Varying brain insulin concentrations differentially regulate the fetal brain insulin receptor

Chronic Intracerebroventricular Infusion of Insulin Failed to Alter Brain Insulin‐Binding Sites, Food Intake, and Body Weight

“…Changes in CSF insulin content had no effect on specific insulin binding sites in various areas of the brain. This is consistent with other in vivo studies showing that a three-to sixfold increase in cellular insulin content by exogenous insulin was without any effect on insulin binding sites in hypothalamus from the rat (Melnyk and Martin, 1984~) or brain from the rabbit fetus (Devaskar et al, 1986). Indeed, it has been shown that in vivo down-regulation of brain insulin receptors is not a physiologic, but a pharmacologic, effect of insulin detected in the rabbit fetus when the cellular insulin level was increased to > 130 ng/g (Devaskar et al, 1986).…”

The Heterogeneity of the Developing Brain Insulin Receptor

“…Again, no differences were observed, suggesting that the N-linked glycosylation did not regulate the ability to down-or up-regulate the fetal and adult liver IR in response to varying insulin concentrations. One could argue that the brain IR N-linked glycosylation failed to change, possibly due to a lack of change in brain insulin and/or insulin receptor number (5). However, the liver, which is exposed to circulating insulin concentrations, did not demonstrate a change in response to hormonal perturbations as well, negating this theory.…”

“…In spite of this persistence of IR heterogeneity in the embryo, fetus, and adult, the fetal IR has been demonstrated to be distinct in other respects from the adult IR, for example, the IR in various fetal tissues is higher in number/mg (38)(39)(40), fails in vivo to down-regulate in response to high circulating insulin concentrations (8)(9)(10) and mediates an immature biologic response of insulin (4 l), specifically with regard to hepatic glucose to glycogen conversion (41). Similarly, the brain IR fails to down regulate in response to insulin both in vivo (5) and in vitro (6) and mediates a unique biologic effect of insulin within the central nervous system (16,17). As suggested previously, if N-linked glycosylation were responsible for down-regulation of the IR, one would expect to see similar glycosylation patterns in the fetal and adult brain IR and the fetal liver IR alone (adult liver IR being different), because these receptors uniformly express an inability to down-regulate in response to insulin.…”

“…The neuronal (-125 kD) and microvascular (-125 kD, -135 kD) IR are deficient in sialic acid, thus conferring neuraminidase-insensitivity to the whole brain, whereas the glial cell IR, similar to the liver IR, exhibits neuraminidase sensitivity and migrates intermediate (-128 The IR, a heterotetrameric glycopeptide composed of two aand two /?-subunits linked by disulfide bonds, mediates the biologic effects of insulin (I). In the brain of both the adult (2) and developing animal (3)(4)(5), insulin and insulin receptors have been demonstrated. These brain IR are unique in the sense that they do not down-regulate in response to high insulin concentrations (5, 6), a phenomenon that has been observed in various fetal neural (5, 7) and nonneural tissues as well (8)(9)(10).…”

Maternal Diabetes-Induced Hyperglycemia and Acute Intracerebral Hyperinsulinism Suppress Fetal Brain Neuropeptide Y Concentrations1

“…The fetuses were delivered by reopening the hysterotomy incision under pentobarbital anesthesia either 4 h (short term) or 24 h (long term) after laparotomy (31). Upon exposure of the uteri, using microinjection syringes (705NWG, Hamilton Co., Reno, Nevada) fetuses received regular crystalline (short term) or NPH isophane (long term) insulin injections (Sigma Diagnostics) either intracerebroventricularly (1 mU in 2 l vehicle) via the anterior fontanelle or ip (5 mU in 5 l vehicle) through the uterine wall while still maintaining an intact feto-placental unit within the uterus.…”