Pregnancy an inflammatory insulinresistant state

Profound metabolic adjustments occur during pregnancy to assure an adequate nutrient supply is available to support fetal growth. Since glucose is the preferred fuel of the fetus, maternal metabolism is shifted toward a hyperglycemic state. This ensures facilitated glucose diffusion from maternal circulation across the placenta to the fetus. Maternal hyperglycemia is created by establishing an insulin-resistant state. Maternal insulin resistance increases throughout gestation, reaching a peak in late gestation when fetal fuel demands are the highest.12 The rise in insulin resistance is ascribed to alterations in maternal cortisol levels and placental hormones (human placental lactogen, progesterone, and estrogen).12 However, the changes in insulin resistance have never been correlated with these hormonal changes in a prospective, longitudinal study.13

The recent evidence that adipokines such as TNF-a and leptin affect insulin sensitivity in non-pregnant individuals has led investigators to propose that similar mechanisms may occur in pregnancy. Pro-inflammatory cytokines may influence insulin metabolism in pregnant as well as non-pregnant women for several reasons. First, pregnant women with adequate food supplies gain fat during the first two trimesters.1 The amounts gained vary from 0 to 10 kg and the average is about 3.5 kg. Expansion of the fat tissue and enlarged adipocytes may increase adipose tissue cytokine secretion and subsequent insulin resistance in pregnant women similar to that seen in non-pregnant individuals. Second, the placenta expresses all known cytokines including TNF-a, IL-6, IL-10, leptin, resistin, and PAI-1.14

The physiological role of these placental cytokines is uncertain, but many of the same cytokines are produced by the placenta as are secreted by adipose tissue. Possibly, the high placental cytokine secretion assists in creating the maternal insulin-resistant state. Since maternal fat gain is very limited or non-existent in pregnant women with limited energy intakes, the placenta is likely to be more important for creating a maternal insulin-resistant state than is an increase in maternal adipose tissue.

To test the hypothesis that placental cytokines play a role in modifying insulin sensitivity in pregnancy, Kirwan and co-workers measured circulating hormones, cytokines, and insulin resistance in 15 women (5 with GDM and 10 with normal glycemia) before pregnancy, at 12 to 14 weeks of gestation, and at 34 to 36 weeks of gestation.13 Changes in insulin sensitivity were compared to placental hormones, cortisol, leptin, and TNF-a. TNF-a was more strongly associated with insulin sensitivity than any other hormone or cytokine measured; higher TNF-a levels were associated with lower insulin sensitivity (r = -0.69, p <0.006). Furthermore, the change in TNF-a from pregravid to late pregnancy was the only factor significantly predicting the decline in insulin sensitivity (r = -0.60, p <0.02). After adjusting for differences in body fat, TNF-a explained 21% of the variance in insulin sensitivity. None of the placental reproductive hormones was correlated with insulin sensitivity in late pregnancy. These data suggest that placental TNF-a plays a major role in causing the decline of insulin sensitivity during pregnancy.

To further evaluate the effects of pro-inflammatory cytokines on insulin resistance during pregnancy, Radaelli and co-workers measured the effect of GDM on the expression of placental genes. Placentas were collected from 15 women at the time of cesarean section (7 GDM women and 8 controls). A total of 22,823 gene sequences were surveyed; 435 genes were significantly modified in GDM placenta. Of those 435 genes modified in the placentas of GDM women, 18% or the largest cluster were related to inflammatory responses. Interleukins, leptin, TNF-a, and their downstream molecular adaptors were up-regulated. These findings confirm that placentas from diabetic mothers create an inflammatory milieu that enhances insulin resistance. These placental adjustments in gene expression may also cause adverse fetal programming.

Studies in non-pregnant individuals show that proinflammatory cytokines promote lipolysis in adipose tissue, enhance the delivery of free fatty acids to liver and muscle, and thereby contribute to insulin resistance. In pregnancy, plasma free fatty acid levels increased, reaching their highest levels in late pregnancy when insulin resistance also peaked.15 This rise in free fatty acids may be linked to the rise in placental cytokines in maternal circulation. However, lipolysis and the release of free fatty acids from maternal adipose tissue were also enhanced by placental hormones, specifically human placental lactogen.16

In fact, artificially elevating plasma free fatty acids concentrations by infusing lipid during euglycemic clamp studies of pregnant women at 14 to 17 weeks of gestation inhibited total body glucose uptake and oxidation to rates similar to those observed in late pregnancy.16 This confirmed that the levels of free fatty acids play an important role in regulating insulin sensitivity in pregnancy. Recent research suggests that the circulating levels of cytokines secreted by the placenta may mediate shifts in free fatty acid concentrations and subsequent insulin resistance.

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