Defects in insulin signal transduction in liver and muscle of pregnant rats

Abstract

Insulin resistance during pregnancy has been reported both in women and in experimental animals [1][2][3][4][5][6][7], but the mechanism of this resistance remains unclear. In vivo studies have shown that pregnant rats become progressively resistant to insulin after day 16 of gestation [5]. In these animals, the insulin resistance of skeletal muscle has been clearly demonstrated in vitro, while the insulin resistance in vivo in peripheral tissues and liver has been substantiated in studies using the euglycaemic-hyperinsulinaemic clamp technique [6,7].Insulin initiates its metabolic and growth-promoting effects by binding to the a subunit of its tetrameric receptor, thereby activating the kinase in the b subunit [8]. This interaction catalyses the intramolecular autophosphorylation of specific tyrosine residues of the b subunit which further enhances the tyrosine kinase activity of the receptor toward other protein substrates [8]. In most cells, this primary event leads to the subsequent tyrosyl phosphorylation of a cytoplasmic protein with an apparent molecular weight of 160-185 kDa, called insulin receptor substrate 1 (IRS-1) [9][10][11]. Considerable evidence indicates that insulin receptor tyrosine Diabetologia (1997) 40: 179-186 Defects in insulin signal transduction in liver and muscle of pregnant rats Summary Pregnancy is known to induce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study, we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1(IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of pregnant rats (day 20 of gestation) by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1, anti-PI 3-kinase and antiphosphotyrosine antibodies. There were no changes in the insulin receptor concentration in the liver and muscle of pregnant rats. However, insulin stimulation of receptor autophosphorylation, as determined by immunoblotting with antiphosphotyrosine antibody, was reduced by 30 ± 6 % (p < 0.02) in muscle and 36 ± 5 % (p < 0.01) in liver at day 20 of gestation. IRS-1 protein levels decreased by 45 ± 6 % (p < 0.002) in liver and by 56 ± 9 % (p < 0.002) in muscle of pregnant rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the muscle and liver of pregnant rats decreased by 70 ± 9 % (p < 0.01) and 75 ± 8 % (p < 0.01), respectively. The insulin-stimulated IRS-1 association with PI 3-kinase decreased by 81 ± 6 % in muscle (p < 0.01) and 79 ± 11 % (p < 0.01) in the liver during pregnancy. These data suggest that changes in the early steps of insulin signal transduction may have a role in the insulin resistance observed in pregnancy. [Diabetologia (1997) 40: 179-186]

Dose- and time-dependent effects of 17beta-oestradiol on insulin sensitivity in insulin-dependent tissues of rat: implications of IRS-1

“…Taking these data together with our own findings, we postulated that the decrease in insulin sensitivity in group E between days 11 and 16 of treatment could be related to a release of IRS-1 protein from the cytoskeletal scaffold, where it is able to interact with the insulin receptor and pass to the cytosol, where it could be recruited by another hormonal signalling pathway. However, our results on IRS-1 seem not to confirm those of Saad et al (1997), who reported a decrease in the expression of IRS-1 in skeletal muscle during late pregnancy. We consider that these differences could have various explanations.…”

Modulation of Insulin Receptor Substrate-1 and Some Inflammatory Variables in Hyperinsulinemic Rats Treated with Cinnamon Extract

“…This is in agreement with the report of Bezerra et al (2000) who stated that there was a significant reduction in the level of hepatic and muscle IRS-1 tyrosine phosphorylation, followed by a reduction in IRS-1/PI3-kinase association in liver and muscle. The decrease observed in this study may be of biological importance because a reduction of receptor phosphorylation has been correlated with insulin resistance in different animal models (Saad et al, 1997). These results differed from those of Deutsch et al (1993) who reported no change in insulin receptor kinase activity in fructose-fed rats.…”

Role of 17beta-estradiol and/or progesterone on insulin sensitivity in the rat: implications during pregnancy

“…However, the effect of the menstrual cycle on this carbohydrate metabolism and insulin sensitivity remains to be determined. Clinical conditions such as pregnancy, where estrogen and progesterone concentrations are markedly raised, have a substantial effect on carbohydrate, lipid, and intermediary metabolism, as well as altering insulin sensitivity (Herrera et al 1991, Baaziz & Curry 1993, Metcalfe et al 1994, Saad et al 1997. Artificially raised levels of the sex steroid hormones, estrogen and progesterone, in women taking the combined oral contraceptive pill were found to affect glucose tolerance and insulin sensitivity (Godsland et al 1991, Watanabe et al 1994.…”