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CLINICAL OBSTETRICS AND GYNECOLOGY Volume 50, Number 4, 938–948 r 2007, Lippincott Williams & Wilkins

Metabolic Changes in Pregnancy KRISTINE Y. LAIN, MD* and PATRICK M. CATALANO, MDw *Departments of Obstetrics and Gynecology and Internal Medicine, University of Kentucky, Lexington, Kentucky; and w Department of Reproductive Biology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio

Abstract: Maternal metabolism changes substantially during pregnancy. Early gestation can be viewed as an anabolic state in the mother with an increase in maternal fat stores and small increases in insulin sensitivity. Hence, nutrients are stored in early pregnancy to meet the feto-placental and maternal demands of late gestation and lactation. In contrast, late pregnancy is better characterized as a catabolic state with decreased insulin sensitivity (increased insulin resistance). An increase in insulin resistance results in increases in maternal glucose and free fatty acid concentrations, allowing for greater substrate availability for fetal growth. Key words: maternal glucose metabolism, insulin sensitivity, gestational diabetes

This article provides an overview of maternal metabolic changes during pregnancy with a focus on maternal glucose and lipid metabolism. Potential mechanisms related to alterations in maternal metabolism during pregnancy complicated by gestational diabetes also are reviewed.

Glucose Metabolism Glucose metabolism, both basal and postprandial, gradually changes over the course of pregnancy to meet the nutritional demands of the mother and fetus. Longitudinal studies in women with normal glucose tolerance demonstrate significant progressive alterations in all aspects of glucose metabolism as early as the end of the first trimester.1,2 The overall direction and magnitude of these changes in measures of maternal Correspondence: Kristine Y. Lain, MD, University of Kentucky, 800 Rose Street, Room C365, Lexington, KY 40536-0293. E-mail: kylain2@email.uky.edu Supported by NIH/HD-22965 (P.M.C.). CLINICAL OBSTETRICS AND GYNECOLOGY

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carbohydrate metabolism in normal pregnancy are listed in Table 1. BASAL METABOLISM

In nonpregnancy, the liver is the predominant source of net endogenous glucose production. The average plasma fasting glucose concentration is approximately 90 mg/dL and the rates of glucose production and utilization are approximately equal. Defects in either production or utilization will result in changes in fasting glucose concentrations. In pregnancy, fasting glucose decreases progressively with advancing gestation.1 The mechanism is complex and not well understood, but potential contributing factors include (1) dilutional effects (increased plasma volume in early gestation), (2) increased utilization (either increased feto-placental glucose utilization in late gestation or increased maternal uptake secondary to increased b-cell function), and/or (3) inadequate production (limitation of hepatic glucose production relative to circulating glucose concentrations). Despite a decrease in fasting glucose, hepatic glucose production is increased (Fig. 1). Cross-sectional and longitudinal investigations using stable isotope methodologies describe increased fasting hepatic glucose production by late gestation even with adjustment for maternal weight gain.2–4 As fasting glucose is decreasing and hepatic glucose production is increasing, there is a concomitant increase in fasting insulin (Fig. 2). Hepatic glucose production, which is normally suppressed by insulin, increases despite increasing fasting insulin concentration. This supports a decrease in maternal hepatic insulin sensitivity, resulting in a decreased suppression of hepatic glucose production in women with normal glucose tolerance. Additionally, in obese women with VOLUME 50

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Metabolic Changes in Pregnancy TABLE 1.

Changes in Measures of Metabolism in Normal Pregnancy From Pregravid Estimates

Basal metabolism Fasting glucose (2) Fasting Insulin (2) Hepatic metabolism Basal hepatic glucose production (2) Hepatic insulin sensitivity Glucose suppression (2) Insulin metabolism Insulin secretion First phase insulin response (1) Second phase insulin response (1) Insulin sensitivity (1)

normal glucose tolerance, there is a decreased ability of infused insulin to fully suppress hepatic glucose production in late gestation as compared with pregravid and early pregnancy measurements. These findings indicate a further decrease in hepatic insulin sensitivity with obesity.5 The decrease in fasting glucose is further exacerbated with prolonged fasting.6 This suggests an incomplete compensation (primarily hepatic) or some restraint on endogenous production compared with the nonpregnant condition. Hepatic glucose production includes both gluconeogenesis and glycogenolysis and whether

180

Early Pregnancy

Late Pregnancy

Unchanged Unchanged

Decreased (0.9  ) Increased (1.65  )

Unchanged Decreased (0.9  )

Increased (1.3  ) Decreased Decreased (0.9  )

Increased (2  ) Increased (1.5  ) Decreased (0.7  )

