Gestational diabetes mellitus

GDM is characterized by carbohydrate intolerance of variable severity, with onset or first recognition during pregnancy.

Increased insulin resistance is part of the altered physiology of pregnancy. It is believed to occur in order to supply the fetus with an abundant supply of nutrients needed for its growth and development. This physiologic rise in insulin resistance gradually increases during the second half of pregnancy and is rapidly alleviated after birth. This increase in the gravida’s resistance to insulin is thought to arise from a combination of increased maternal adiposity and the effects of the hormonal products of the placenta. This progressive increase in insulin resistance is countered by an increase in the levels of insulin secreted by pancreatic β cells. Islet cells have a remarkable ability to adopt to these changes in insulin resistance by increased production of insulin so that glucose homeostasis is maintained during normal pregnancy and glucose levels are only minimally influenced by such robust changes in insulin resistance.

However, the glucose homeostasis is a continuum. There is a gradual decline between normal although altered physiologic state of insulin resistance towards the deranged state of gestational diabetes and ending at the extreme end at overt diabetes. The obese population suffers from elevated blood glucose levels, insulin resistance, and high rates of overt diabetes. Obese women are characterized by a significantly higher postprandial glucose peak value, increased 1- and 2-h postprandial glucose levels, increased time interval for glucose peak, and significantly lower mean blood glucose during the night . Maternal hyperglycemia during pregnancy was thought to be one of the most important predictive factors of pregnancy complications in the obese population. It is now recognized that other maternal parameters associated with obesity and/or overnutrition during pregnancy are also involved including hyperglycemia and hypertriglyceridemia. The altered endocrine milieu associated with obesity (increased levels of insulin, androgens, and leptin) is also associated with a number of maternal metabolic disturbances such as insulin resistance, diabetes, and increased blood pressure . Usually, glucose tolerance returns to normal post partum in most women with GDM. However, population-based studies have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Furthermore, from a historical perspective of the diagnosis of GDM, the definition of an abnormal 100-g oral glucose tolerance test (OGTT) in pregnancy was selected to identify women at a risk of subsequent T2DM .

Alternations in insulin resistance

As previously mentioned, insulin resistance plays a pivotal role in the pathogenesis of gestational diabetes. How can we measure insulin resistance? Some indirect measure of insulin sensitivity can be obtained by measurement of fasting blood levels of insulin and glucose concentrations and by calculating the fasting insulin to glucose ratio. This can provide a qualitative but not a quantitative estimation of insulin sensitivity. In order to obtain a more quantitative measure for insulin resistance, investigators have been using hyperinsulinemic–euglycemic clamps and minimal-model analysis of intravenous glucose tolerance tests (IVGTT) . The IVGTT model provides data on the glucose infusion that is required to maintain euglycemia during constant insulin infusion.

This model was applied to obese pregnant subjects by Catalano et al. They produced direct measures of insulin sensitivity during the third trimester of pregnancy and found that, in women with GDM, there is an increased resistance to insulin’s ability to stimulate glucose utilization. Differences in insulin sensitivity between diabetic and nondiabetic subjects were also reported by Ryan et al. Furthermore, insulin sensitivity was lower in patients diagnosed later with GDM than in patients with normal pregnancies even at 12–14 weeks of gestation iii. Therefore, women who developed GDM were more insulin resistant than women without GDM .

Although these methods are probably more useful in the experimental setting, measuring maternal serum levels of glucose and C-peptide taken at fasting and 1 hour after 75 g of oral glucose can also be used to assess insulin sensitivity in a more clinical setting with strong correlation to the methods mentioned above . The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study evaluated pregnant women with a 75-g oral glucose test. The results of this study clearly show a continuous linear relationship between any given glucose level and adverse pregnancy outcomes including preeclampsia, cesarean sections, etc. There was no specific threshold above which these adverse outcomes were more common, but rather a continuum in which increased glucose levels resulted in increased prevalence adverse pregnancy outcomes.

Which tissues are responsible for this increase in insulin resistance? Currently, we have no conclusive answer to this question. An indirect explanation can be derived from data obtained from animal models . These data show a 40% reduction in insulin-mediated glucose utilization by skeletal muscle and a similar effect in cardiac muscles and adipose tissues. It remains unclear whether hepatic sensitivity to insulin is also reduced, therefore lowering hepatocyte suppression of gluconeogenesis in response to insulin.

