Amir Aviram, MD Yariv Yogev, MD
Science, like life, feeds on its own decay. New facts burst old rules; then newly divined conceptions bind an old and new together into a reconciling law.
—William James
Key Points
• Hormonal changes in pregnancy result in changes in glucose tolerance that resemble a “diabetogenic state.”
• Maternal insulin resistance is associated with increased adipose tissue early in gestation and nutrient availability in late gestation.
• The hyperinsulinemia of pregnancy is mainly the result of pancreatic β-cell compensation for physiologic insulin resistance.
• Postreceptor defects in insulin signaling may contribute to the pathogenesis of gestational diabetes mellitus and the increased risk for type 2 diabetes later in life.
• Placental and maternal adipose tissue hormones are associated with increased insulin resistance and directly related to the increase in placental growth and endocrine function.
• Nutrients and essential trace elements are associated with insulin resistance in normal and diabetic pregnancies.
INTRODUCTION
This chapter will address the development of insulin resistance during pregnancy; the role of hormones and other factors associated with insulin resistance and secretion; the insulin-signaling system during normal and diabetic pregnancy; and the metabolic predictors of diabetes. Glucose homeostasis and the development of insulin resistance in normal pregnancy as well as in pregnancies complicated by gestational diabetes mellitus (GDM) are discussed in detail in Chapter 12.
DEVELOPMENT OF INSULIN RESISTANCE DURING PREGNANCY
Normal pregnancy has been characterized as a “diabetogenic state” due to the change in the pattern of secretion of insulin, resulting in increased postprandial glucose and insulin response to this increase in late pregnancy. Therefore, pregnancy is a progressive condition in which increasing insulin resistance leads to an increase in insulin secretion. The association between increased insulin resistance and the resulting increase in insulin secretion (hyperinsulinemia) is met in the majority of pregnant women; otherwise, abnormal glucose tolerance develops. After delivery, the diabetogenic state of pregnancy resolves.1,2 Some have reported that women who developed GDM were more insulin resistant than women without GDM.1,3,4 In addition, it has been suggested that due to the high level of estrogen early in pregnancy, there is an increased insulin sensitivity in both normal and GDM pregnancies.5
Glucose is transferred through the placenta by facilitated diffusion, and as mentioned earlier, the changes in the patterns of insulin secretion cause postprandial hyperglycemia. In turn, the postprandial elevation will increase nutrient availability (glucose) to the fetus. In addition, peripheral insulin resistance is more pronounced in the skeletal muscle than in the adipose tissue, resulting in ingested nutrients being shunted toward the adipose tissue. This promotes maternal anabolism and energy storage needed in late pregnancy when fetal growth is maximal.
ASSESSMENT OF INSULIN RESISTANCE
As early as in 1956, Burt6 demonstrated that pregnant women experience fewer hypoglycemic events in response to insulin infusion than nongravid women. Since then, several mathematical and physiological models have been developed to assess insulin resistance and sensitivity, including the hyperinsulinemic-euglycemic clamp, the Bergman model, IS-QUICKI index (quantitative insulin sensitivity check index), and IS-HOMA index (homeostasis model assessment of insulin resistance). The minimal Bergman model and the hyperinsulinemic-euglycemic clamp7,8 have become the premier standard techniques for studying secretion, resistance, and sensitivity relationships during the pregnant and nonpregnant states. It has been demonstrated that insulin sensitivity derived from an oral glucose tolerance test (IS-OGTT) or fasting glucose/insulin levels (IS-QUICKI or IS-HOMA) is comparable with that derived from the clamp, and that all methods can be used to predict insulin sensitivity in women before and during pregnancy. Yet, although univariate analysis yielded significant correlation between the clamp results and IS-QUICKI, IS-HOMA, and IS-OGTT, multivariate analysis taking into account normal glucose tolerant (NGT) women versus GDM patients demonstrated that the IS-OGTT is the superior method of all three.9 The use of the oral glucose tolerance test (OGTT), Bergman model, IS-QUICKI, or IS-HOMA for studying insulin sensitivity is easier to perform, less costly, and may serve as a rapid screening test even in clinical settings, while the hyperinsulinemic-euglycemic clamp is more labor intensive and costlier but provides the ultimate standard for this investigation.
