metabolismogesatcion08

Metabolic Changes in Pregnancy

KRISTINE Y. LAIN, MD* and PATRICK M. CATALANO, MDw*Departments of Obstetrics and Gynecology and Internal Medicine, Universityof Kentucky, Lexington, Kentucky; and wDepartment of ReproductiveBiology, Case Western Reserve University at MetroHealth Medical Center,Cleveland, Ohio

Abstract: Maternal metabolism changes substantiallyduring pregnancy. Early gestation can be viewed asan anabolic state in the mother with an increase inmaternal fat stores and small increases in insulinsensitivity. Hence, nutrients are stored in early preg-nancy to meet the feto-placental and maternal de-mands of late gestation and lactation. In contrast,late pregnancy is better characterized as a catabolicstate with decreased insulin sensitivity (increased in-sulin resistance). An increase in insulin resistanceresults in increases in maternal glucose and free fattyacid concentrations, allowing for greater substrateavailability for fetal growth.Key words: maternal glucose metabolism, insulinsensitivity, gestational diabetes

This article provides an overview of maternalmetabolic changes during pregnancy with a fo-cus on maternal glucose and lipid metabolism.Potential mechanisms related to alterations inmaternal metabolism during pregnancy compli-cated by gestational diabetes also are reviewed.

Glucose MetabolismGlucose metabolism, both basal and postpran-dial, gradually changes over the course of preg-nancy to meet the nutritional demands of themother and fetus. Longitudinal studies in wo-men with normal glucose tolerance demonstratesignificant progressive alterations in all aspectsof glucose metabolism as early as the end of thefirst trimester.1,2 The overall direction and mag-nitude of these changes in measures of maternal

carbohydrate metabolism in normal pregnancyare listed in Table 1.

BASAL METABOLISMIn nonpregnancy, the liver is the predominantsource of net endogenous glucose production.The average plasma fasting glucose concentra-tion is approximately 90mg/dL and the rates ofglucose production and utilization are approxi-mately equal. Defects in either production orutilization will result in changes in fasting glu-cose concentrations.

In pregnancy, fasting glucose decreases pro-gressively with advancing gestation.1 The me-chanism is complex and notwell understood, butpotential contributing factors include (1) dilu-tional effects (increased plasma volume in earlygestation), (2) increased utilization (either in-creased feto-placental glucose utilization in lategestation or increased maternal uptake second-ary to increased b-cell function), and/or (3)inadequate production (limitation of hepaticglucose production relative to circulating glu-cose concentrations). Despite a decrease infasting glucose, hepatic glucose production isincreased (Fig. 1). Cross-sectional and longitu-dinal investigations using stable isotope meth-odologies describe increased fasting hepaticglucose production by late gestation even withadjustment for maternal weight gain.2–4 As fast-ing glucose is decreasing and hepatic glucoseproduction is increasing, there is a concomitantincrease in fasting insulin (Fig. 2). Hepatic glu-cose production, which is normally suppressedby insulin, increases despite increasing fastinginsulin concentration. This supports a decreasein maternal hepatic insulin sensitivity, resultingin a decreased suppression of hepatic glucoseproduction in women with normal glucosetolerance. Additionally, in obese women with

938

Supported by NIH/HD-22965 (P.M.C.).

Correspondence: Kristine Y. Lain, MD, University ofKentucky, 800 Rose Street, Room C365, Lexington,KY 40536-0293. E-mail: [email protected]

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 50 / NUMBER 4 / DECEMBER 2007

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

normal glucose tolerance, there is a decreasedability of infused insulin to fully suppress hepaticglucose production in late gestation as comparedwith pregravid and early pregnancy measure-ments. These findings indicate a further decreasein hepatic insulin sensitivity with obesity.5

The decrease in fasting glucose is furtherexacerbated with prolonged fasting.6 This sug-gests an incomplete compensation (primarilyhepatic) or some restraint on endogenous pro-duction compared with the nonpregnant condi-tion. Hepatic glucose production includes bothgluconeogenesis and glycogenolysis andwhether

gluconeogenesis remains constant during preg-nancy is unclear. The availability of substrates,such as alanine may play an important role.7–9

Finally, decreased fasting glucose concentra-tions may be secondary to enhanced b-cell func-tion resulting in fasting insulin concentrationsthat are elevated relative to the ambient glucoseconcentrations.