Which hormones play an important part in increasing insulin resistance during pregnancy? Several hormones are thought to take place in this process:

Cortisol – Cortisol levels increase with advancing pregnancy reaching a level threefold higher than the prepregnancy state by the end of the third trimester . An observational study comparing pregnant women with gestational diabetes and impaired glucose tolerance to women with normal glucose tolerance found significantly lower levels of serum cortisol in the normal pregnancy group . Animal models demonstrate that this may be the result of hepatic insulin resistance related to cortisol’s influence on the post-receptor mechanism .

Leptin – Leptin is secreted from adipose tissue. Increased body fat causes elevations in leptin concentrations. There is also a correlation between serum levels of fasting insulin and leptin, making leptin a good marker of obesity and insulin resistance. Leptin levels are significantly higher in pregnancy than in the nonpregnant state, especially during the second and third trimesters . A study investigating plasma concentrations of leptin and B-cell hormones in pregnant and nonpregnant women was conducted by Kautzky-Willer et al. They measured leptin and insulin at 28 weeks of gestation at fasting and after an oral glucose load (OGTT: 75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant . Plasma leptin was significantly higher in women with gestational diabetes than in women with normal glucose tolerance and increased in both groups when compared with nonpregnant women. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose, insulin, and proinsulin as well as with BMI making leptin an indirect measure of diabetes severity as well. Other investigators also found that leptin levels are elevated in pregnant women with gestational diabetes, and that its metabolism depends on insulin levels and the severity of diabetes.

Human Placental Lactogen (hPL) – This is secreted from the placenta. Its level increased during the second half of pregnancy. Beck et al. demonstrated that an infusion of hPL in physiologic amounts causes impairment of glucose tolerance despite increased plasma insulin. They showed that hPL is a physiologic antagonist to insulin during pregnancy. Animal models demonstrated that hPL (similar to cortisol) exceeds its action in increasing insulin resistance by way of a post-binding defect in the insulin receptor mechanism during pregnancy.

Alternations in insulin resistance

As previously mentioned, insulin resistance plays a pivotal role in the pathogenesis of gestational diabetes. How can we measure insulin resistance? Some indirect measure of insulin sensitivity can be obtained by measurement of fasting blood levels of insulin and glucose concentrations and by calculating the fasting insulin to glucose ratio. This can provide a qualitative but not a quantitative estimation of insulin sensitivity. In order to obtain a more quantitative measure for insulin resistance, investigators have been using hyperinsulinemic–euglycemic clamps and minimal-model analysis of intravenous glucose tolerance tests (IVGTT) . The IVGTT model provides data on the glucose infusion that is required to maintain euglycemia during constant insulin infusion.

This model was applied to obese pregnant subjects by Catalano et al. They produced direct measures of insulin sensitivity during the third trimester of pregnancy and found that, in women with GDM, there is an increased resistance to insulin’s ability to stimulate glucose utilization. Differences in insulin sensitivity between diabetic and nondiabetic subjects were also reported by Ryan et al. Furthermore, insulin sensitivity was lower in patients diagnosed later with GDM than in patients with normal pregnancies even at 12–14 weeks of gestation iii. Therefore, women who developed GDM were more insulin resistant than women without GDM .

Although these methods are probably more useful in the experimental setting, measuring maternal serum levels of glucose and C-peptide taken at fasting and 1 hour after 75 g of oral glucose can also be used to assess insulin sensitivity in a more clinical setting with strong correlation to the methods mentioned above . The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study evaluated pregnant women with a 75-g oral glucose test. The results of this study clearly show a continuous linear relationship between any given glucose level and adverse pregnancy outcomes including preeclampsia, cesarean sections, etc. There was no specific threshold above which these adverse outcomes were more common, but rather a continuum in which increased glucose levels resulted in increased prevalence adverse pregnancy outcomes.

Which tissues are responsible for this increase in insulin resistance? Currently, we have no conclusive answer to this question. An indirect explanation can be derived from data obtained from animal models . These data show a 40% reduction in insulin-mediated glucose utilization by skeletal muscle and a similar effect in cardiac muscles and adipose tissues. It remains unclear whether hepatic sensitivity to insulin is also reduced, therefore lowering hepatocyte suppression of gluconeogenesis in response to insulin.