Increased (3  ) Increased (3  ) Decreased (0.4  )

gluconeogenesis remains constant during pregnancy is unclear. The availability of substrates, such as alanine may play an important role.7–9 Finally, decreased fasting glucose concentrations may be secondary to enhanced b-cell function resulting in fasting insulin concentrations that are elevated relative to the ambient glucose concentrations. BASAL METABOLISM IN GESTATIONAL DIABETES

Gestational diabetes mellitus (GDM) is defined as the presence of glucose concentrations

Lean Control Obese Control Lean GDM Obese GDM

45 40 35

160

Insulin (µU/ml)

Hepatic Glucose (mg/min)

200

939

140

120

Lean Control Obese Control Lean GDM Obese GDM

30 25 20 15 10

100

Pregravid

Early Pregnancy

Late Pregnancy

FIGURE 1. Basal endogenous (primarily hepatic) glucose production in lean (percent body fat <25%) and obese white women (percent body fat >25%) with GDM or normal glucose tolerance during pregnancy. These studies were conducted using stable isotopes of glucose (dideuterated 6,6, D2 glucose) before pregnancy (‘‘pregravid’’), and during gestational weeks 12 to 14 (‘‘early pregnancy’’) and 34 to 36 (late pregnancy).10,13,67

5 0

Pregravid

Early Pregnancy

Late Pregnancy

FIGURE 2. Fasting insulin concentrations in lean and obese women with GDM or normal glucose tolerance pregravid, early pregnancy, and late pregnancy.10,13,67 Reproduced with permission from Obstetrics: Normal and Problem Pregnancies 5th Edition, Diabetes Mellitus Complicating Pregnancy. 2007:976–1010. Copyright Elsevier.85


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that are at the upper end of the population distribution for glucose in pregnant women and are first detected during pregnancy. On average, women with GDM have higher fasting glucose concentrations. Basal hepatic production, however, is not different from women without GDM (Fig. 1).10 Fasting insulin also increases during pregnancy in obese women with GDM and is greater than in women without GDM (Fig. 2).10 The increase in circulating glucose concentrations despite increased insulin concentrations and similar endogenous production in women with GDM compared to normal glucose tolerant women supports an imbalance between tissue insulin requirements for glucose regulation and the ability of the pancreatic b-cells to meet those requirements. INSULIN SENSITIVITY IN NORMAL PREGNANCY

Overall, insulin sensitivity decreases during pregnancy. Estimates of peripheral insulin sensitivity in pregnancy include measurement of the insulin response to a fixed oral or intravenous glucose challenge, the ratio of insulin to glucose under a variety of experimental conditions, computer modeling of an intravenous glucose tolerance test, and the euglycemic-hyperinsulinemic clamp.11,12

Early Pregnancy In lean women during early pregnancy, maternal insulin sensitivity, defined as a decrease in the glucose infusion rate during the euglycemichyperinsulinemic clamp to maintain euglycemia (90 mg/dL) decreases.13 Because maternal insulin concentrations vary at different times during pregnancy despite a constant insulin infusion based on subject weight or surface area, net glucose utilization rates must be expressed relative to steady state insulin concentrations. The effects of insulin on peripheral glucose utilization and hepatic production can be assessed separately if labeled glucose (stable isotopes) is infused during the clamps. When glucose turnover is expressed relative to steady state insulin levels, there is a 10% decrease in insulin sensitivity from pregravid to early gestation in lean subjects. In contrast, there is a 15% increase in insulin sensitivity in obese women in early pregnancy as compared with pregravid estimates.10 Hence, the decrease in insulin requirements in early gestation observed in some women requiring insulin may be a consequence of a relative increase in insulin sensitivity.14 This may be particularly prominent in obese women with decreased insulin sensitivity before conception.

Late Pregnancy Peripheral insulin sensitivity decreases further in late gestation. Early studies demonstrated that pregnant women experienced less hypoglycemia in response to exogenous insulin in comparison with nonpregnant subjects15 and have an increased insulin response to exogenous glucose in late gestation.16 Additional studies using high-dose glucose infusion testing, Bergman computer modeling of the intravenous glucose tolerance test, and euglycemic-hyperinsulinemic clamp studies have all demonstrated a decrease in insulin sensitivity in late gestation ranging from 33% to 78%.1,17â&#x20AC;&#x201C;19 The decrease in insulin sensitivity in late pregnancy is profound relative to other conditions, approaching the degree observed in individuals with established type 2 diabetes. Of note, the quantitative estimates of insulin sensitivity from glucose clamps conducted at a single insulin concentration may underestimate the degree of insulin resistance, because there is a large increase in noninsulin requiring glucose disposal during pregnancy resulting from utilization by the fetus and placenta. In a pregnant ewe model, approximately one third of maternal glucose utilization was accounted for by uterine, placental, and fetal tissue.20 Additionally, fetal glucose concentration based on human fetal blood sampling is a function of fetal size and gestational age in addition to maternal glucose concentration.21 Measurements of insulin sensitivity performed by computer modeling of intravenous glucose tolerance test data are not influenced by fetal tissues, because that approach measures insulindependent and insulin-independent net glucose disposal separately.11 INSULIN SENSITIVITY IN GESTATIONAL DIABETES

