Pathophysiology and Pathogenesis of GDM

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Normal pregnancy and GDM are states of profound insulin resistance and the mediating factors are similar, if not identical. However, women who develop GDM tend also to be insulin-resistant when not pregnant and become even more insulin-resistant during pregnancy [18]. GDM develops when p cells are unable to compensate the increasing insulin resistance with sufficiently greater insulin secretion to maintain normal fasting and/or postprandial glucose concentrations [18, 19].

Placental Factors

For many years, clinical and research evidence has indicated a role for the placenta in the development of insulin resistance and the list of putative mediators of this effect is long (table 2). The placenta is also an endocrine organ and numerous studies have demonstrated potential mechanisms for hormones of placental origin to contribute to insulin resistance. Furthermore, insulin sensitivity is restored quickly after the placenta is expelled. In the last several years, it has been demonstrated that the placenta synthesizes and potentially secretes an array of mediators and cytokines (e.g. leptin, C-reac-tive protein, tumor necrosis factor (TNF)-a, interleukins 6 and 8) that may influence maternal metabolism and insulin sensitivity directly or indirectly [20]. Radaelli et al. [21] compared patterns of gene expression in placentas from pregnancies with normal glucose metabolism or GDM. They found major differences in the expression profiles with increases in markers and mediators of inflammation (interleukins, leptin and TNF-a receptors and downstream adaptors) in GDM. Whether these alterations of gene expression

Table 2. Factors of placental origin that putatively contribute to insulin resistance

Large placenta size Human placental lactogen

Human chorionic gonadotropin

Prolactin Estradiol

Progesterone Human growth hormone

(placental variant) Corticotrophin-releasing factor/cortisol Leptin Resistin

Interleukin 6 Interleukin 8

Tumor necrosis factor-a C-reactive protein

Pathophysiology Gdm

Fig. 2. The correlation between a change in TNF-a and a change in insulin sensitivity from before pregnancy to late pregnancy in subjects with normal carbohydrate metabolism (•) or gestational diabetes (♦) is plotted. Adapted from Kirwan et al. [23, fig. 4] with permission.

Fig. 2. The correlation between a change in TNF-a and a change in insulin sensitivity from before pregnancy to late pregnancy in subjects with normal carbohydrate metabolism (•) or gestational diabetes (♦) is plotted. Adapted from Kirwan et al. [23, fig. 4] with permission.

represent primary events or occur as a secondary response to the increased delivery of nutrients, hormones and mediators from maternal tissues and their accumulation/storage in the placenta, e.g. triglycerides and glycogen [22], remains to be determined. Kirwan et al. [23] measured insulin sensitivity serially during pregnancy in a group of women with normal glucose tolerance or GDM and correlated these indices with measures of body composition, plasma TNF-a, leptin cortisol and reproductive hormones. Levels of TNF-a, leptin cortisol, fat mass, and all reproductive hormones measured were increased in late gestation compared to early in pregnancy; however, only a change in TNF-a from early to late pregnancy predicted the magnitude of change in insulin sensitivity over the same time (fig. 2).

Adipocyte-Derived Mediators

Leptin is synthesized in both adipose tissue and placenta. Plasma leptin concentrations are increased during pregnancy. Its potential contribution to insulin resistance is uncertain [24]. Adiponectin is another adipocyte-derived protein that may also play a role in insulin resistance and predisposition to altered glucose metabolism. Adiponectin levels tend to be low in insulin-resistant states including GDM and have been found to correlate with p-cell function in late pregnancy [25].

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Responses

  • prima bolger-baggins
    When are insulin resistance the worse with gdm?
    2 years ago

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