Fruit of the Womb
Fruit of the Womb

Diabetes in Pregnancy -3 - Normal Changes in Insulin Sensitivity

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In our second post on diabetes in pregnancy, we gave a simple overview of glucose metabolism and discussed the essential role insulin plays in assuring that glucose gets into the cell. Pregnancy alters the normal balances involved in glucose metabolism and insulin production, regulation, and action in a dynamic way that changes throughout gestation. Although, pregnancy is often referred to as a ‘diabetogenic state’ with progressively increasing postprandial (after eating) blood sugar levels, presumably, secondary to an increase in insulin resistance, point in fact is that most pregnant women do not actually develop overt diabetes, and those that do, usually do not do so until late in the second or early in the third trimesters. In normal women, compensatory increases in insulin production overcome the increased resistance to its action.

Interestingly, during the first trimester, insulin requirements usually decrease, resulting in lower blood sugars and a concomitant increase in maternal fat stores. Indeed, early pregnancy can be a particularly dangerous time for long-term diabetics, even if they are under good control before conception, because they may develop an unexpected over-response to the same doses of insulin on which they have been stable, resulting in episodes of hypoglycemia (low blood sugars). Although numerous mechanisms for the decrease in maternal insulin requirements have been proposed, the one that seems to make the most sense to me is that this represents a true increase in sensitivity to insulin (not just an increase in production, although this also occurs in women who are not diabetic and diabetics who are not insulin-dependent). Otherwise it is hard to explain how long-standing “type 1” diabetics, who can make virtually no insulin on their own, experience this effect. It is also one of the main reasons I believe that any woman who has hyperglycemia in first trimester should be classified as a true ‘pregestational diabetic’ even if she did not have the diagnosis of diabetes made prior to the pregnancy.

What causes the increase in insulin sensitivity is really not known. However, it is likely to be pregnancy hormones, and since the early rise and subsequent fall in insulin sensitivity closely parallels the rapid rise and fall in human chorionic gonadotropin (hCG) – THE ‘pregnancy hormone’ measured in all pregnancy tests – my money is that hCG has something to do with it. Nor is it understood what role the increase in insulin sensitivity might play in early pregnancy. Some have proposed that the increase in maternal fat stores resulting from insulin action helps to protect the mother from the metabolic demands of the baby and placenta later in pregnancy. I have often wondered too, since insulin is a potent growth factor, if the increased sensitivity in early pregnancy is somehow related to a role in early placentation, placental growth, and in modulation of the maternal immune response to the pregnancy.

Regardless, by the end of first trimester, a variety of placental and maternal hormones are produced at elevated and increasing levels that have the potential to contribute to the progressively increasing insulin resistance that develops after first trimester. Some of these include progesterone, estrogen, human placental lactogen (hPL), cortisol, and prolactin. In recent years, two other factors produced by the placenta, tumor necrosis factor (TNF)-? and leptin, have also been proposed as mediators of insulin resistance. TNF-?, in particular, has been found by Kirwan and colleagues (Diabetes 2002;51:2207-13) to be inversely correlated with changes in insulin sensitivity from prior to conception through the third trimester and, when analyzed statistically with other placental hormones, alone accounts for about half the variance in the decrease in insulin sensitivity throughout pregnancy.

Just as increased sensitivity to insulin in normal early pregnancy may play an important role in the establishment of a successful pregnancy, decreased sensitivity later in pregnancy must also as well in the maintenance of the baby. Again, looking at this simplistically, if the mother cannot readily process glucose into glycogen and fat stores because of insulin resistance, then it frees it up for the baby to help support its rapid growth and high metabolic resource demands. To the mother’s advantage, insulin resistance also decreases the risk of maternal hypoglycemia. Remember, the baby has demands 24 hours per day (even while in utero) and these do not lessen while the mother is fasting. In the presence of decreased influence of insulin, the liver can increase glucose production to maintain maternal blood sugar levels and to supply the continuous needs of the baby.

In the next post on this topic, we will define the different types of diabetes and the criteria we use for the diagnosis of ‘gestational diabetes’ during pregnancy.
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About the Author

Dr. Trofatter is an expert on maternal-fetal medicine.

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