Insulin-like growth factor-I genotype and birthweight

Abstract

Norbert Vaessen and colleagues1Vaessen N Janssen JA Heutink P et al.Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight.Lancet. 2002; 359: 1036-1037Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar describe the interesting observation that a polymorphism of the IGF-I gene is closely associated with low birthweight and an increased incidence of type 2 diabetes mellitus. It is relevant in this context that a phenotypic association between low birthweight and increased incidence of type 2 diabetes is supported by a large Scandinavian study.2Eriksson JG Forsen T Tuomilehto J Jaddoe VW Osmond C Barker DJ Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals.Diabetologia. 2002; 45: 342-348Crossref PubMed Scopus (272) Google Scholar From their results, Vaessen and colleagues propose that a specific IGF-I polymorphism is related to the extent of plasma IGF-I expression, a key factor in the development of pancreatic insulin-secreting cells. This proposal is supported by previous animal knock-out and transgenic models in which the concentration of plasma IGF-I is a determinant of the development and maturation of the insulin secreting β cells in fetal life, which consequently affects insulin-secreting properties of the β cells in adult-life.3Hill DJ Petrik J Arany E Growth factors and the regulation of fetal growth.Diabetes Care. 1998; 21: B60-B69Crossref PubMed Google Scholar Most IGF-I in plasma is bound to IGF-binding protein-3 (IGFBP-3). Due to the heritability of expression of IGF-I and IGFBP-3 (more with respect to IGFBP-3 than IGF-I4Harrela M Koistinen H Kaprio J et al.Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3.J Clin Invest. 1996; 98: 2612-2615Crossref PubMed Scopus (274) Google Scholar), we have assessed whether the relation between plasma IGF-I concentration and IGFBP-3 expression in insulin-secreting cells, or both, is conserved in adult-life. We did a standard oral glucose tolerance test (75 g glucose), and a hyperglycaemic clamp (10 mmol/L during 180 min) with measurement of first and second (average plasma insulin in 140–80 min period) phase insulin secretion in 53 non-diabetic individuals (mean age 46 years, SD 6; 13 men, 40 women; mean body-mass index 25·9 kg/m2Eriksson JG Forsen T Tuomilehto J Jaddoe VW Osmond C Barker DJ Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals.Diabetologia. 2002; 45: 342-348Crossref PubMed Scopus (272) Google Scholar, SD 3·8). Plasma IGF-I concentrations were not related to variables of insulin secretion, but plasma concentrations of IGFBP-3 were significantly correlated with second-phase insulin secretion (p=0·025) in the clamp, and with baseline (p=0·056) and 120-min plasma insulin after the oral glucose tolerance test (p=0·037). Multiple linear regression showed that the effect of IGFBP-3 on insulin secretion could be accounted for by body-mass index. Thus, IGFBP-3 concentrations are closely related to insulin secretion in the adult pancreas. Several factors, including growth hormone status, age, nutrition, and hepatic function affect plasma concentrations of IGFBP-3. However, the variation between individuals of concentrations of IGFBP-3 in the circulation seems to be largely determined by a genetic component.4Harrela M Koistinen H Kaprio J et al.Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3.J Clin Invest. 1996; 98: 2612-2615Crossref PubMed Scopus (274) Google Scholar Hence, at least to a certain extent, IGFBP-3 concentrations at the tissue level are also affected by genetic factors. IGFBP-3 plays an important part in the modulation (inhibitory or stimulatory) of IGF action at the cellular level. During fetal development, local concentrations of IGF and IGFBP-3 may affect the balance between cell apoptosis and the maturing of functional β cells,3Hill DJ Petrik J Arany E Growth factors and the regulation of fetal growth.Diabetes Care. 1998; 21: B60-B69Crossref PubMed Google Scholar and hence the insulin secretory capacity in adult life. This may explain the intriguing finding that a relation exists between plasma IGFBP-3 and insulin secretion by the adult pancreas. The apparent effect of body-mass index on this relation remains puzzling. Considered together with the data of Vaessen and colleagues, we also suggest that pancreatic β-cell function may be primarily determined early in life. ThBT has received personal financial support from the foundation De Drie Lichten and a grant from the Dutch Association of Science (NWO).