Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes

Women who develop gestational diabetes mellitus (GDM) have severe insulin r esistance and markedly increased risk to develop subsequent type 2 diabetes . We investigated the effects of pregnancy and GDM on glucose transport act ivity and the expression and phosphorylation of the insulin receptor and in sulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in v itro, Rectus abdominis muscle biopsies were obtained at the time of cesarea n section from 11 pregnant women with normal glucose tolerance (pregnant co ntrol), 7 pregnant women with GDM, and 11 non-pregnant women undergoing ele ctive surgery (nonpregnant control), Subjects were matched for age and simi lar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulate d 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips f rom the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs, pregnant control). The maximal effect of insulin on tyrosine phos phorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subject s than in pregnant control subjects and was not related to changes in the a bundance of the insulin receptor, Compared with nonpregnant control subject s, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significan tly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in mu scle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0. 01) and p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0,05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-I protein. However, in GDM subjects, a decr ease in tyrosine phosphorylation of the insulin receptor P-subunit is assoc iated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction unde rlying muscle insulin resistance in young women with GDM, and it may underl ie future risk for the development of type 2 diabetes.