Initial studies using glucose clamp methodology demonstrated a 40% further decrease in whole body insulin sensitivity in women with severe GDM in late pregnancy.19 Longitudinal clamp studies using labeled glucose in both lean and obese women who develop GDM demonstrated a lower insulin sensitivity among women with GDM compared with weight-matched controls (Fig. 3).10,13 The difference was most evident before and during early pregnancy. By late gestation, the acquired insulin resistance of pregnancy was marked in both groups so that the intergroup differences were less pronounced but still statistically significant. Of interest, there was an (15% to 20%) increase in insulin sensitivity from the time before conception through


Metabolic Changes in Pregnancy Lean Control

0.20

Obese Control Insulin Sensitivity Index

Lean GDM Obese GDM

0.15

941

production after an overnight fast despite higher basal insulin concentrations in women with GDM compared with women who had normal glucose tolerance has not been consistent.10,13,17,23 These findings, however, support a role for hepatic insulin resistance in the overnight-fasted state.

0.10

MECHANISM OF INSULIN RESISTANCE IN PREGNANCY 0.05

0.00

Pregravid

Early Pregnancy

Late Pregnancy

FIGURE 3. Insulin sensitivity in lean and obese women with GDM or normal glucose tolerance pregravid, early pregnancy, and late pregnancy. Insulin-mediated glucose uptake during the steady state period of glucose clamps [(glucose infusion rate)+ (residual endogenous glucose production rate)]/(state insulin concentration).10,13 Reproduced with permission from Diabetes Mellitus Complicating Pregnancy. 5th ed. 2007:976–1010. Copyright Elsevier.85

early pregnancy (12 to 14 wk), particularly in those women with the lowest insulin sensitivity before conception. The changes in insulin sensitivity from the time before conception through early pregnancy were inversely correlated with the changes in maternal weight gain and energy expenditure.22 The associations between insulin’s effect on glucose metabolism, weight gain, and energy expenditure may help explain the decreases in maternal weight gain and insulin requirements in women with diabetes in early gestation.14,22 From a large cohort of Hispanic women with GDM who did not have diabetes soon after pregnancy, insulin sensitivity in the third trimester assessed by glucose clamps with labeled glucose was reduced by a small amount compared with women who had normal glucose tolerance.23 In addition, insulin resistance was observed not only for the stimulation of glucose utilization, but also for the suppression of hepatic or endogenous glucose production. The suppression was tightly linked to the suppression by insulin of free fatty acids (FFA), which was also impaired in women with GDM. Reduced suppression of hepatic glucose production by infused insulin has also been noted in lean and obese women with GDM in late gestation. In contrast, the finding of an elevation of glucose

The physiologic factors responsible for the decrease of insulin sensitivity or insulin resistance of pregnancy are not known with certainty, but are partially related to the metabolic effects of several hormones and cytokines that are elevated in the maternal circulation during pregnancy. Potential hormones include human placental lactogen (HPL), progesterone, prolactin, and cortisol. Evidence to support an impact of these hormones on insulin action include the parallel between the pattern of insulin resistance during pregnancy and simultaneous growth of the fetal-placental unit and increasing concentrations of placental hormones.24,25 Also, administration of HPL, progesterone, or glucocorticoids to nonpregnant individuals induces metabolic changes (hyperinsulinemia without hypoglycemia) that are consistent with a blunting of insulin action.25–28 Finally, in vitro exposure of insulin target cells such as adipocytes to pregnancy hormones results in impaired insulin-mediated glucose uptake by those cells.29 Tumor necrosis factor-a (TNF-a) is associated with decreased insulin sensitivity in a number of conditions, including obesity, aging, and sepsis.30–32 In vitro studies have shown that TNF-a down-regulates insulin receptor signaling in cultured adipocytes and skeletal muscle cells.33,34 TNF-a activates a pathway that increases sphingomyelinases and ceramides, which interfere with insulin receptor autophosphorylation. Also, TNF-a promotes serine phosphorylation of insulin receptor substrate-1 (IRS-1), thus impairing its association with the insulin receptor.35 During pregnancy, circulating TNFa concentrations have an inverse correlation with insulin sensitivity as estimated from euglycemic-clamp studies.36 Furthermore, among leptin, cortisol, HPL, human chorionic gonadotropin, estradiol, progesterone, and prolactin, TNF-a was the only significant predictor of the change in insulin sensitivity from pregravid through late gestation.36 In addition, in late gestation skeletal muscle, insulin receptor, and IRS-1 tyrosine phosphorylation are impaired and serine phosphorylation is increased.37,38


