Central actions of insulin during pregnancy and lactation

Abstract

Pregnancy and lactation are highly metabolically demanding states. Maternal glucose is a key fuel source for the growth and development of the fetus, as well as for the production of milk during lactation. Hence, the maternal body undergoes major adaptations in the systems regulating glucose homeostasis to cope with the increased demand for glucose. As part of these changes, insulin levels are elevated during pregnancy and lower in lactation. The increased insulin secretion during pregnancy plays a vital role in the periphery; however, the potential effects of increased insulin action in the brain have not been widely investigated. In this review, we consider the impact of pregnancy on brain access and brain levels of insulin. Moreover, we explore the hypothesis that pregnancy is associated with site-specific central insulin resistance that is adaptive, allowing for the increases in peripheral insulin secretion without the consequences of increased central and peripheral insulin functions, such as to stimulate glucose uptake into maternal tissues or to inhibit food intake. Conversely, the loss of central insulin actions may impair other functions, such as insulin control of the autonomic nervous system. The potential role of low insulin in facilitating adaptive responses to lactation, such as hyperphagia and suppression of reproductive function, are also discussed. We end the review with a list of key research questions requiring resolution.

Keywords: insulin; lactation; pregnancy.

FIGURE 1

The key question of central insulin action in the brain during pregnancy: does elevated insulin level increase central insulin function or does central insulin resistance develop? Insulin is secreted from beta-cells in the pancreas (as indicated by the brown immunoreactive staining in the cross-section of pancreas) and maternal adaptation in glucose regulation leads to increased insulin levels to compensate for increased peripheral insulin resistance during pregnancy. The effect of increased insulin levels during pregnancy on central insulin functions are yet to be thoroughly explored

FIGURE 2

Changes in cellular insulin signalling in various hypothalamic nuclei in the non-pregnant and pregnant state. Insulin is transported from the blood into the brain, where it acts in various regions, including hypothalamic areas such as the arcuate nucleus, paraventricular nucleus (PVN), dorsomedial nucleus (DMH) and ventromedial nucleus (VMH). Interaction of insulin with its receptor leads to phosphorylation of Akt (pAkt) as part of insulin-induced intracellular signalling cascade. In the arcuate nucleus, insulin suppresses (solid red arrow) mRNA expression of orexigenic neuropeptide Y (NPY) and agouti-related peptide (AGRP) and stimulates (solid green arrow) mRNA expression of anorectic pro-opiomelanocortin (POMC). Phosphatase and tensin homolog (PTEN) is a negative regulator of Akt and phosphorylation leads to deactivation of this function of PTEN. During pregnancy (middle) insulin transport into the brain is not reduced, whereas insulin-induced pAkt in the arcuate nucleus and VMH is attenuated. NPY, AgRP and POMC mRNA expression in the arcuate nucleus is dissociated from peripheral insulin levels. Reduced phosphorylated PTEN (pPTEN) in the VMH suggests that a reduction in the deactivation of this inhibitory signalling molecule might contribute to attenuated insulin-induced pAkt during pregnancy. During lactation (bottom), the low plasma insulin concentrations are likely to limit the effects of insulin in the brain. Exogenously administrated insulin can regulate NPY, AgRP and POMC mRNA levels, indicating that there is a restoration of insulin sensitivity in these neurones compared to pregnancy, yet the low endogenous insulin levels likely contribute to high NPY and AgRP mRNAs and low POMC mRNA observed during lactation. Whether there are changes in insulin transport into the brain or insulin responses in other neurone populations during lactation has yet to be determined. Green arrows indicate stimulatory effects of insulin, whereas red arrows indicate inhibitory effects. Grey arrows/text indicates the attenuated actions of insulin during pregnancy. 3V, third ventricle