding protein-3 levels, had a significantly increased risk of developing IHD during a 15-year follow-up period. In summary, the GH/IGF-I axis is involved in the regulation of fetal growth. Furthermore, it has been suggested that low IGF-I may increase the risk of IHD in otherwise healthy subjects. Hypothetically, intrauterine programming of the GH/IGF axis may influence postnatal growth, insulin resistance and consequently the risk of cardiovascular disease. Thus IGF-I may serve as a link between fetal growth and adult-onset disease.

This study showed an increased spontaneous postnatal growth velocity in the carriers of the d3-GHR allele. Interestingly, we found the opposite effect on prenatal growth in the SGA group, with a decreased FGV in carriers of the d3-GHR allele.

Poor growth in early life is associated with numerous adverse outcomes later in life. In 123 adolescents 16-18 yr of age, the previous findings of a positive relation between size in early life and later bone mass was confirmed. These associations were mediated by the current height and weight, but it was not confirmed that alterations of the GH-IGF axis cause this.Introduction: Numerous studies have found associations between low birth weight and disease later in life, including decreased bone mass. Materials and Methods: A longitudinal cohort of 16-to 19-year-old adolescents (n ‫ס‬ 123) with data on third trimester fetal growth velocity (FGV) was assessed by serial ultrasound measurements, birth weight (BW), and weight at 1 yr. A follow-up study included DXA scan, anthropometric measurements, and measurements of the growth hormone (GH) -IGF-I axis in a representative subpopulation (n ‫ס‬ 30). Results: BW and weight at 1 yr were positively associated with whole body BMC (p ‫ס‬ 0.02 and p < 0.0001, respectively), lumbar spine BMC (p ‫ס‬ 0.001 and p ‫ס‬ 0.03, respectively), and lumbar spine BMD (p ‫ס‬ 0.04). After correction for adolescent height and weight, no association remained significant. There was no relation between IGF-I and IGF binding protein 3 (IGFBP-3) levels in adolescence and size in early life or bone mass. In the subpopulation, GH secretion (median, 2.58 versus 4.05), GH pulse mass (median, 10.7 versus 19.4 mU/liter), and total GH (median, 74.9 versus 108.8 mU/liter/12 h) were decreased in the small for gestational age (SGA) group compared with the appropriate for gestational age (AGA) group; this did not reach statistical significance. Likewise, there were no differences in IGF-I, IGF-II, and IGFBP-1, -2, and -3 levels between the SGA and AGA groups. A statistically significant positive association between FGV and adolescent IGF-II was found (B ‫ס‬ 199.9, p ‫ס‬ 0.006). Significant negative associations between GH measurement and BMC, as well as BMD, were found (B ‫ס‬ -0.008, p ‫ס‬ 0.005 and B ‫ס‬ -0.008, p ‫ס‬ 0.006, respectively). Conclusions: This study confirms the previous findings of a positive relation between size in early life and later BMC, an association apparently independent of the distal part of the GH/IGF-I axis. However, this association may be mediated mainly by postnatal growth determining size of the skeletal envelope rather than an effect of fetal programming on bone mass per se.