Recently, it has been shown that 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 with strong correlation to the methods mentioned earlier.10 In addition, IS-HOMA has been studied in a clinical setting and was found to corroborate with severity of GDM and obstetrical outcomes.11,12
OBESITY, INSULIN RESISTANCE, AND GLUCOSE PROFILE
Catalano et al.,13,14 using the hyperinsulinemic-euglycemic clamp model, reported 60% increase in the first-phase insulin response to intravenous glucose infusion and a 130% increase in the second phase among obese women with normal glucose tolerance test with advancing gestation, compared with 200%-250% increase among their lean counterparts. He speculated that relative Β-cell dysfunction due to chronic decrease in insulin sensitivity was partially responsible for this phenomenon. In the same study, it was demonstrated that obese women with GDM had significantly greater second-phase insulin response, but not first-phase response, compared with obese women without GDM. In addition, obese women with GDM had lower insulin sensitivity and experienced less suppression of endogenous glucose production in response to insulin infusion, with respect to obese women without GDM. Some of these finding were also supported by an earlier study of obese non-GDM patients, which demonstrated a reduction in the endogenous suppression of hepatic glucose production, thereby indicating a further decrease in hepatic insulin sensitivity.15 The relationship between decreased maternal insulin sensitivity and fetal overgrowth particularly in obese women and women with GDM may help explain the increased incidence of adolescent obesity and related glucose intolerance in the offspring of these women.
Due to the diverse characteristics of obese and nonobese patients, we investigated the ambulatory daily glycemic profile in the second half of pregnancy in obese and nonobese, nondiabetic women using continuous glucose monitoring.16 Obese subjects were characterized by higher postprandial glucose peak values, increased one- and two-hour postprandial glucose levels, and increased time interval for glucose peak in comparison with nonobese subjects. Moreover, obese subjects had significantly lower mean blood glucose levels during the night (23:00 pm to 06:00 am) in comparison with nonobese subjects.
PANCREATIC в-CELL FUNCTION AND INSULIN SIGNALING SYSTEM
Most commonly, assessment of Β-cell function is performed by measuring fasting insulin concentration or as a response to glucose infusion. The cellular determinants of insulin resistance are still not fully understood. During pregnancy, fasting plasma insulin increases gradually; these levels are twofold higher in the third trimester than before pregnancy. Women whose pregnancies are compromised by GDM have fasting insulin levels equal to or higher than those of nondiabetic pregnant women, with the highest levels among obese women with GDM. Oral and intravenous glucose tolerance deteriorates only slightly despite the reduction in insulin sensitivity during normal pregnancy.2 A gradual increase in insulin secretion by the β-cells is the prime apparatus responsible for this phenomenon. Kuhl17 and Bergman et al.18 reported an exaggerated relationship between insulin sensitivity and β-cell responsiveness to glucose in both pregnant and nonpregnant women, which indicatethat β-cell dysfunction plays a role in pathological states such as GDM and signify the magnitude of the change in insulin secretion that is necessary to maintain glucose tolerance. The flexibility of Β-cell function allows the maintenance of normal circulating glucose levels despite wide deviations in insulin action. In pregnant and nonpregnant women, a comparable association between β-cell function and insulin secretion has been noted.2,19 These findings further corroborate the hypothesis that the hyperinsulinemia of pregnancy is largely the result of pancreatic β-cell compensation for physiologic insulin resistance. The ability of β-cells to maintain normal capacity of insulin secretion in response to increased insulin resistance is associated with only slight deterioration in glucose tolerance late in pregnancy.20
Other studies have validated the contribution of the β-cell inability to compensate the rising insulin resistance to the development of GDM. Catalano et al.21 prospectively and longitudinally followed up 16 patients from 12 weeks of gestation onward and found that regardless of glucose tolerance, as pregnancy progressed, the efficacy of infused insulin decreased basal C-peptide concentrations (surrogate for β-cell function) in clamp studies. Saisho et al.22 in their prospective study using insulin-resistance mathematical models found that β-cell function deteriorates as pregnancy advances, and more so among glucose intolerant parturients than in NGT parturients. They later compared a larger cohort of women with GDM with NGT women and found that the disposition index (a surrogate marker for β-cell function) correlated with the severity of GDM and with the total insulin dosage needed to achieve glycemic control.23
The insulin receptor is part of the growth factor receptor family that possesses an intrinsic tyrosine kinase activity.24 Insulin binding to surface receptors of circulating RBC has generally been reported to be normal in pregnant women.25,26 Others have reported a decline in binding of insulin to adipocytes in pregnant versus nonpregnant women.27,28 Most notably, binding of insulin to the skeletal muscle, the target tissue that mainly contributes to the total body insulin resistance, has been reported to be similar in pregnant and nonpregnant states.29 This finding supports the assumption that insulin resistance is mainly a postreceptor defect.
