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Discovery of a Met³⁰⁰Val Variant in Shc and Studies of Its Relationship to Birth Weight and Length, Impaired Insulin Secretion, Insulin Resistance, and Type 2 Diabetes Mellitus¹

Steno Diabetes Center and Hagedorn Research Institute (K.A., M.G.A., T.H., S.A.U., O.P.), and the Center of Preventive Medicine, Glostrup University Hospital (J.O.C.), DK-2820 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Katrine Almind, Ms.Sci., Steno Diabetes Center, Niels Steensensvej 2, Gentofte, DK-2820 Copenhagen, Denmark.

The Shc adaptor proteins corresponding to the 46-, 52-, and 66-kDa isoforms are key transducers of growth promotion and gene expression, which are being 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 retardation 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 plausible candidate. Therefore, the aim of this study was to analyze whether genetic variability of the Shc isoforms causes a decrease in cell growth and cell differentiation that could be manifested by a decrease in birth weight and length, impaired acute insulin secretion after iv glucose, insulin resistance, and eventually a higher prevalence of type 2 diabetes. By single strand conformation polymorphism-heteroduplex analysis of 70 patients with diabetes mellitus and subsequent nucleotide sequencing of identified single strand conformation polymorphism variant, we discovered a Met³⁰⁰Val substitution of the 52-kDa isoform. The amino acid variant was predicted to be present 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 carriers and noncarriers in birth weight and length, the acute insulin response to iv glucose, or the insulin sensitivity index, as estimated from an iv glucose tolerance test. In an association study of 313 type 2 diabetic patients and 226 matched glucose-tolerant subjects, there was no significant difference in allelic frequency of the Shc variant (5.1% in diabetic patients vs. 3.1% in control subjects; P = 0.11). In conclusion, by itself the Met³⁰⁰Val polymorphism of Shc has no major impact on birth weight and length, insulin sensitivity index, acute glucose-induced insulin secretion, or prevalence of random type 2 diabetes mellitus.

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