Endocrine Abstracts (2006) 11 P413

Polymorphisms in insulin-like growth factor binding protein-1 (IGFBP-1) are associated with altered circulating IGF-I and lower body mass index in type-2 diabetes mellitus

AH Heald1, RH Stephens2, P McElduff4, K Kaushal2, K Siddals2, JP New2, J Worthington3, WE Ollier3 & JM Gibson2

1Bishop Auckland General Hospital, Bishop Auckland, United Kingdom; 2Vascular Research Group, Hope Hospital, Salford, United Kingdom; 3Centre for Integrated Genomic Research, Stopford Building, Manchester, United Kingdom; 4School of Epidemiology and Health Sciences, Stopford Building, Manchester, United Kingdom.

Introduction: Dysregulation of the insulin-like Growth Factor (IGF) system and particularly IGF-I and IGF binding protein-1 (IGFBP-1) has been implicated in the pathogenesis of obesity, diabetes mellitus and its complications such as cardiovascular disease and nephropathy, but relatively little is known about the genomics of the IGF system in health and disease.

Methods: Six single nucleotide polymorphisms (SNPs) were genotyped in the IGFBP-1 gene, in a representative sample of 732 Type-2 Diabetes patients from the Salford Diabetes Register, using ABI TAQMAN endpoint PCR.

Results: Minor alleles of two SNPs, one in the second intron (C2877T) and one in the 3′ flanking region (A5881G) of the IGFBP-1 gene, were associated with altered circulating total IGF-I. One of these SNP’s (A5881G), and four others, from the promoter (G-575A), intron 1 (A643G and T555C), and exon 4 (A4403G) were associated with consistently lower BMI over the ten years 1993–2003, and all of these except G-575A were further associated with a reduced rate of increase in BMI over time. Total, non-fasted plasma IGFBP-1 levels were negatively associated with BMI, but not with any genotype.

Discussion: Given the importance of IGFBP-1 in modulating IGF bioavailablity in relation to nutrient intake, it is quite conceivable that subtle changes in IGFBP-1 expression could have a significant long term impact on an individual’s predisposition to weight gain, whether or not they have type 2 diabetes. We propose that genetic variation in the IGFBP-1 gene may have a direct influence on the development of obesity and type 2 diabetes.