EVIDENCE FOR POSTRECEPTOR DEFECT IN INSULIN SIGNALING
A family of membrane proteins, GLUT1 to GLUT4, which have a significant sequence likeness, is responsible for glucose uptake by cells. GLUT4 is the main insulin-sensitive glucose transport whose action is required in the skeletal and cardiac muscles and adipose tissue. Garvey et al.30 were the first to demonstrate that there were no significant differences in the glucose transport (GLUT4) responsible for insulin action in the skeletal muscles in pregnant GDM, pregnant NGT, and nonpregnant women, although they did find that in GDM pregnant women, binding capacity to the receptor was diminished. Later, it was reported that the insulin-stimulated glucose transport in adipose tissue was reduced by 60% at term in women with GDM compared to nondiabetic pregnant women, and that at 50% of patients with GDM, GLUT4 content in adipocytes was profoundly depleted.31 Additional factors such as cytokine tumor necrosis factor have been cited as a potential influence on insulin receptor substrate function in the signaling cascade.24
PROTEIN METABOLISM
In addition to glucose, protein is essential for fetal growth. Nitrogen retention is increased during pregnancy, in both maternal and fetal compartments. It is estimated that there is a 500-g increase in protein accumulation by about week 30. A significant decrease occurs in most fasting concentrations of maternal amino acid in early pregnancy, before the accumulation of significant maternal or fetal tissue.32 The impending changes in fasting amino acid metabolism occur after a shorter period of fasting in contrast to nonpregnant women. This occurrence may be another manifestation of the accelerated starvation in pregnancy. Duggleby and Jackson33 reported that during pregnancy, protein synthesis in the first trimester is similar to that of nonpregnant women, increased by 15% during the second trimester and by further 25% in the third trimester. Amino acids can be used for either protein accretion or oxidized as an energy source. In general, there is a modest shift in oxidation in early pregnancy with an accretion of amino acids for protein synthesis in late gestation.33 Kalhan et al. have suggested that there are significant pregnancy-related changes in maternal protein metabolism early in gestation before any significant increase in fetal protein accumulation.34 There is paucity of data on the effects of insulin infusion on amino acid turnover during pregnancy in women with and without GDM. It appears that there may be a slight decrease in the rate of protein breakdown during fasting35 and a slight increase in protein turnover during the day.36
Zimmer et al.37 aimed to assess protein metabolism in untreated GDM patients compared with NGT patients in the third trimester. They reported that although hepatic glucose release and whole body proteolysis were not different between the groups, fasting insulin levels needed to maintain homeostasis were three- to fivefold higher among GDM patients. Butte et al.38 later reported that in insulin-treated GDM parturients, protein turnover was normalized, while the concentration of amino acids was elevated both antepartum and 6 weeks postpartum, despite good glycemic control.
LIPID METABOLISM
Darmady and Postle measured serum cholesterol and triacylglycerol before, during, and after pregnancy in nondiabetic women and found that cholesterol and triacylglycerol decreased at about 7 weeks of gestation and increased progressively thereafter until term.39 In the fed state, the release of free fatty acids (FFAs) from adipose tissue is suppressed by the antilipolytic actions of insulin so that FFA levels are only slightly higher in pregnancy during the first hours postprandial. On the other hand, the stimulation of lipolysis in pregnancy causes an increase in circulating FFA when insulin levels decrease. Therefore, fasting and postprandial FFA levels are augmented in pregnancy in comparison to the nonpregnant state.40 Increases in maternal FFA in late gestation have been purported to be related to the decrease in maternal glucose insulin sensitivity in late pregnancy. FFA have also been associated with fetal overgrowth, especially of adipose tissue. It has also been hypothesized that neonatal birth weight is positively correlated with triacylglycerol and FFA concentrations.41 Infants of obese women were reported to have not only increased birth weight and skin fold measurements but increased serum FFAs compared with infants of lean women.42 In GDM, especially during the third trimester, there has been a reported associated increase in triacylglycerol and decrease in high-density lipoprotein concentration.43 Montelongo et al.44 reported little change in FFA concentrations throughout pregnancy. It has also been demonstrated that GDM women have an increase in total triacylglycerol but lower low-density lipoprotein cholesterol.45 Studies in nondiabetic pregnant and GDM women46,47 using the hyperinsulinemic-euglycemic clamp showed a decreased ability of insulin to suppress FFA with advancing gestation in both groups. This ability of insulin to suppress plasma FFA was significantly lower in women with GDM.47 These studies demonstrate that insulin resistance to nutrients decreases in all women with advancing gestation.