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Therefore, the increased TNF-a concentrations in late pregnancy may attenuate the insulin signaling cascade and result in some of the observed decreased insulin sensitivity. The source of increased TNF-a is most likely placental with supporting evidence from a dually perfused in vitro human placental cotyledon model. In this model, 94% of placental TNF-a was released into the maternal circulation and 6% was released to the fetal side. Hence, it seems that the progressive decrease in insulin sensitivity in pregnancy results from the metabolic action of hormones and cytokines secreted from the fetoplacental unit. Finally, the potential role of other factors, such as FFA may also contribute to the insulin resistance of pregnancy. The cellular determinants of insulin resistance during pregnancy are not well characterized but defects in the insulin signaling cascade in human skeletal muscle and adipose tissue may play an important role (Fig. 4). In theory, one or

more of the steps in the insulin signaling cascade involved in insulin stimulated glucose uptake or suppression could be impaired in pregnant individuals. Skeletal muscle is the target tissue that is quantitatively most important for total-body insulin-mediated glucose uptake during the clamp. Insulin binding to skeletal muscle is similar in nonpregnant and pregnant women, suggesting that the cellular determinants of peripheral insulin resistance of pregnancy occurs at steps downstream from cell surface receptor binding.39 The intracellular actions of insulin are mediated by autophosphorylation of the insulin receptor-b subunit on tyrosine. This is followed by the activation of the insulin receptor tyrosine kinase (IRTK) and phosphorylation of insulin receptor substrates, particularly IRS-1. Tyrosine phosphorylation of the insulin receptor and of IRS-1 is required for the activation of the enzyme phosphatidyl-inositol-3-kinase (PI-3kinase), and this step is necessary for several

FIGURE 4. The insulin signaling pathway in skeletal muscle. ADP indicates adenosine diphosphate; Akt, serine/threonine kinase; aPKC, atypical protein kinase C subfamily; ATP, adenosine triphosphate; IRS-1/2, IRS 1 and 2; Gsk3, glycogen synthase kinase 3; P, phosphorylation; PDK1/ PDK2, phosphoinositide-dependent protein kinase 1 and 2; PI 3-kinase, phosphoinositol 3-kinase; PIP3, phosphatidylinositol (3,4,5) triphosphate; p85, PI 3-kinase regulatory subunit; p110, PI 3-kinase catalytic subunit.


Metabolic Changes in Pregnancy effects of insulin, including translocation of glucose transporter 4 (GLUT-4) to the cell surface where glucose transport occurs. There are no significant differences in GLUT-4 concentration in skeletal muscle from pregnant as compared with nonpregnant women.40 Pregnant women do have reduced IRS-1 protein compared with nonpregnant women.37 The downregulation of the IRS-1 protein closely parallels the decreased ability of insulin to induce additional steps in the insulin signaling cascade, such as stimulation of 2-deoxy glucose uptake, that lead to impaired glucose transport. In summary, based on available data, there are significant alterations in insulin sensitivity in normal pregnancy. In early pregnancy, insulin sensitivity is variable and dependent on maternal pregravid insulin sensitivity and other speculative mechanisms. Changes in late gestation are more consistent with significant decreases in insulin sensitivity. The stimulus for decreased insulin sensitivity in muscle and adipose tissue seems to be placental, not maternal, production of cytokines such as TNF-a and leptin. There is an improvement in insulin sensitivity and concomitant decrease in serum concentration of these cytokines postpartum. Additionally, the mechanisms by which TNF-a affects the IRS-1 function in the insulin signaling cascade is intact during gestation. The mechanisms resulting in decreased hepatic insulin sensitivity are less well characterized, but the increase in maternal FFA concentration certainly may play a role. INSULIN RESISTANCE IN GESTATIONAL DIABETES

In addition to postreceptor insulin signaling changes in normal pregnancy, studies in human skeletal muscle and adipose tissue demonstrate additional defects in insulin signaling in women with GDM. In addition to down-regulation of the IRS-1 protein and decreased ability of insulin to induce movement of the GLUT-4 to the cell surface membrane, women with GDM have a decrease in the ability of the insulin receptor-b (the component of the insulin receptor not on the cell surface) to undergo tyrosine phosphorylation. This defect is not found in either pregnant or nonpregnant women with normal glucose tolerance,37 and results in a 25% lower glucose transport activity. The tyrosine phosphorylation of the insulin receptor substrate proteins are balanced by dephosphorylation reactions carried out by cellular and membrane-bound protein phosphatases. Vandate inhibits protein-tyrosine phosphatase activity.41 During in