BASAL METABOLISM IN GESTATIONALDIABETESGestational diabetes mellitus (GDM) is definedas the presence of glucose concentrations

TABLE 1. Changes in Measures of Metabolism in Normal Pregnancy From Pregravid Estimates

Early Pregnancy Late Pregnancy

Basal metabolismFasting glucose (2) Unchanged Decreased (0.9� )Fasting Insulin (2) Unchanged Increased (1.65� )Hepatic metabolismBasal hepatic glucose production (2) Unchanged Increased (1.3� )Hepatic insulin sensitivity DecreasedGlucose suppression (2) Decreased (0.9� ) Decreased (0.9� )

Insulin metabolismInsulin secretionFirst phase insulin response (1) Increased (2� ) Increased (3� )Second phase insulin response (1) Increased (1.5� ) Increased (3� )

Insulin sensitivity (1) Decreased (0.7� ) Decreased (0.4� )

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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 preg-nancy. These studies were conducted using stableisotopes of glucose (dideuterated 6,6, D2 glucose)before pregnancy (‘‘pregravid’’), and during gesta-tional weeks 12 to 14 (‘‘early pregnancy’’) and 34 to36 (late pregnancy).10,13,67

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FIGURE 2. Fasting insulin concentrations in leanand obese women with GDM or normal glucosetolerance pregravid, early pregnancy, and late preg-nancy.10,13,67 Reproduced with permission fromObstetrics: Normal and Problem Pregnancies 5thEdition, Diabetes Mellitus Complicating Pregnancy.2007:976–1010. Copyright Elsevier.85

Metabolic Changes in Pregnancy 939

that are at the upper end of the populationdistribution for glucose in pregnant womenand are first detected during pregnancy. Onaverage, women with GDM have higher fastingglucose concentrations. Basal hepatic produc-tion, however, is not different from womenwithout GDM (Fig. 1).10 Fasting insulin alsoincreases during pregnancy in obese womenwithGDM and is greater than in women withoutGDM (Fig. 2).10 The increase in circulatingglucose concentrations despite increased insulinconcentrations and similar endogenous produc-tion in women with GDM compared to normalglucose tolerant women supports an imbalancebetween tissue insulin requirements for glucoseregulation and the ability of the pancreaticb-cells to meet those requirements.

INSULIN SENSITIVITY IN NORMALPREGNANCYOverall, insulin sensitivity decreases during preg-nancy.Estimates of peripheral insulin sensitivity inpregnancy include measurement of the insulinresponse to a fixed oral or intravenous glucosechallenge, the ratio of insulin to glucose under avariety of experimental conditions, computermodeling of an intravenous glucose tolerance test,and the euglycemic-hyperinsulinemic clamp.11,12

Early PregnancyIn leanwomen during early pregnancy,maternalinsulin sensitivity, defined as a decrease in theglucose infusion rate during the euglycemic-hyperinsulinemic clamp to maintain euglycemia(90mg/dL) decreases.13 Because maternal insu-lin concentrations vary at different times duringpregnancy despite a constant insulin infusionbased on subject weight or surface area, netglucose utilization rates must be expressed rela-tive to steady state insulin concentrations. Theeffects of insulin on peripheral glucose utiliza-tion and hepatic production can be assessedseparately if labeled glucose (stable isotopes) isinfused during the clamps. When glucose turn-over is expressed relative to steady state insulinlevels, there is a 10% decrease in insulin sensi-tivity from pregravid to early gestation in leansubjects. In contrast, there is a 15% increase ininsulin sensitivity in obese women in early preg-nancy as compared with pregravid estimates.10

Hence, the decrease in insulin requirements inearly gestation observed in some women requir-ing insulin may be a consequence of a relativeincrease in insulin sensitivity.14 This may beparticularly prominent in obese women withdecreased insulin sensitivity before conception.