Pappa et al. reported that in diet-controlled GDM, ketogenic amino acids are released in slow rates from skeletal muscle and are catabolized mainly in the liver, in contrast to NGT pregnancies in which fatty acids are catabolized in both the liver and the peripheral tissues.48 Chen et al. assessed the circulating FFA and fatty acid intake among GDM patients, patients with abnormal glucose challenge test (GCT) but normal OGTT (termed by them hyperglycemia less severe than GDM), and NGT controls. They found that there was a graded increase among groups in total FFA in the third trimester and that the increase correlated with body mass index (BMI).49
Adipocyte fatty acid-binding protein (AFABP) is an adipokine whose serum levels correlate with the development of metabolic syndrome and cardiovascular disease. In a study among GDM patients in comparison with NGT controls, it was found that AFABP levels were significantly higher in GDM patients (22.9 Fg/L vs. 18.3 Fg/L, P < 0.05) and those markers of adiposity such as BMI, leptin, triglycerides, and serum creatinine were also independently associated with ADABP levels.50 In another report, AFABP levels in maternal serum were higher in GDM patients compared with NGT controls, whereas they were found to be lower in cord blood. In addition, AFABP levels were higher in cord blood than in maternal serum. The conclusion of this study was that fetal tissues are the main source of AFABP, and that in GDM patients, the fetus AFABP values correlate with adiposity markers.51
HORMONAL EFFECT IN NORMAL AND DIABETIC PREGNANCY
The physiological changes responsible for insulin resistance in pregnancy appear to be related to the metabolic effects of several hormones and other factors that are elevated in the maternal circulation. Evidence to support the impact of these hormones on insulin resistance is related to the fact that development of insulin resistance during pregnancy tends to parallel the growth of the fetomaternal unit and the levels of hormones secreted by the placenta.
Estrogen and Progesterone
Early in pregnancy, progesterone and estrogen levels increase but their effect on insulin activity are offset, that is, progesterone causes insulin resistance while estrogen is protective.52 It has been reported that progesterone accelerates the development of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor, reduces blood glucose levels. Furthermore, after obstruction of the progesterone receptor, pancreatic islets appeared larger and secreted more insulin as a result of an increase in β-cell mass due to an increase in β-cell production.53 Progesterone signaling may play a vital role in insulin release and pancreatic function and may affect susceptibility to diabetes. An intravenous glucose tolerance test given to estrogen-treated rats showed a significant decrease in glucose concentrations and a twofold increase in insulin concentration.54 With the addition of progesterone, there was a 70% increase in the insulin response to the glucose challenge test; no alterations in glucose tolerance were observed.55 In cultured rat adipocyte tissue treated with estrogen, there was no effect on glucose transport, but maximum insulin binding was increased. Progesterone was noted to decrease maximum glucose transport and insulin binding.54,55
A more recent report examined the expression profile of estrogen receptors (among other potential genes responsible for insulin resistance) in subcutaneous adipose tissue, visceral adipose tissue, and placenta of GDM parturients. The expression of estrogen receptor alpha and beta genes was significantly reduced in subcutaneous adipose tissue of GDM patients compared with controls, which may play a role in the pathogenesis of GDM.56
To simulate the plasma levels in normal pregnancy, ovariectomized rats were treated with different doses of progesterone and/or 17 β -estradiol; steroid hormones lead to the decreased insulin sensitivity. The increased insulin sensitivity during early pregnancy, when plasma concentrations of 17 β -estradiol and progesterone are low, may be the result of 17 β -estradiol.57 Conversely, during late pregnancy, when plasma concentrations of 17 β -estradiol and progesterone are elevated, 17 β -estradiol may impede the effect of progesterone, diminishing insulin sensitivity. Therefore, the data suggest that progesterone prohibits normal adaptation of the pancreatic β -cell reserve during pregnancy and is a major contributor to increased insulin resistance.