943

vitro studies, vandate failed to normalize glucose transport activity in women with GDM, suggesting that decreased glucose uptake in women with GDM is not the result of impaired tyrosine phosphorylation alone.41 Additionally, in GDM, plasma cell membrane glycoprotein-1 (PC-1), an inhibitor of IRTK activity, was increased in comparison with pregnant and nonpregnant controls. The increase in PC-1 content suggests excessive phosphorylation of serine/ threonine residues in skeletal muscle insulin receptors, thus contributing to decreased IRTK activity or decreased insulin sensitivity.38 Of interest, TNF-a which was described earlier as a potential placental factor relating to decreased maternal insulin sensitivity, acts as a serine/ threonine kinase to inhibit IRS-1 and insulin receptor tyrosine phosphorylation. Thus, these receptor defects may contribute in part to the pathogenesis of GDM and increased risk of type 2 diabetes later in life. Adiponectin, a collagenlike protein which is adipose specific,42 is negatively associated with obesity,43 hyperinsulinemia, and insulin resistance.44 Unlike many other cytokines which are increased in disease states, plasma concentrations of adiponectin are lower in individuals with polycystic ovarian syndrome, hypertension, coronary artery disease, impaired glucose tolerance, type 2 diabetes, and GDM.44â&#x20AC;&#x201C;51 Adiponectin and TNF-a produce opposing effects on insulin signaling. Adiponectin increases tyrosine phosphorylation of the insulin receptor and the ratio of adiponectin/TNF-a may be an important factor for insulin sensitivity. Adiponectin is decreased during pregnancy, and these changes are correlated with decreased insulin sensitivity of glucose disposal.52 INSULIN SECRETION IN NORMAL PREGNANCY

There are progressive increases in insulin secretion in response to an intravenous glucose challenge with advancing gestation (Fig. 5). The increases in insulin concentration are more pronounced in lean as compared with obese women, because lean women most likely begin their pregnancies with better insulin sensitivity. Lean women have a greater total decrease in insulin sensitivity in contrast to obese women with normal glucose tolerance. The normal response of b-cells to insulin resistance is to increase insulin secretion, thereby minimizing the impact of insulin resistance on circulating glucose levels.53â&#x20AC;&#x201C;55 Increased insulin secretion (or increased b-cell function) during


Lain and Catalano

944

Insulin (ÂľU/ml)

A 900 800

Lean Control Obese Control

700

Lean GDM Obese GDM

600 500 400 300 200 100 0

B 8000 7000

Insulin (ÂľU/ml)

6000

Pregravid

Early Pregnancy

Late Pregnancy

Lean Control Obese Control Lean GDM Obese GDM

5000 4000 3000 2000 1000 0

Pregravid

Early Pregnancy

Late Pregnancy

FIGURE 5. Longitudinal changes in insulin secretion. Increases in (A) first phase (area under the curve from 0 to 5 min) and (B) second phase (area under the curve from 5 to 60 min) insulin response (left panel and right panel, respectively) to an intravenous glucose challenge in lean and obese women with GDM or normal glucose tolerance pregravid, early pregnancy, and late pregnancy.10,13

pregnancy most likely represents compensation for progressive insulin resistance rather than vice versa, because insulin resistance occurs even in the absence of endogenous insulin secretion (as in type 1 diabetes).56 However, given that insulin secretion increases as much as 50% early in the second trimester before insulin resistance of pregnancy becomes manifest, the hormonal milieu of pregnancy may exert a primary effect to increase insulin secretion independent of insulin resistance. The mechanisms that lead to enhanced insulin secretion in pregnancy, whether primary or as

compensation for insulin resistance, are not completely known. In animal studies, an increase in b-cell mass results from a combination of b-cell hypertrophy and hyperplasia.57,58 Hyperplasia of pancreatic islets has also been observed in human pregnancy.59 The increased b-cell mass may contribute to the pattern of increased fasting insulin concentrations despite normal or lowered fasting glucose concentrations in late pregnancy.2 Increased b-cell mass may also contribute to an enhanced insulin response to secretogogues during pregnancy. The 2-fold to 3-fold increase in b-cell responsiveness above nonpregnant levels, however, cannot be explained on the basis of only a 10% to 15% increase in b-cell mass.10,13,18,19,59 Thus, the responsiveness of individual b-cells to nutrients must also be increased during pregnancy, but mechanistic information supporting increased responsiveness is limited. Two groups have reported increased activities of protein kinase A or C in pancreatic tissue from pregnant compared with nonpregnant rats.60,61 Another report revealed enhanced cell-to-cell communication in pancreatic islets from pregnant compared with nonpregnant animals.62 The relation of these phenomena to enhanced insulin secretion in vivo is not known. Data regarding insulin clearance in pregnancy are scant. There was no difference in insulin disappearance rate when insulin was infused intravenously in late gestation in comparison with nongravid subjects.63â&#x20AC;&#x201C;65 In contrast, a 25% increase in insulin turnover in a pregnant as compared with a nonpregnant rat model was observed when a radio-labeled insulin was used.66 Also, a 20% and 30% increase in insulin clearance occurred by late pregnancy in lean and obese women, respectively, using the euglycemic-clamp model (Fig. 6).67 Although the placenta may be partially responsible for insulin clearance secondary to the abundance of insulinase, the exact mechanism for the changes in clearance remains speculative. INSULIN SECRETION IN GESTATIONAL DIABETES