Late PregnancyPeripheral insulin sensitivity decreases further inlate gestation. Early studies demonstrated thatpregnant women experienced less hypoglycemiain response to exogenous insulin in comparisonwith nonpregnant subjects15 and have an in-creased insulin response to exogenous glucosein late gestation.16 Additional studies usinghigh-dose glucose infusion testing, Bergmancomputer modeling of the intravenous glucosetolerance test, and euglycemic-hyperinsulinemicclamp studies have all demonstrated a decreasein insulin sensitivity in late gestation rangingfrom 33% to 78%.1,17–19 The decrease in insulinsensitivity in late pregnancy is profound relativeto other conditions, approaching the degreeobserved in individuals with established type 2diabetes. Of note, the quantitative estimates ofinsulin sensitivity from glucose clamps con-ducted at a single insulin concentration mayunderestimate the degree of insulin resistance,because there is a large increase in noninsulinrequiring glucose disposal during pregnancyresulting from utilization by the fetus and pla-centa. In a pregnant ewe model, approximatelyone third of maternal glucose utilization wasaccounted for by uterine, placental, and fetaltissue.20 Additionally, fetal glucose concentra-tion based on human fetal blood sampling is afunction of fetal size and gestational age inaddition to maternal glucose concentration.21

Measurements of insulin sensitivity performedby computer modeling of intravenous glucosetolerance test data are not influenced by fetaltissues, because that approach measures insulin-dependent and insulin-independent net glucosedisposal separately.11

INSULIN SENSITIVITY IN GESTATIONALDIABETESInitial studies using glucose clamp methodologydemonstrated a 40% further decrease in wholebody insulin sensitivity in women with severeGDM in late pregnancy.19 Longitudinal clampstudies using labeled glucose in both lean andobese women who develop GDM demonstrateda lower insulin sensitivity among women withGDM compared with weight-matched controls(Fig. 3).10,13 The difference was most evidentbefore and during early pregnancy. By lategestation, the acquired insulin resistance of preg-nancy was marked in both groups so that theintergroup differences were less pronounced butstill statistically significant. Of interest, therewas an (15% to 20%) increase in insulin sensi-tivity from the time before conception through

940 Lain and Catalano

early pregnancy (12 to 14wk), particularly inthose women with the lowest insulin sensitivitybefore conception. The changes in insulin sensi-tivity from the time before conception throughearly pregnancy were inversely correlated withthe changes in maternal weight gain and energyexpenditure.22 The associations between insu-lin’s effect on glucose metabolism, weight gain,and energy expenditure may help explain thedecreases in maternal weight gain and insulinrequirements in women with diabetes in earlygestation.14,22 From a large cohort of Hispanicwomen with GDM who did not have diabetessoon after pregnancy, insulin sensitivity in thethird trimester assessed by glucose clamps withlabeled glucose was reduced by a small amountcompared with women who had normal glucosetolerance.23 In addition, insulin resistance wasobserved not only for the stimulation of glucoseutilization, but also for the suppression of hepa-tic or endogenous glucose production. The sup-pression was tightly linked to the suppression byinsulin of free fatty acids (FFA), which was alsoimpaired in women with GDM. Reduced sup-pression of hepatic glucose production by in-fused insulin has also been noted in lean andobese women with GDM in late gestation. Incontrast, the finding of an elevation of glucose

production after an overnight fast despite higherbasal insulin concentrations in women withGDM compared with women who had normalglucose tolerance has not been consis-tent.10,13,17,23 These findings, however, supporta role for hepatic insulin resistance in the over-night-fasted state.

MECHANISM OF INSULIN RESISTANCEIN PREGNANCYThe physiologic factors responsible for the de-crease of insulin sensitivity or insulin resistanceof pregnancy are not known with certainty, butare partially related to the metabolic effects ofseveral hormones and cytokines that are ele-vated in the maternal circulation during preg-nancy. Potential hormones include humanplacental lactogen (HPL), progesterone, prolac-tin, and cortisol. Evidence to support an impactof these hormones on insulin action include theparallel between the pattern of insulin resistanceduring pregnancy and simultaneous growthof the fetal-placental unit and increasing con-centrations of placental hormones.24,25 Also,administration of HPL, progesterone, or gluco-corticoids to nonpregnant individuals inducesmetabolic changes (hyperinsulinemia withouthypoglycemia) that are consistent with a blunt-ing of insulin action.25–28 Finally, in vitro ex-posure of insulin target cells such as adipocytesto pregnancy hormones results in impaired in-sulin-mediated glucose uptake by those cells.29