Human Placental Lactogen
Human placental lactogen (hPL) levels increase at the onset of the second trimester causing a decrease in phosphorylation of insulin receptor substrate-1 and intense insulin resistance.52 Overnight infusion of hPL results in abnormal glucose tolerance and enhanced insulin and glucose concentration in response to the oral glucose challenge.58 In islet cell culture, hPL directly stimulates insulin secretion.59 This may indicate that hPL directly regulates islet cell function and is the prime hormone responsible for enhanced islet function observed during normal pregnancy. Maternal plasma concentration of hPL increases steadily until about 34-36 weeks of gestation and is approximately proportional to placental mass. Thus, with increasing insulin, resistance is enhanced. Moreover, the levels of placental mRNA coding for hPL were found to be higher in GDM patients in comparison with nondiabetic women.60
Prolactin
During pregnancy, maternal prolactin levels increase 7- to 10-fold. It has been reported that the basal insulin concentration and postchallenge glucose and insulin response were greater in women with hyperprolactinemia than in healthy control sub- jects.61 Corroborating studies showed that the culture of pancreatic islet cells with prolactin induces increased insulin secretion.62 The relationship between the deterioration in glucose tolerance and plasma prolactin levels was assessed in patients with normal and diabetic pregnancies that reported no difference in basal prolactin concentrations between the two groups at either time point.63 The prolactin levels were also not altered during the OGTTs; and there was no correlation between the deterioration in glucose tolerance and the prolactin concentrations in either group. These data suggest that abnormal prolactin levels may not be a part of the pathophysiology cascade in the development of insulin resistance and GDM. Moreover, amniotic fluid prolactin concentrations were found to be alike in GDM and non-GDM patients.64
Nonetheless, a recent report discovered a significant association between two minor alleles single-nucleotide polymorphism (SNP) in the prolactin receptor gene and the development of GDM, with an increased risk of 2.4-fold among those carrying the SNPs. More research is needed to rule out any potential role of prolactin in the pathogenesis of GDM.65
Cortisol
There is a continuous increase in cortisol levels throughout pregnancy, with concentration up to threefold at the end of pregnancy compared with nonpregnant state. One study demonstrated that under infusion of high amounts of cortisol, hepatic glucose production increased and insulin sensitivity decreased.66 An excess of glucocorticoid in a skeletal muscle model was characterized by decreased total tyrosine phosphorylation of the insulin receptor. It is plausible to assume that glucocorticoid-induced insulin resistance is another proof for the postreceptor defect mechanism. When pregnant women with GDM were compared to pregnant women with normal glucose tolerance, the GDM subjects were found to have significantly higher levels of serum cortisol than the control group.67 These findings may provide the foundation for the role of cortisol in the deterioration of blood glucose tolerance in pregnancy.
Leptin
Leptin is a 16-kDa protein encoded by the ob/ob (obesity) gene secreted by adipocyte tissue and also produced by a number of other tissues including the stomach, intestine, and the placenta in humans. It acts on hypothalamic receptors to decrease food intake and increase energy expenditure. Fasting insulin and leptin concentrations closely correlate with body fat, making leptin a good marker of obesity and insulin resistance. Since receptors to leptin are found in the skeletal muscle, liver, pancreas, adipocyte tissue, uterus, and placenta, it may be responsible for peripheral and central insulin resistance. Reductions in leptin concentrations are caused by weight loss, fasting, and starvation; leptin concentrations are increased with weight gain and hyperinsulinemia. Using the hyperinsulinemic-euglycemic clamp studies in animal models, infusion of leptin was reported to increase the glucose utilization rate, which translates to increased insulin sensitivity.68 Leptin levels are significantly higher in pregnancy than in the nonpregnant state, especially during the second and third trimesters, and this change in circulating leptin concentrations is generally consistent with changes in maternal fat stores and glucose metabolism.69-71 Results of studies by Laivuori et al. suggest that pregnancy-associated increases in maternal plasma leptin may result from an upregulation of adipocyte leptin synthesis in the presence of increasing insulin resistance and hyperinsulinemia in the latter half of pregnancy.72 Investigators have also shown that leptin directly affects whole body insulin sensitivity by regulating the efficiency of insulin-mediated glucose metabolism by skeletal muscle73 and hepatic regulation of gluconeogenesis.74 Leptin may also wield an acute inhibitory effect on insulin secretion.75
Leptin Animal Models
Leptin deficiency in ob/ob mice and leptin resistance (db/db mice with a defective leptin receptor) result in hyperphagia and decreased energy expenditure. As a result, the affected animals become obese and develop insulin resistance.76 Moreover, an alteration in leptin action may affect GDM and fetal overgrowth.77 Pregnant mice treated with leptin had noticeably lower glucose levels than controls during glucose and insulin challenge tests. However, despite the reduced energy intake and improved glucose tolerance, fetal overgrowth was not lowered. These results may provide confirmation that leptin administration during late gestation can decrease adiposity and enhance glucose tolerance in spontaneous GDM. Alterations in placental leptin levels may contribute to the regulation of fetal growth independently of maternal glucose levels.