Most cases of GDM result from inadequate insulin secretion that arises in women with chronic insulin resistance and, therefore, seem to be related to type 2 diabetes. The b-cell defects in GDM could reflect the spectrum of b-cell defects that lead to diabetes in nonpregnant individuals. Very few studies of insulin secretion have focused on specific subtypes of GDM, and


Metabolic Changes in Pregnancy

Insulin Clearance (ml/m2/min)

800

700

Lean Control Obese Control Lean GDM Obese GDM

600

500

400

300

Pregravid

Early Pregnancy

Late Pregnancy

FIGURE 6. Whole body insulin clearance rates measured during hyperinsulinemic clamps in lean and obese women with GDM or normal glucose tolerance pregravid, early pregnancy, and late pregnancy.10,67

therefore, information about the etiology of inadequate insulin secretion is scant. In women with circulating markers of pancreatic autoimmunity, poor insulin secretion is likely the result of ongoing b-cell destruction. Likewise, in women with genetic markers for autosomal dominant or maternally inherited diabetes, poor insulin secretion likely reflects abnormalities of b-cell function that have been described in association with those diseases outside of pregnancy.68,69 Virtually all studies of women with GDM reveal b-cell function that is decreased 30% to 70% relative to women who maintain normal glucose tolerance during pregnancy. These studies also demonstrate chronic insulin resistance in women with or with a history of gestational diabetes, and therefore most b-cell dysfunction in GDM occurs on a background of insulin resistance. Indeed, when insulin sensitivity and secretion have been compared between normal and gestational diabetic women during and after pregnancy, the defect in b-cell compensation for insulin resistance in GDM has been of similar magnitude in both situations.13,19 Longitudinal data reveal that women with GDM follow a pattern of change in insulin sensitivity that parallels controls (slight increase in early gestation, the large fall by late gestation), albeit at lower insulin sensitivity overall (Fig. 3).10 Their b-cell function, assessed as acute insulin response to intravenous glucose, likewise

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follows a pattern that is similar to controls (slight increase early in gestation, before insulin sensitivity declines, then further increase in late gestation when insulin sensitivity falls), but a lower insulin secretion overall relative to the decreases insulin sensitivity (Fig. 5).10 A lower insulin secretion in women with GDM despite their increased insulin resistance means that their b-cell defect is even greater than can be appreciated by insulin levels or responses alone. Importantly, women with GDM increase their insulin secretion during pregnancy, just as normal glucose tolerant women do, but not to the same extent.70 Calculation of the relative defect in b-cell compensation for insulin resistance between GDM and control women reveals a similar defectâ&#x20AC;&#x201D;41% during pregnancy and 50% after pregnancy.67,70 This consistency in the magnitude of the b-cell defect combined with the fact that women with GDM do increase their insulin responses during pregnancy, demonstrates that GDM is not simply a fixed limitation in insulin secretory reserve that becomes manifest as hyperglycemia when insulin needs increase during pregnancy. Instead, GDM represents the detection during pregnancy of chronic metabolic abnormalities that antedate pregnancy but are detected when pregnancy leads to the first evaluation of glucose tolerance in otherwise healthy young women.71 The common association between a b-cell defect detected during pregnancy (ie, under conditions of acquired insulin resistance) in women who also have chronic insulin resistance may provide clues to the cause of the b-cell defect in GDM. One possibility is that women who have chronic insulin resistance and a separate b-cell problem are the individuals whose glucose levels rise to the level of GDM at a relatively young age. In addition, a b-cell defect may be caused or worsened by insulin resistance as supported by the findings that weight gain and an additional pregnancy independently increase the risk of diabetes (3-fold for a pregnancy and 2-fold for 10 pounds of weight gain).72 These observations led to an interventional study in Hispanic women using a thiazolidinedione drug (Tripod Study) with the goal of decreasing insulin resistance after pregnancy.73 Diabetes rates were reduced 55% compared with placebo-treated patients, and the protection from diabetes was very closely linked to the degree of reduction of endogenous insulin requirements when patients were initially started on the drug.73 These results suggest that reducing the secretory demands placed on b-cells by improving or decreasing


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Lipid Metabolism LIPID METABOLISM IN NORMAL PREGNANCY