Tumor necrosis factor-a (TNF-a) is asso-ciated with decreased insulin sensitivity in anumber of conditions, including obesity, aging,and sepsis.30–32 In vitro studies have shown thatTNF-a down-regulates insulin receptor signal-ing in cultured adipocytes and skeletal musclecells.33,34 TNF-a activates a pathway that in-creases sphingomyelinases and ceramides, whichinterfere with insulin receptor autophosphoryla-tion. Also, TNF-a promotes serine phosphory-lation of insulin receptor substrate-1 (IRS-1),thus impairing its association with the insulinreceptor.35 During pregnancy, circulating TNF-a concentrations have an inverse correlationwith insulin sensitivity as estimated fromeuglycemic-clamp studies.36 Furthermore,among leptin, cortisol, HPL, human chorionicgonadotropin, estradiol, progesterone, and pro-lactin, TNF-a was the only significant predictorof the change in insulin sensitivity from pregra-vid through late gestation.36 In addition, in lategestation skeletal muscle, insulin receptor, andIRS-1 tyrosine phosphorylation are impairedand serine phosphorylation is increased.37,38

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FIGURE 3. Insulin sensitivity in lean and obesewomen with GDM or normal glucose tolerancepregravid, early pregnancy, and late pregnancy. In-sulin-mediated glucose uptake during the steady stateperiod of glucose clamps [(glucose infusion rate)+(residual endogenous glucose production rate)]/(stateinsulin concentration).10,13 Reproduced with permis-sion from Diabetes Mellitus Complicating Pregnancy.5th ed. 2007:976–1010. Copyright Elsevier.85


Therefore, the increased TNF-a concentrationsin late pregnancy may attenuate the insulinsignaling cascade and result in some of theobserved decreased insulin sensitivity. Thesource of increased TNF-a is most likely placen-tal with supporting evidence from a dually per-fused in vitro human placental cotyledonmodel.In this model, 94% of placental TNF-a wasreleased into the maternal circulation and 6%was released to the fetal side.Hence, it seems thatthe progressive decrease in insulin sensitivity inpregnancy results from the metabolic action ofhormones and cytokines secreted from the feto-placental unit. Finally, the potential role of otherfactors, such as FFA may also contribute to theinsulin resistance of pregnancy.

The cellular determinants of insulin resis-tance during pregnancy are not well character-ized but defects in the insulin signaling cascade inhuman skeletal muscle and adipose tissue mayplay an important role (Fig. 4). In theory, one or

more of the steps in the insulin signaling cascadeinvolved in insulin stimulated glucose uptake orsuppression could be impaired in pregnant in-dividuals. Skeletal muscle is the target tissue thatis quantitatively most important for total-bodyinsulin-mediated glucose uptake during theclamp. Insulin binding to skeletal muscle issimilar in nonpregnant and pregnant women,suggesting that the cellular determinants of per-ipheral insulin resistance of pregnancy occurs atsteps downstream from cell surface receptorbinding.39 The intracellular actions of insulinare mediated by autophosphorylation of theinsulin receptor-b subunit on tyrosine. This isfollowed by the activation of the insulin receptortyrosine kinase (IRTK) and phosphorylation ofinsulin receptor substrates, particularly IRS-1.Tyrosine phosphorylation of the insulin receptorand of IRS-1 is required for the activation of theenzyme phosphatidyl-inositol-3-kinase (PI-3-kinase), and this step is necessary for several

FIGURE 4. The insulin signaling pathway in skeletal muscle. ADP indicates adenosine dipho-sphate; Akt, serine/threonine kinase; aPKC, atypical protein kinase C subfamily; ATP, adenosinetriphosphate; 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, PI3-kinase catalytic subunit.


effects of insulin, including translocation ofglucose transporter 4 (GLUT-4) to the cell sur-face where glucose transport occurs. There areno significant differences in GLUT-4 concentra-tion in skeletal muscle from pregnant as com-pared with nonpregnant women.40 Pregnantwomen do have reduced IRS-1 protein com-pared with nonpregnant women.37 The down-regulation of the IRS-1 protein closely parallelsthe decreased ability of insulin to induce addi-tional steps in the insulin signaling cascade, suchas stimulation of 2-deoxy glucose uptake, thatlead to impaired glucose transport.

In summary, based on available data, thereare significant alterations in insulin sensitivity innormal pregnancy. In early pregnancy, insulinsensitivity is variable and dependent onmaternalpregravid insulin sensitivity and other specula-tive mechanisms. Changes in late gestation aremore consistent with significant decreases ininsulin sensitivity. The stimulus for decreasedinsulin sensitivity in muscle and adipose tissueseems to be placental, not maternal, productionof cytokines such as TNF-a and leptin. There isan improvement in insulin sensitivity and con-comitant decrease in serum concentration ofthese cytokines postpartum. Additionally, themechanisms by which TNF-a affects the IRS-1function in the insulin signaling cascade is intactduring gestation. The mechanisms resulting indecreased hepatic insulin sensitivity are less wellcharacterized, but the increase in maternal FFAconcentration certainly may play a role.