Leptin in Humans
Research results in whether leptin is a diabetogenic or antidiabetogenic hormone have produced conflicting statements. Data from a large epidemiological study demonstrated that plasma leptin concentrations were positively associated with insulin resistance in men and nonpregnant women.78 Investigators have also observed that chronic hyperglycemia is associated with a reduction in leptin concentration in the peripheral circulation.79 Data suggest a complex relation between leptin and glucose homeostasis in humans.
Kautzky-Willer et al.80 measured plasma concentrations of leptin and β -cell hormones during fasting and after an oral glucose load (OGTT of 75 g) in GDM women and pregnant NGT women at 28 weeks gestation and compared them with nonpregnant women. Plasma leptin was higher in the GDM women than in NGT women, and higher in both these groups than in the nonpregnant controls. No change in plasma leptin concentration was induced by OGTT in any group. Basal insulin release was higher in GDM women than in the NGT women. The authors suggested that women with GDM and no change in plasma leptin on oral glucose loading have increased plasma leptin concentrations during and after pregnancy. Leptin levels and the relationship between leptin substance and insulin were assessed in pregnant GDM women.81 There was a correlation of plasma leptin levels with fasting plasma insulin levels and plasma glucose levels measured 1 hour after oral administration of 50 g of glucose. The serum leptin levels in GDM women were significantly higher than in the women whose pregnancies were not compromised by GDM. The GDM group also showed a significant, positive correlation of serum leptin levels with glycosylated hemoglobin levels, fasting serum insulin levels, and plasma glucose levels measured 1 hour after administration of 50 g of glucose.
Leptin levels are elevated in GDM women, and leptin metabolism depends on insulin levels and the severity of the diabetes. It has been suggested that umbilical cord leptin concentration may be an independent risk factor for fetal macrosomia in nondiabetic pregnant women.82
Later reports further established association between leptin levels and GDM. In 2007, Maghbooli et al.83 reported that increased leptin concentrations correlated with insulin levels, BMI, and HOMA index, and that after adjusting for possible con- founders, GDM was independently associated with leptin levels. They concluded that leptin concentration >20ng/mL may assist in the prediction of GDM. Qiu et al.84 reported that hyperleptinemia up to 16 weeks of gestation may predict higher risk of GDM later in pregnancy, independent of maternal adiposity. Nevertheless, other reports have failed to establish this association, but their sample sizes were considerably smaller.85,86
In light of the accumulated data, leptin appears to provide a key role in mediating glucose metabolism in pregnancy. Measurement of leptin alone, or combined with the assessment of other risk factors, may help identify women at high risk for developing GDM.
