Polymorphisms in igf-Binding Protein 1 Are Associated With Impaired Renal Function in Type 2 Diabetes

Abstract

The dysregulation of the IGF system has been implicated in the pathogenesis of obesity, diabetes, and diabetes complications such as nephropathy, but little is known about the genomics of the IGF system in health and disease. We genotyped 13 single nucleotide polymorphisms (SNPs) in IGFBP1 gene in 732 representative type 2 diabetic patients from the Salford Diabetes Register. Of the 13 SNPs, 8 were polymorphic and 7 of those had minor allele frequencies >0.1, one of which was in the gene promoter and one of which was nonsynonymous in exon 4. The minor alleles of these SNPs and two others were associated with a reduced prevalence of diabetic nephropathy. Haplotype analysis revealed that 97% of the genetic variation for IGFBP1 in the population sample could be accounted for using two of the "reno-protective" SNPs, with other SNPs adding little extra information. One of these two SNPs was the nonsynonymous mutation in exon 4, lying close to the integrinbinding RGD motif, which is thought to affect tissue delivery of IGF-I by IGF-binding protein 1 (IGFBP-1), possibly suggesting a "reno-protective" effect via altered IGFBP-1 binding. In conclusion, we have described the first genomic markers to be associated with diabetic microvascular complications within the human IGFBP1 gene. Diabetes 54: [3547][3548][3549][3550][3551][3552][3553] 2005 T he IGF system is increasingly implicated in the development of type 2 diabetes and its complications. IGF-I and -II possess significant structural homology with insulin and consequently exert acute metabolic effects on carbohydrate and protein metabolism in addition to their potent mitogenic effects. IGF-I and -II have been linked to the pathogenesis of diabetic nephropathy, retinopathy, cardiovascular disease, deteriorating glucose tolerance, and weight gain (1-13).Unlike insulin, the effects of IGFs are modulated by specific IGF-binding proteins (IGFBPs), six of which have been well characterized (14,15). Of the six IGFBPs, IGFBP-1 is considered to be the principal acute regulator of IGF-I activity (16), forming a link between dietary ingestion, glucose metabolism, and the IGF axis. IGFBP-1 synthesis is limited to the liver, decidua, and kidney and is acutely inhibited by insulin via binding of hepatocyte nuclear factor-3␤ (HNF-3␤) to the insulin-response elements of the gene promoter. Conversely, increased IGFBP-1 production is primarily associated with cAMP and glucocorticoids acting via specific promoter elements, although increased synthesis is also associated with hyperglycemia (via upstream stimulatory factor 1 [USF-1]) and hypoxia (via the hypoxia-inducible transcription factor 1␣ [HIF-1␣] and nitric oxide) (17-22). Thus, IGFBP-1 is acutely metabolically regulated, unlike other IGFBPs (16). Rodent models and clinical observations have underlined the potential importance of IGFBP-1 dysregulation in the etiology of diabetic complications such as macrovascular disease and microvascular conditions such as nephropathy and retinopathy. Renal hypertrophy is an earlyonset feat...

Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect

“…In a study by Stephens et al (2005) two tightly linked SNPs were associated with a reduced prevalence of diabetic nephropathy with the Ile253Met determining the strongest protection. This SNP would most likely affect some aspects of post-translational function of the protein as it is located close to the RGD motif in S Pechlivanis et al: Insulin pathway related genes and risk of CRC www.endocrinology-journals.org the C terminus and may affect the interaction with IGFI (Stephens et al 2005). In our study, we did not observe any association of the Ile253Met polymorphism with the risk of CRC.…”

“…High LD has been reported across the entire IGFBPI gene (Stephens et al 2005, Cheng et al 2006. The Ile253Met SNP is the only validated non-synonymous SNP and has been associated with diabetic nephropathy (Stephens et al 2005).…”

“…So far, prostate cancer is the most intensively studied cancer with regard to the effect of polymorphisms in the INS, IRS1, IRS2, and IGFBPI genes on cancer susceptibility (Ho et al 2003, Claeys et al 2005, Li et al 2005, Neuhausen et al 2005, Stephens et al 2005, Cheng et al 2006. Only one study has focused on IRS1 and IRS2 polymorphisms and the risk of CRC (Slattery et al 2004).…”

“…The Ile253Met SNP is the only validated non-synonymous SNP and has been associated with diabetic nephropathy (Stephens et al 2005).…”

Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes

“…A locally developed ELISA was used to measure IGFBP-1 and this assay detects all phosphoforms of this protein as reported in a previous study. 8 This assay had intraassay and inter-assay %CV of <9% and <15%, respectively. The lower limit of detection of IGFBP-1 assay was 0.1 ng/mL.…”