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Down-Regulation of Insulin Receptor Substrates (IRS)-1 and IRS-2 and Src Homologous and Collagen-Like Protein Shc Gene Expression by Insulin in Skeletal Muscle Is Not Associated with Insulin Resistance or Type 2 Diabetes

Wallenberg Laboratory, Department of Endocrinology, University of Lund, 20502 Malmo, Sweden

Address all correspondence and requests for reprints to: Xudong Huang, Wallenberg Laboratory, Department of Endocrinology, MAS 46 P 3, 20502 Malmo, Sweden. E-mail: xudong.huang{at}endo.mas.lu.se

To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. Insulin-stimulated glucose uptake was decreased both in the diabetic and nondiabetic twin, compared with healthy control subjects (5.2 ± 0.7 and 8.5 ± 0.8 vs. 11.4 ± 0.9 mg/kg·min^-1; P < 0.01 and P < 0.02, respectively). Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 ± 0.06 to 0.21 ± 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 ± 0.10 to 0.16 ± 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 ± 0.04 to 0.71 ± 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. There was an inverse correlation between postclamp Shc mRNA concentration and glucose uptake (r = -0.53, P = 0.01; n = 22) in the controls and nondiabetic twins. However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance.

This work was supported by grants from Albert Pahlsson Foundation, Crafoord Foundation, Sigrid Juselius Foundation, MAS Foundation at Lund University, and Ingabritt and Arne Lundberg Foundation.

Abbreviations: FFM, Fat free mass; IRS, insulin receptor substrate; M-value, insulin-mediated glucose uptake; RT, reverse transcriptase; Shc, Src homologous and collagen-like protein.

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