Which hormones play an important part in increasing insulin resistance during pregnancy? Several hormones are thought to take place in this process:

Cortisol – Cortisol levels increase with advancing pregnancy reaching a level threefold higher than the prepregnancy state by the end of the third trimester . An observational study comparing pregnant women with gestational diabetes and impaired glucose tolerance to women with normal glucose tolerance found significantly lower levels of serum cortisol in the normal pregnancy group . Animal models demonstrate that this may be the result of hepatic insulin resistance related to cortisol’s influence on the post-receptor mechanism .

Leptin – Leptin is secreted from adipose tissue. Increased body fat causes elevations in leptin concentrations. There is also a correlation between serum levels of fasting insulin and leptin, making leptin a good marker of obesity and insulin resistance. Leptin levels are significantly higher in pregnancy than in the nonpregnant state, especially during the second and third trimesters . A study investigating plasma concentrations of leptin and B-cell hormones in pregnant and nonpregnant women was conducted by Kautzky-Willer et al. They measured leptin and insulin at 28 weeks of gestation at fasting and after an oral glucose load (OGTT: 75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant . Plasma leptin was significantly higher in women with gestational diabetes than in women with normal glucose tolerance and increased in both groups when compared with nonpregnant women. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose, insulin, and proinsulin as well as with BMI making leptin an indirect measure of diabetes severity as well. Other investigators also found that leptin levels are elevated in pregnant women with gestational diabetes, and that its metabolism depends on insulin levels and the severity of diabetes.

Human Placental Lactogen (hPL) – This is secreted from the placenta. Its level increased during the second half of pregnancy. Beck et al. demonstrated that an infusion of hPL in physiologic amounts causes impairment of glucose tolerance despite increased plasma insulin. They showed that hPL is a physiologic antagonist to insulin during pregnancy. Animal models demonstrated that hPL (similar to cortisol) exceeds its action in increasing insulin resistance by way of a post-binding defect in the insulin receptor mechanism during pregnancy.

Alternations in insulin secretion

We have discussed the causes for the increase in insulin resistance during pregnancy. Most normal pregnant women are able to counteract the peripheral resistance to insulin by a significant increase of their basal and nutrient-stimulated insulin secretion. Insulin secretion from pancreatic β cells increases as pregnancy progresses reaching levels twice as high at the end of pregnancy compared to nonpregnant levels . This increase in insulin secretion compensates for the gradual increase in insulin resistance and helps explain why blood glucose levels are minimally altered during normal pregnancy . However, some pregnant women do not appear to have the capability to significantly augment their insulin secretion and therefore are not able to overcome the increasing peripheral resistance to insulin. These include women who become glucose intolerant to such an extent that the diagnostic criteria for gestational diabetes are fulfilled. The exact mechanisms by which such an abundant increase in pancreatic β-cell insulin secretion is mediated are still mostly unknown. There are some findings that may be related to this process; for instance, during pregnancy, maternal prolactin levels increase seven-to tenfold. Gustafson et al. reported that the basal insulin concentration and insulin levels post glucose challenge along with insulin responses were greater in women with hyperprolactinemia than in healthy controls. These findings were supported by an experimental model of cultured pancreatic islet cells that showed that prolactin (PRL) induces an increase in insulin secretion . However, Skouby et al. failed to demonstrate a clear relationship between severity of hyperprolactinemia and GDM . They studied pregnant women diagnosed with GDM compared with normal pregnancy. In their study, there was no difference in basal prolactin concentrations between the two groups either in pregnancy or post partum. The prolactin levels were not altered during the OGTTs and no correlation between the deterioration of glucose tolerance and the PRL concentrations could be demonstrated in either group. They concluded that prolactin levels are not of pathophysiologic importance in the development of GDM. Brelje et al. found that, in islet cell culture, hPL directly stimulates insulin secretion. This may indicate that hPL directly regulates islet cell function and is probably the principal hormone responsible for the increase in islet function observed during normal pregnancy. These examples illustrate the complexity of the hormonal interactions related to the pathogenesis of GDM and its complications.

Lipid metabolism and gestational diabetes

As mentioned above, alternations in insulin resistance and secretion are pivotal in the pathophysiology of gestational diabetes. However, these factors influence the homeostasis of many metabolites besides glucose.

The alternations in peripheral insulin resistance cause ingested nutrients to be directed towards storage in the adipose tissue. During early pregnancy, an accumulation of maternal fat tissue occurs followed by increased adipose tissue lipolysis and subsequent hyperlipidemia, which mainly corresponds to increased TGs in all circulating lipoproteins . Maternal serum levels of cholesterol and triacylglycerol decrease at about 7 weeks of gestation and increase progressively thereafter until term . Maternal anabolism and energy storage are needed in late pregnancy to facilitate fetal growth when it is maximal.