INSULIN RESISTANCE IN GESTATIONALDIABETESIn addition to postreceptor insulin signalingchanges in normal pregnancy, studies in humanskeletal muscle and adipose tissue demonstrateadditional defects in insulin signaling in womenwith GDM. In addition to down-regulation ofthe IRS-1 protein and decreased ability of in-sulin to induce movement of the GLUT-4 to thecell surface membrane, women with GDM havea decrease in the ability of the insulin receptor-b(the component of the insulin receptor not on thecell surface) to undergo tyrosine phosphoryla-tion. This defect is not found in either pregnantor nonpregnant women with normal glucosetolerance,37 and results in a 25% lower glucosetransport activity. The tyrosine phosphorylationof the insulin receptor substrate proteins arebalanced by dephosphorylation reactions car-ried out by cellular and membrane-boundprotein phosphatases. Vandate inhibits pro-tein-tyrosine phosphatase activity.41 During in

vitro studies, vandate failed to normalize glucosetransport activity inwomenwithGDM, suggest-ing that decreased glucose uptake inwomenwithGDM is not the result of impaired tyrosinephosphorylation alone.41 Additionally, inGDM, plasma cell membrane glycoprotein-1(PC-1), an inhibitor of IRTK activity, was in-creased in comparison with pregnant and non-pregnant controls. The increase in PC-1 contentsuggests excessive phosphorylation of serine/threonine residues in skeletal muscle insulinreceptors, thus contributing to decreased IRTKactivity or decreased insulin sensitivity.38 Ofinterest, TNF-a which was described earlier asa potential placental factor relating to decreasedmaternal insulin sensitivity, acts as a serine/threonine kinase to inhibit IRS-1 and insulinreceptor tyrosine phosphorylation. Thus, thesereceptor defects may contribute in part to thepathogenesis of GDMand increased risk of type2 diabetes later in life.

Adiponectin, a collagenlike protein which isadipose specific,42 is negatively associated withobesity,43 hyperinsulinemia, and insulin resis-tance.44 Unlike many other cytokines whichare increased in disease states, plasma concen-trations of adiponectin are lower in individualswith polycystic ovarian syndrome, hyperten-sion, coronary artery disease, impaired glucosetolerance, type 2 diabetes, and GDM.44–51 Adi-ponectin and TNF-a produce opposing effectson insulin signaling. Adiponectin increases tyr-osine phosphorylation of the insulin receptorand the ratio of adiponectin/TNF-a may be animportant factor for insulin sensitivity. Adipo-nectin is decreased during pregnancy, and thesechanges are correlated with decreased insulinsensitivity of glucose disposal.52

INSULIN SECRETION IN NORMALPREGNANCYThere are progressive increases in insulin secre-tion in response to an intravenous glucose chal-lenge with advancing gestation (Fig. 5). Theincreases in insulin concentration are more pro-nounced in lean as compared with obese women,because lean women most likely begin theirpregnancies with better insulin sensitivity. Leanwomen have a greater total decrease in insulinsensitivity in contrast to obese women withnormal glucose tolerance.

The normal response of b-cells to insulinresistance is to increase insulin secretion, therebyminimizing the impact of insulin resistance oncirculating glucose levels.53–55 Increased insulinsecretion (or increased b-cell function) during


pregnancy most likely represents compensationfor progressive insulin resistance rather than viceversa, because insulin resistance occurs even inthe absence of endogenous insulin secretion (asin type 1 diabetes).56 However, given that insulinsecretion increases as much as 50% early in thesecond trimester before insulin resistance ofpregnancy becomes manifest, the hormonalmilieu of pregnancy may exert a primary effectto increase insulin secretion independent ofinsulin resistance.