Although alterations in glucose metabolism are often considered the primary metabolic adaptations during pregnancy, significant alterations occur in lipid metabolism as well. From a whole body perspective, the increases in maternal adipose tissue in nonobese pregnant women are secondary only to the significant increases in total-body water. Nonobese women gain qapproximately 3.5 kg of fat during normal pregnancy but there is a wide variation both within and among various ethnic and racial groups.75–77 Subcutaneous fat mass, primarily centrally distributed (mid-thorax to mid-thigh area) significantly increases in early gestation (Fig. 7).78 Data on visceral fat accrual are scarce. Using ultrasound, investigators reported an increase in both preperitoneal and subcutaneous fat regions by the late third trimester of pregnancy. In addition, the ratio of preperitoneal and subcutaneous fat increased, suggesting that intra-abdominal fat increases in pregnancy.79 Hence, there is a significant increase in adipose tissue stores in healthy pregnant women during pregnancy. The subcutaneous stores are a ready

9 8

Lean Obese

7

Total

6 5 4 3 2

Upper Thigh

Suprailiac

Costal

Subscap

Bicep

0

Tricep

1 Lower Thigh

chronic insulin resistance can arrest failing b-cell function, thereby preventing diabetes. Also, chronic insulin resistance causes or worsens the b-cell dysfunction, possibly through b-cell exhaustion that leads to GDM and subsequent type 2 diabetes in tested subsets of women. In general, insulin resistance provides the ‘‘stress’’ needed to initiate or enhance a progressive loss of b-cell function in susceptible individuals. The progressive loss of function leads to a gradual loss of glucose tolerance (diagnosed as GDM during pregnancy) and, eventually, to type 2 diabetes. Whether the biology of the b-cell defect observed in this subset of women who develop GDM applies to other ethnic groups remains to be tested, but this model provides strong rationale for avoiding insulin resistance to prevent GDM in the first place and to prevent type 2 diabetes after pregnancy. Prevention is critical given that the risk of diabetes after GDM ranges from 20% to 50% and may be as high as 60% for certain high-risk groups such as women who required insulin therapy during pregnancy or those with a body mass index>30.74

Skinfold (mm)

946

FIGURE 7. Longitudinal changes in subcutaneous fat distribution in lean and obese women from pregravid through late gestation. Figure adapted from Am J Obstet Gynecol. 2003;189:944–948.

source of calories for the mother and fetus, particularly in late pregnancy and during lactation. The increases in visceral fat may relate to the decreases in insulin sensitivity in late gestation. Lipid metabolism differs between lean and obese women with normal glucose metabolism. Prospective longitudinal studies of lean women using hyperinsulinemic-euglycemic clamps and indirect calorimetry demonstrate net lipogenesis pregravid and in early pregnancy (12 to 14 wk), but net lipolysis in late gestation (34 to 36 wk).22 In contrast in obese women under similar experimental conditions, lipogenesis occurs only pregravid and lipolysis is predominate in both early and late gestation.80 These data support increased insulin resistance (the inability of insulin to suppress lipolysis) with advancing gestation in all women and further evidence of increased insulin resistance in obese as compared with nonobese women even earlier in gestation. Biochemical data exist that support these observed physiologic changes in lipid metabolism. Total triglyceride concentrations increase 2 to 4-fold and total cholesterol concentrations increase 25% to 50% during normal human pregnancy.81 Furthermore, there is a 50% increase in LDL cholesterol and a 30% increase in HDL cholesterol by mid-gestation, followed by a slight decrease in HDL at term.81 The effects of insulin of FFA turnover using stable isotopes of glycerol during a euglycemic clamp were evaluated relative to direct measures of insulin


Metabolic Changes in Pregnancy

LIPID METABOLISM IN GESTATIONAL DIABETES

Similar to what has been observed in the nonpregnant state, women with either pregestational type 2 diabetes or GDM have increased triglyceride and decreased HDL concentrations as compared with pregnant women with normal glucose tolerance.83 In a prospective study, women with GDM had steady state plasma FFA concentrations which were significantly greater during insulin infusion (euglycemic clamps) as compared with matched controls (Fig. 8).23 In addition, in a small longitudinal study from pregravid through late gestation, insulin suppression of FFA declined in all subjects with suppression less in women who developed GDM (Fig. 9).84 These studies support the hypothesis that women with GDM have decreased lipid insulin sensitivity, particularly in late gestation as compared with matched controls. The potential mechanisms relating to the decrease in lipid insulin sensitivity in women with GDM were evaluated in a cross-sectional