Postprandial insulin has an antilipolytic action so that the release of free fatty acids (FFAs) from adipose tissue is suppressed. Therefore, FFA levels are only slightly higher in pregnancy during the first hours after meals. During fasting, the insulin levels decrease and there is an increase in lipolysis and, as a result, an increase in the serum level of FFAs (“accelerated starvation of pregnancy”). The net result is an increase in the circulating levels of FFAs during pregnancy. As pregnancy advances and insulin resistance increases, insulin shows a decrease in its ability to suppress FFA levels. This was demonstrated using the hyperinsulinemic–euglycemic clamp in GDM patients and normal-glycemic pregnancies . The ability of insulin to suppress plasma FFA was significantly lower in women with GDM.

In GDM, especially during the third trimester, there is an associated increase in triacylglycerol and decrease in HDL concentration . Other studies showed lower low-density lipoprotein (LDL) cholesterol levels in pregnant insulin-resistant women with GDM, compared with women with normal glucose tolerance. The authors hypothesized decreased LDL cholesterol production and increased direct removal of TG-enriched VLDL cholesterol due to insulin resistance and the effect of elevated estrogen on LDL cholesterol catabolism . A positive correlation between increased maternal serum TGs and neonatal body weight or fat mass has been found in pregnancies complicated by GDM. This is another mechanism by which GDM causes an increase in pregnancy complications such as macrosomia.

The aforementioned accumulation of maternal adipose tissue during pregnancy has other metabolic effects. Adipose tissue secretes several specific proteins called adipocytokines that modulate the action of insulin in different tissues. One of the novel adipokines studied is adipocyte fatty acid-binding protein (AFABP), a member of the intracellular fatty acid-binding protein multigene family . This adipokine is a protein responsible for intracellular fatty acid transfer and it also plays a role in the regulation of hormone-sensitive lipase activity . Maternal serum levels of AFABP show a strong association with maternal prepregnancy BMI in both normal-glycemic women and GDM women . Other adipokines also secreted by adipose tissue have been reported to modulate the insulin response such as leptin and adiponectin , but it is beyond the scope of this short review to discuss their contribution in any detail. However, it is important to mention that the accumulation of adipose tissue is associated with a chronic state of inflammation as well as alternation in the homeostasis of cytokines and adipokines . Increase in adiposity may also be associated with tissue-specific changes in mitochondrial function and elevated production of reactive oxygen species (ROS) leading to increased oxidative stress . The combination of excess maternal serum fatty acids and oxidative stress leads to the production of oxidized lipids. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism, and lipid transport , which may explain some of the adverse pregnancy outcomes related to obesity such as preeclampsia.

Karacay et al. aimed to assess the plasma and serum maternal total antioxidant status, circulating levels of lipid peroxidation breakdown products (malonyldialdehyde (MDA)), protein oxidation markers (advanced oxidation protein products (AOPPs)), myeloperoxidase (MPO) and lipid hydroperoxide (LHP) in preeclampsia and GDM patients and compare them with noncomplicated normal pregnancies between 24 and 36 weeks of gestation. They concluded that increased oxidative stress and reduction in antioxidant defense mechanisms may contribute to disease processes in both GDM and preeclampsia.

Insulin resistance – an underlining common pathological explanation

Insulin resistance with secondary hyperinsulinemia is suspected to be the link between hypertension and diabetes. The hypertensive effect of hyperinsulinemia is postulated to be due to weight gain, extra cellular fluid volume expansion because of renal sodium retention probably resulting from increased sympathetic activity due to insulin . Several studies have suggested that gestational hypertension, but not preeclampsia, is associated with insulin resistance , while others have illustrated that the association is true for the entire spectrum of hypertensive disorders . This is not uniformly accepted as there are studies that do not concur with these findings. Still, the majority of studies supports the role of insulin resistance in the pathogenesis of the hypertensive disorders in pregnancy – from gestational hypertension, to preeclampsia and eclampsia, as is the case for nonpregnancy essential hypertension. As for dyslipidemia, it is unknown whether abnormal lipid and inflammatory pathways observed in women with preeclampsia are present prior to pregnancy leading to hypertension and other disease manifestations or these develop as a result of the disease process of preeclampsia. Although a correlation between elevated maternal TG levels and the risk of preeclampsia was found , it was not found to be an independent predictor .