Discovery of a Met(300)Val variant in Shc and studies of its relationship to birth weight and length, impaired insulin secretion, insulin resistance,and type 2 diabetes mellitus

The Shc adaptor proteins corresponding to the 46-, 52-, and 66-kDa isoforms are key transducers of growth promotion and gene expression, which are bei ng phosphorylated by all known receptor tyrosine kinases after stimulation by growth factors such as insulin and insulin-like growth factor I. Several studies have demonstrated a relationship between intrauterine growth retar dation and impaired glucose tolerance or type 2 diabetes later in life. It is unclear whether this finding is partially explained by genetic factors. In this context, abnormalities in Shc proteins are considered to be a plaus ible candidate. Therefore, the aim of this study was to analyze whether gen etic variability of the Shc isoforms causes a decrease in cell growth and c ell differentiation that could be manifested by a decrease in birth weight and length, impaired acute insulin secretion after iv glucose, insulin resi stance, and eventually a higher prevalence of type 2 diabetes. By single st rand conformation polymorphism-heteroduplex analysis of 70 patients with di abetes mellitus and subsequent nucleotide sequencing of identified single s trand conformation polymorphism variant, we discovered a Met(300)Val substi tution of the 52-kDa isoform. The amino acid variant was predicted to be pr esent in all 3 isoforms of Shc. In a genotype-phenotype study of 360 young healthy subjects, the allelic frequency of the codon 300 polymorphism was 4 .2%. In this cohort, no significant differences could be shown between carr iers and noncarriers in birth weight and length, the acute insulin response to iv glucose, or the insulin sensitivity index, as estimated from an iv g lucose tolerance test. In an association study of 313 type 2 diabetic patie nts and 226 matched glucose-tolerant subjects, there was no significant dif ference in allelic frequency of the Shc variant (5.1% in diabetic patients us. 3.1% in control subjects; P = 0.11). In conclusion, by itself the Met(3 00)Val polymorphism of Shc has no major impact on birth weight and length, insulin sensitivity index, acute glucose-induced insulin secretion, or prev alence of random type 2 diabetes mellitus.