Changes in the Kinase Activity of the Insulin Receptor Account for an Increased Insulin Sensitivity of Mammary Gland in Late Pregnancy

Abstract

Mammary gland is an organ that undergoes cycles of growth, differentiation, and function during pregnancy and lactation. Although it is known that the gland enhances its sensitivity to insulin during lactation, it remains to be investigated whether this increased sensitivity develops during pregnancy and which are the molecular mechanisms underlying such a change. To address this issue, virgin and late-pregnant rats were subjected to a continuous infusion with 50% glucose for 72 h to produce a prolonged hyperinsulinemic-euglycemic condition. Insulin sensitivity in mammary gland was determined as the glucose utilization index by using 2-[3H]-deoxyglucose. Furthermore, binding characteristics and kinase activity were studied by means of both [125I]insulin binding and in vitro phosphorylation studies with insulin receptors partially purified from mammary gland. Whereas the glucose utilization index in mammary gland from nonpregnant rats remained unaffected by hyperinsulinemia, glands from pregnant rats displayed a high insulin-dependent glucose uptake. This effect was not paralleled by changes in the binding characteristics of insulin to the high-affinity receptor, suggesting that the high insulin sensitivity of mammary gland in pregnancy is not accounted for by changes at the level of hormone-receptor interaction. Autophosphorylation studies showed that insulin-stimulated kinase activity of insulin receptors from mammary gland was 6- and 20-fold higher in pregnant than in virgin animals under normo- and hyperinsulinemic conditions, respectively. Moreover, insulin dose-response curves revealed that the efficacy of insulin to stimulate kinase activity of the insulin receptor was markedly higher in pregnant than in virgin rats, whereas its potency (ED50 approximately 15 nM) was not changed. These data, therefore, show that mammary glands develop increased insulin sensitivity during late pregnancy, caused by an augmented kinase activity of the insulin receptor.

Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy

“…1A). These data fit well with the observation that the amount of IR protein does not change in the skeletal muscle of pregnant women (30) and support the hypothesis that, similar to other situations of insulin resistance like obesity or type 2 diabetes (24), postbinding receptor defects play a major role on development of peripheral insulin resistance at late pregnancy.…”

Expression, activity, and localization of hormone-sensitive lipase in rat mammary gland during pregnancy and lactation

“…Different from the insulin-resistant condition that is normally present during late pregnancy in adipose tissue (54,55) and skeletal muscle (55)(56)(57), the mammary gland shows increased insulin sensitivity caused by an augmented kinase activity of the insulin receptor (42). It has also been shown that insulin participates in the enhanced expression of LPL in the mammary gland during late pregnancy (58), whereas it is responsible for the decrease of LPL activity normally seen in maternal white adipose tissue (59,60).…”

“…To attain a better understanding of the potential function of HSL in the mammary gland, the present work was addressed at determining the cell types that might express this protein and the changes that take place in its expression and activity in the mammary gland during pregnancy and lactation in the rat. In addition, because insulin is well known as the most active antilipolytic hormone (39,40) and during late pregnancy and lactation the mammary gland remains highly sensitive to it (41,42), the study was extended to determine the potential relationship between plasma insulin levels and mammary gland HSL activity during those same stages.…”

Changes in mammary fat pad composition and lipolytic capacity throughout pregnancy

“…Since insulin has been shown to decrease β 3 -AR levels (Engfeldt et al 1988;Feve et al 1994;Hadri et al 1997), the decrease observed in this adrenoceptor, mainly in late pregnancy, might be explained by both hyperinsulinaemia and enhanced insulin sensitivity in the mammary gland in late-pregnant rats (Carrascosa et al 1998), contrary to the insulin resistance present in most tissues. During late pregnancy, the lower specific content of the rate-limiting enzyme of lipolysis, HSL, also points to decreased lipolytic activity in this tissue, which might contribute to its increased lipid storage.…”