The mechanisms that lead to enhanced insu-lin secretion in pregnancy, whether primary or as

compensation for insulin resistance, are notcompletely known. In animal studies, an in-crease in b-cell mass results from a combinationof b-cell hypertrophy and hyperplasia.57,58

Hyperplasia of pancreatic islets has also beenobserved in human pregnancy.59 The increasedb-cell mass may contribute to the pattern ofincreased fasting insulin concentrations despitenormal or lowered fasting glucose concentra-tions in late pregnancy.2 Increased b-cell massmay also contribute to an enhanced insulinresponse to secretogogues during pregnancy.The 2-fold to 3-fold increase in b-cell respon-siveness 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 nutri-ents must also be increased during preg-nancy, but mechanistic information supportingincreased responsiveness is limited. Twogroups have reported increased activities ofprotein kinase A or C in pancreatic tissuefrom pregnant compared with nonpregnantrats.60,61 Another report revealed enhancedcell-to-cell communication in pancreaticislets from pregnant compared with nonpreg-nant animals.62 The relation of these phenomenato enhanced insulin secretion in vivo is notknown.

Data regarding insulin clearance in preg-nancy are scant. There was no difference ininsulin disappearance rate when insulin wasinfused intravenously in late gestation in com-parison with nongravid subjects.63–65 In con-trast, a 25% increase in insulin turnover in apregnant as compared with a nonpregnant ratmodel was observed when a radio-labeled insu-lin was used.66 Also, a 20% and 30% increase ininsulin clearance occurred by late pregnancy inlean and obese women, respectively, using theeuglycemic-clamp model (Fig. 6).67 Althoughthe placenta may be partially responsible forinsulin clearance secondary to the abundanceof insulinase, the exact mechanism for thechanges in clearance remains speculative.

INSULIN SECRETION IN GESTATIONALDIABETESMost cases of GDM result from inadequateinsulin secretion that arises in women withchronic insulin resistance and, therefore, seemto be related to type 2 diabetes. The b-cell defectsin GDM could reflect the spectrum of b-celldefects that lead to diabetes in nonpregnantindividuals. Very few studies of insulin secretionhave focused on specific subtypes of GDM, and


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FIGURE 5. Longitudinal changes in insulin secre-tion. Increases in (A) first phase (area under the curvefrom 0 to 5min) and (B) second phase (area under thecurve from5 to 60min) insulin response (left panel andright panel, respectively) to an intravenous glucosechallenge in lean and obese women with GDM ornormal glucose tolerance pregravid, early pregnancy,and late pregnancy.10,13


therefore, information about the etiology ofinadequate insulin secretion is scant. In womenwith circulating markers of pancreatic autoim-munity, poor insulin secretion is likely the resultof ongoing b-cell destruction. Likewise, in wo-men with genetic markers for autosomal domi-nant or maternally inherited diabetes, poorinsulin secretion likely reflects abnormalities ofb-cell function that have been described in asso-ciation with those diseases outside of preg-nancy.68,69 Virtually all studies of women withGDM reveal b-cell function that is decreased30% to 70% relative to women who maintainnormal glucose tolerance during pregnancy.These studies also demonstrate chronic insulinresistance in women with or with a history ofgestational diabetes, and therefore most b-celldysfunction in GDMoccurs on a background ofinsulin resistance. Indeed, when insulin sensitiv-ity and secretion have been compared betweennormal and gestational diabetic women duringand after pregnancy, the defect in b-cell com-pensation for insulin resistance in GDM hasbeen of similarmagnitude in both situations.13,19

Longitudinal data reveal that women withGDM follow a pattern of change in insulinsensitivity that parallels controls (slight increasein early gestation, the large fall by late gestation),albeit at lower insulin sensitivity overall(Fig. 3).10 Their b-cell function, assessed as acuteinsulin response to intravenous glucose, likewise

follows a pattern that is similar to controls(slight increase early in gestation, before insulinsensitivity declines, then further increase in lategestation when insulin sensitivity falls), but alower insulin secretion overall relative to thedecreases insulin sensitivity (Fig. 5).10 A lowerinsulin secretion in women with GDM despitetheir increased insulin resistance means thattheir b-cell defect is even greater than can beappreciated by insulin levels or responses alone.Importantly, women with GDM increase theirinsulin secretion during pregnancy, just as nor-mal glucose tolerant women do, but not to thesame extent.70 Calculation of the relative defectin b-cell compensation for insulin resistancebetween GDM and control women reveals asimilar defect—41% during pregnancy and50% after pregnancy.67,70 This consistency inthemagnitude of the b-cell defect combined withthe fact that womenwithGDMdo increase theirinsulin responses during pregnancy, demon-strates thatGDM is not simply a fixed limitationin insulin secretory reserve that becomes mani-fest as hyperglycemia when insulin needsincrease during pregnancy. Instead, GDM re-presents the detection during pregnancy ofchronic metabolic abnormalities that antedatepregnancy but are detected when pregnancyleads to the first evaluation of glucose tolerancein otherwise healthy young women.71

