Changes in the Kinase Activity of the Insulin Receptor Account for an Increased Insulin Sensitivity of Mammary Gland in Late Pregnancy¹

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-[ 3 H]-deoxyglucose. Furthermore, binding characteristics and kinase activity were studied by means of both [125 I]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 (ED 50 ϳ 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. (Endocrinology 139: 520 -526, 1998)

Lipid metabolism in the fetus and the newborn

“…Through this mechanism, plasma triglycerides are driven to be taken up by mammary glands for milk synthesis instead of being accumulated in adipose tissue [33,93] (see Figure 3). Besides the induction effect of prolactin on mammary glands LPL [94,95], these changes are mediated by the opposite responsiveness to insulin seen around parturition between mammary glands and adipose tissue, which is enhanced in the former [42,96] and decreased in the latter [41,42,97]. These changes allow essential fatty acids from maternal diet circulating as triglyceride-rich lipoproteins in maternal plasma to become available to the suckling newborn.…”

Introductory Chapter: Milk Protein Synthesis, Progress, and Projections

“…The mammary gland is known to be hypersensitive to insulin during lactation and at the onset of pregnancy, with an increased sensitivity until the end of pregnancy, primarily due to an augmented kinase activity of the insulin receptor [10]. One of the primary functions of insulin in the mammary gland is the control of milk protein synthesis by inducing translation via activation of mTOR pathway and activation of signal transducer and activator of transcription (STAT5) through phosphorylation [9].…”

Microproteomic-Based Analysis of the Goat Milk Protein Synthesis Network and Casein Production Evaluation

“…Due to the high kinase activity of insulin receptors, the mammary gland remains highly sensitive to insulin throughout pregnancy and the lactation period [8]. Milk protein synthesis requires the activity of insulin, amino acids, and amino acid transporters, as well as the mammalian target of rapamycin (mTOR) pathway [9][10][11].…”