600

Labeled Glucose Insulin

umol/l

400

* 200

0

Plasma FFA -180

-120

-60

0 60 Minutes

120

180

FIGURE 8. Plasma FFA concentrations during euglycemic clamps in normal glucose tolerant pregnant women () and women with GDM (*). *P = 0.0002 between groups.23

study evaluating subcutaneous adipose tissue from women with GDM and matched controls. IRS-1 and IRS-2 were decreased and the P85 a-subunit of PI-3-kinase was significantly increased in women with GDM.84 These changes in the postreceptor insulin signaling cascade may contribute to the decreased ability of insulin to suppress FFA concentrations in women with GDM. In the same subjects, there was also a decrease in peroxisome proliferator-activated 100

Insulin Suppression of Plasma FFA Levels (%)

resistance.82 Glycerol turnover during insulin infusion remained unchanged in the second trimester and postpartum. However, there was significantly less suppression of glycerol turnover in late gestation.82 This supports the concept of significant insulin resistance of both glucose and lipid metabolism in late gestation. Last, basal FFA concentrations and hepatic glucose production are significantly correlated as demonstrated using similar methodologies.23 The increase in FFA concentrations in late pregnancy is hypothesized to be another possible mechanism relating to decreased sensitivity of maternal glucose utilization. Finally, our understanding of the role of adipocytes has evolved considerably over the last decades. Fat not only stores maternal calories for the increased energy demands of late pregnancy, but is an active metabolic tissue playing a key role in an individualâ&#x20AC;&#x2122;s metabolism. Adipocytes and their stroma are a rich source of cytokines and inflammatory mediators that can both increase insulin resistance (TNF-a) or decrease insulin resistance (adiponectin). Their role in modulating the metabolic changes in pregnancy is incompletely understood at this time as all adipokines, with the possible exception of adiponectin, are also expressed in placental tissue. The interplay between cytokines from both maternal adipose and placental sources may play a much larger role in maternal metabolism than was previously appreciated.

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Pgroup = 0.448 Ptime = 0.026 Ptg = 0.049 PtimeGDM = 0.025

Preg-Con GDM

90

80

70

60

50

Pre

Early

Late

FIGURE 9. Longitudinal changes in insulin suppression of FFA in pregnant control (Preg-Con) and GDMsubjects. The data were analyzed by analysis of variance and Fisher protected least significant difference testing for post hoc analysis between groups. Data are means Âą SD for Preg-Con (n = 4) and GDM (n = 5) subjects. Change over time P = 0.03 for both groups, group difference, P = 0.049. Insulinâ&#x20AC;&#x2122;s ability to suppress plasma FFA was significantly lower over time (P = 0.025) in the GDM subjects compared with the pregnant controls.84


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receptor-g mRNA and protein concentration that was more pronounced in women with GDM. The decrease in peroxisome proliferator-activated receptor-g and the decreases in lipoprotein lipase mRNA are consistent with increased insulin resistance in late pregnancy and may contribute to the increased lipolysis and decrease in fat mass in late pregnancy. Ultimately, these changes result in increased FFA concentrations and fat oxidation in late gestation in women who are either obese and/or have GDM. SUMMARY

There are significant alterations in maternal glucose and lipid metabolism through gestation. The differences observed between obese/gestational diabetic women as compared with matched controls in large part are a function of pregravid metabolic status and are exacerbated by the metabolic stress of pregnancy. Note: Following is an abbreviated reference list. The complete reference list is available on line at: www.clinicalobgyn.com

References 1. Catalano PM, Tyzbir ED, Roman NM, et al. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991;165: 1667–1672. 2. Catalano PM, Tyzbir ED, Wolfe RR, et al. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. Am J Obstet Gynecol. 1992;167:913–919. 5. Sivan E, Chen X, Homko CJ, et al. Longitudinal study of carbohydrate metabolism in healthy obese pregnant women. Diabetes Care. 1997;20:1470–1475. 6. Metzger BE, Ravnikar V, Vileisis RA, et al. ‘‘Accelerated starvation’’ and the skipped

breakfast in late normal pregnancy. Lancet. 1982;1:588–592. 10. Catalano PM, Huston L, Amini SB, et al. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999;180: 903–916. 13. Catalano PM, Tyzbir ED, Wolfe RR, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol. 1993;264: E60–E67. 18. Buchanan TA, Metzger BE, Freinkel N, et al. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol. 1990;162:1008–1014. 22. Catalano PM, Roman-Drago NM, Amini SB, et al. Longitudinal changes in body composition and energy balance in lean women with normal and abnormal glucose tolerance during pregnancy. Am J Obstet Gynecol. 1998;179: 156–165. 23. Xiang AH, Peters RK, Trigo E, et al. Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes. 1999;48:848–854. 52. Catalano PM, Hoegh M, Minium J, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;49:1677–1685. 70. Homko C, Sivan E, Chen X, et al. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab. 2001;86:568–573. 71. Harris MI. Gestational diabetes may represent discovery of preexisting glucose intolerance. Diabetes Care. 1988;11:402–411. 73. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51: 2796–2803.


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