The common association between a b-celldefect detected during pregnancy (ie, under con-ditions of acquired insulin resistance) in womenwho also have chronic insulin resistance mayprovide clues to the cause of the b-cell defect inGDM. One possibility is that women who havechronic insulin resistance and a separate b-cellproblem are the individuals whose glucose levelsrise to the level of GDM at a relatively youngage. In addition, a b-cell defect may be caused orworsened by insulin resistance as supported bythe findings that weight gain and an additionalpregnancy independently increase the risk ofdiabetes (3-fold for a pregnancy and 2-fold for10 pounds of weight gain).72 These observationsled to an interventional study in Hispanicwomen using a thiazolidinedione drug (TripodStudy) with the goal of decreasing insulin resis-tance after pregnancy.73 Diabetes rates werereduced 55% compared with placebo-treatedpatients, and the protection from diabetes wasvery closely linked to the degree of reduction ofendogenous insulin requirements when patientswere initially started on the drug.73 These resultssuggest that reducing the secretory demandsplaced on b-cells by improving or decreasing


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FIGURE 6. Whole body insulin clearance ratesmeasured during hyperinsulinemic clamps in leanand obese women with GDM or normal glucosetolerance pregravid, early pregnancy, and late preg-nancy.10,67


chronic insulin resistance can arrest failing b-cellfunction, thereby preventing diabetes. Also,chronic insulin resistance causes or worsens theb-cell dysfunction, possibly through b-cellexhaustion that leads to GDM and subse-quent type 2 diabetes in tested subsets of women.In general, insulin resistance provides the‘‘stress’’ needed to initiate or enhance aprogressive loss of b-cell function in susceptibleindividuals. The progressive loss of functionleads to a gradual loss of glucose tolerance(diagnosed as GDM during pregnancy) and,eventually, to type 2 diabetes. Whether the bio-logy of the b-cell defect observed in this subsetof women who develop GDM applies to otherethnic groups remains to be tested, but thismodel provides strong rationale for avoidinginsulin resistance to prevent GDM in the firstplace and to prevent type 2 diabetes after preg-nancy. Prevention is critical given that the risk ofdiabetes after GDM ranges from 20% to 50%and may be as high as 60% for certain high-riskgroups such as women who required insulintherapy during pregnancy or those with a bodymass index>30.74

Lipid Metabolism

LIPID METABOLISM IN NORMALPREGNANCYAlthough alterations in glucose metabolism areoften considered the primary metabolic adapta-tions during pregnancy, significant alterationsoccur in lipid metabolism as well. From a wholebody perspective, the increases in maternaladipose tissue in nonobese pregnant womenare secondary only to the significant increasesin total-body water. Nonobese women gainqapproximately 3.5 kg of fat during normalpregnancy but there is a wide variation bothwithin and among various ethnic and racialgroups.75–77 Subcutaneous fat mass, primarilycentrally distributed (mid-thorax to mid-thigharea) significantly increases in early gestation(Fig. 7).78 Data on visceral fat accrual are scarce.Using ultrasound, investigators reported an in-crease in both preperitoneal and subcutaneousfat regions by the late third trimester of preg-nancy. In addition, the ratio of preperitonealand subcutaneous fat increased, suggesting thatintra-abdominal fat increases in pregnancy.79

Hence, there is a significant increase in adiposetissue stores in healthy pregnant women duringpregnancy. The subcutaneous stores are a ready

source of calories for the mother and fetus,particularly in late pregnancy and during lacta-tion. The increases in visceral fat may relateto the decreases in insulin sensitivity in lategestation.

Lipid metabolism differs between lean andobese women with normal glucose metabolism.Prospective longitudinal studies of lean womenusing hyperinsulinemic-euglycemic clamps andindirect calorimetry demonstrate net lipogenesispregravid and in early pregnancy (12 to 14wk),but net lipolysis in late gestation (34 to 36wk).22

In contrast in obese women under similar experi-mental conditions, lipogenesis occurs only preg-ravid and lipolysis is predominate in both earlyand late gestation.80 These data support in-creased insulin resistance (the inability of insulinto suppress lipolysis) with advancing gestation inall women and further evidence of increasedinsulin resistance in obese as compared withnonobese women even earlier in gestation.