Adiponectin
Adiponectin is an adipose tissue hormone, which is a specific plasma protein that is secreted by adipocytes. It may facilitate the regulation of the glucose and lipid metabolism. Adiponectin decreases the hepatic glucose production and insulin resistance by up-regulating fatty acid oxidation.87 Adiponectin also suppresses the secretion of tumor necrosis factor-а by adipose tissue, a factor that is known to contribute to insulin resistance.88 Studies have shown that adiponectin serum levels were decreased in obese sub- jects89 and patients with type 2 diabetes.90 In studies with rhesus monkeys, adiponectin plasma levels were significantly decreased with the progression of obesity and insulin resistance.91 In all probability, adiponectin increases insulin sensitivity by enhancing the P-oxidation of FFAs and by decreasing the intracellular concentrations of triglycerides.92,93
In patients with type 2 diabetes, who share the same risk factors for GDM (i.e., obesity, maternal age, ethnic origin, family history, etc.), lower serum levels of adiponectin were detected. In mice, intravenous administration of adiponectin was associated with loss of weight and reduced plasma concentrations of fatty acids94; the proportion of total body fat mass correlated negatively with adiponectin serum levels.95 The data suggest that low plasma adiponectin concentration during even early pregnancy may be associated with subsequent development of GDM,96-98 and recent reports support this theory. Lacroix et al.99 collected blood samples from 445 women at the first and second trimesters during pregnancy. Overall, 38 women developed GDM. Compared with NGT women, GDM patients has lower adiponectin levels (9.67 µg/mL vs. 11.92 µg/mL), and the odds ratio (OR) for developing GDM was 1.12 per 1 µg/mL decrease in adiponectin (P = 0.02). Ferreira et al.100 also performed a prediction analysis, by measuring serum levels of both adiponectin and visfatin at 11-13 weeks gestation. They reported that the combination of high visfatin and low adiponectin produced a prediction rate of 68% at a false positive rate of 10%. Hedderson et al.101 examined whether prepregnancy adiponectin levels may assist in the prediction of GDM. They found that when comparing quartiles of adiponectin levels, the risk of developing GDM increases with decreasing quartile (OR 1.5 [95% confidence interval [CI] 0.72.9], OR 3.7 [95% CI 1.9-7.2], and OR 5.2 [95% CI 2.6-10.1], respectively, P < 0.001). They also observed that the combination of low adiponectin level and overweight produces ad sevenfold increase in GDM risk compared with women with normal weight and above the median adiponectin level.
At the molecular biology level, a recent study evaluated the association between adiponectin gene SNP and GDM. It was found that the SNP45TG in adiponectin gene is associated with the development of GDM,102 and Beltcheva et al.103 discovered a significant association between the rs266729 SNP and GDM.
Levels of adiponectin have been assessed in fetal cord at delivery.104 Cord blood adiponectin levels were extremely high in comparison with serum levels in children and adults and were positively correlated to fetal birth weights. No correlation was found between cord adiponectin levels and maternal BMI, cord leptin, or insulin levels. Cord adiponectin levels were significantly higher compared with maternal levels at birth, and no correlation was found between cord and maternal adiponectin levels. There were no significant differences between adiponectin levels at birth and four days postpartum. These findings indicate that adiponectin in cord blood is derived from fetal and not from placental or maternal tissues. The high adiponectin levels in newborns compared with adults may be the result of deficient negative feedback on adiponectin production stemming from lack of adipocyte hypertrophy, low percentage of body fat, or a different distribution of fat storage in newborns. Adiponectin may emerge as a significant factor in carbohydrate-fat metabolism and in the development of insulin resistance during pregnancy. Data suggest that there are decreased adiponectin levels in women with GDM compared with healthy control subjects. This finding supports the concept of a common pathogenesis between type 2 diabetes and GDM. Although adiponectin level appears to rise throughout pregnancy, its contribution to gestation remains unclear.
NUTRIENTS AND ESSENTIAL TRACE ELEMENTS: THE ASSOCIATION TO INSULIN RESISTANCE IN NORMAL AND DIABETIC PREGNANCY
The metabolism of zinc, magnesium, and chromium may be altered in women with GDM. Increases in urinary excretion and lower circulating levels of these nutrients have been reported in diabetic women.
Zinc
Animal studies of zinc depletion show that zinc is required for normal glucose metabolism. A correlation has been shown between zinc and the degree of glycosuria and serum hemoglobin A1c concentrations.105 Serum zinc concentrations may have an insulin-like effect on glucose transport into adipocytes. Zinc enables insulin-induced glucose transport into cells by influencing the insulin signaling pathway. Therefore, zinc deficiency may explain why glucose utilization is reduced and lipolysis is enhanced. Zinc depletion also alters glucose metabolism in humans. In a study of zinc depletion in men, the results showed a rise in plasma glucose concentrations.106 Since pregnancy is associated with increased insulin resistance, a marginal maternal zinc ingestion may be a risk factor for developing GDM. Diabetes per se also appears to alter zinc metabolism. Urinary zinc excretion is elevated in diabetic patients compared with control subjects,107,108 and this increase may be explained with urinary protein losses. Failure to maintain established levels of glycemic control may also be related to a decrease in serum zinc levels.109 The role of zinc in GDM has not been ascertained. Zinc transport to the fetus in diabetic rats is reduced because of either a decrease in placental transport or altered maternal or fetal zinc-binding ligands.110 In humans, no differences in serum zinc were observed between insulin-dependent diabetic women maintaining established levels of glycemic control and pregnant control subjects.111 Additional research is needed to establish the effects of marginal zinc status on glucose homeostasis in women during pregnancy.
Magnesium
The reduction in serum magnesium during pregnancy in both healthy and diabetic women may, in part, be due to the decline in serum albumin concentrations. Magnesium depends on insulin for the transport process into cells. Intensive insulin treatment during pregnancy in women with GDM may lead to a further decline in circulating magnesium. There are no data on the functional consequences of this lower level of magnesium during gestation in diabetic women. However, decreased levels of magnesium are associated with increased urinary loss of magnesium112 in type 1 diabetes in comparison with controls. Serum magnesium concentrations are inversely related to glycosylated hemoglobin concentrations and glucosuria. The increased urinary losses may be related to hyperfiltration in combination with impaired tubular reabsorption. Lower levels of striated muscle magnesium were measured in patients with diabetes requiring insulin.112 Decreases in serum magnesium and increased urinary losses of magnesium were reported in GDM women; these lower levels persisted after good glycemic control was achieved.111
Chromium
Chromium has been identified as an essential nutrient because it restores glucose tolerance in rats fed diets low in chromium.113 Although rat studies may indicate that chromium facilitates insulin function, that role has not yet been specified; it is also unclear whether chromium affects pathogenesis of diabetes in humans. To test the effect of chromium supplementation on glucose tolerance in pregnancy, subjects given supplemental chromium had lower fasting and peak blood glucose levels.113 However, the added chromium did not lower blood glucose concentrations in women with severe glucose intolerance enough to eliminate the need to receive insulin. Recent report showed that GDM patients has lower concentrations of chromium compared with NGT controls, but this observation was not significant after adjusting for parity.114
Vitamin D
Vitamin D was studied with relation to GDM. Wang et al.115 investigated vitamin D deficiency among 400 Chinese women (half of which with GDM) and found that rates of serum 25-hydroxy vitamin D (25OHD) deficiency were significantly higher among GDM patients. They reported that patients with 25OHD levels <25 nmol/L has 1.8-fold risk for developing GDM. Their findings were later reproduced when it was reported that lower 25OHD levels correlated with higher HOMA-IS indices.116 Perez-Ferre et al.117 prospectively followed up 266 women and found 25OHD deficiency (<20 nmol/L) among 59% of them. There was inverse correlation between 25OHD levels and HOMA-IS, glycosylated hemoglobin A1c, serum insulin glucose levels at fasting and 1 hour after OGTT. Soheilykhah et al.118 assessed vitamin D supplementation on insulin resistance in a randomized clinical trial of 120 participants starting 12 weeks of gestation. One group received 200 IU of vitamin D per day, another groups 50,000 IU per month, and the third group 50,000 IU twice a month. Insulin resistance was measured using HOMA-IS. They found that vitamin D supplementation of 50,000 IU twice a months improved insulin resistance significantly.
SUMMARY
During pregnancy, there are significant alterations in maternal metabolism that provide for the metabolic demands of the developing fetus. The development of insulin resistance in late gestation is a process common to all human pregnancies. The development of maternal insulin resistance is associated with an increase in maternal adipose tissue in early pregnancy and increased fetoplacental nutrient availability in late gestation, when 70% of fetal growth occurs. In women who develop GDM, insulin resistance is increased before conception, often in association with maternal obesity and increased risk of fetal macrosomia or overgrowth. The macrosomic infants of these women have an increased risk for the development of adolescent obesity and type 2 diabetes. GDM is also a predictor or even an early manifestation of the metabolic (insulin resistance) syndrome.
During the second trimester, there is an increase in maternal placental and adipose tissue hormones causing decreased phosphorylation of IRS-1 and profound insulin resistance. In most women, the pancreatic insulin secretion increases to meet this demand; for those with underlying Β-cell malfunction, the result is hyperglycemia. In women with GDM, the insulin resistance of pregnancy is exaggerated, especially if fasting hyperglycemia is present and is related to additional postreceptor defects. Women who develop significant and predictable metabolic abnormalities may themselves be compromised and threaten their offspring’s well-being.
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