Biochemical data exist that support theseobserved physiologic changes in lipid metabo-lism. Total triglyceride concentrations increase 2to 4-fold and total cholesterol concentrationsincrease 25% to 50% during normal humanpregnancy.81 Furthermore, there is a 50% in-crease in LDL cholesterol and a 30% increase inHDL cholesterol by mid-gestation, followed bya slight decrease inHDL at term.81 The effects ofinsulin of FFA turnover using stable isotopesof glycerol during a euglycemic clamp wereevaluated relative to direct measures of insulin

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FIGURE 7. Longitudinal changes in subcutaneousfat distribution in lean and obese women from preg-ravid through late gestation. Figure adapted fromAm J Obstet Gynecol. 2003;189:944–948.


resistance.82 Glycerol turnover during insulininfusion remained unchanged in the second tri-mester and postpartum. However, there wassignificantly less suppression of glycerol turn-over in late gestation.82 This supports the con-cept of significant insulin resistance of bothglucose and lipid metabolism in late gestation.Last, basal FFA concentrations and hepaticglucose production are significantly correlatedas demonstrated using similar methodologies.23

The increase in FFA concentrations in latepregnancy is hypothesized to be another possiblemechanism relating to decreased sensitivity ofmaternal glucose utilization.

Finally, our understanding of the role ofadipocytes has evolved considerably over thelast decades. Fat not only stores maternal cal-ories for the increased energy demands of latepregnancy, but is an active metabolic tissueplaying a key role in an individual’s metabolism.Adipocytes and their stroma are a rich source ofcytokines and inflammatory mediators that canboth increase insulin resistance (TNF-a) or de-crease insulin resistance (adiponectin). Theirrole in modulating the metabolic changes inpregnancy is incompletely understood at thistime as all adipokines, with the possible excep-tion of adiponectin, are also expressed in pla-cental tissue. The interplay between cytokinesfrom both maternal adipose and placentalsources may play a much larger role in maternalmetabolism than was previously appreciated.

LIPID METABOLISM IN GESTATIONALDIABETESSimilar to what has been observed in the non-pregnant state, women with either pregesta-tional type 2 diabetes or GDM have increasedtriglyceride and decreased HDL concentrationsas compared with pregnant women with normalglucose tolerance.83 In a prospective study, wo-men with GDM had steady state plasma FFAconcentrations which were significantly greaterduring insulin infusion (euglycemic clamps) ascompared with matched controls (Fig. 8).23 Inaddition, in a small longitudinal study frompregravid through late gestation, insulin sup-pression of FFA declined in all subjects withsuppression less in womenwho developedGDM(Fig. 9).84 These studies support the hypothesisthat women with GDM have decreased lipidinsulin sensitivity, particularly in late gestationas compared with matched controls.

The potential mechanisms relating to thedecrease in lipid insulin sensitivity in womenwith GDM were evaluated in a cross-sectional

study evaluating subcutaneous adipose tissuefrom women with GDM and matched controls.IRS-1 and IRS-2 were decreased and the P85a-subunit of PI-3-kinase was significantly in-creased in women with GDM.84 These changesin the postreceptor insulin signaling cascademaycontribute to the decreased ability of insulin tosuppress FFA concentrations in women withGDM. In the same subjects, there was also adecrease in peroxisome proliferator-activated

Insulin

Labeled Glucose

Plasma FFA

Minutes

600

400

200

um

ol/l

-180 -120 -60 00

60 120 180

*

FIGURE 8. Plasma FFA concentrations during eu-glycemic clamps in normal glucose tolerant pregnantwomen (�) and women with GDM (*). *P=0.0002between groups.23

Pre Early Late50

60

70

80

90

100 Preg-Con

GDM

Insu

lin S

uppr

essi

on o

f Pl

asm

a FF

A L

evel

s (%

)

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

FIGURE 9. Longitudinal changes in insulin sup-pression of FFA in pregnant control (Preg-Con) andGDMsubjects. The data were analyzed by analysis ofvariance and Fisher protected least significant differ-ence testing for post hoc analysis between groups.Data are means±SD for Preg-Con (n=4) andGDM (n=5) subjects. Change over time P=0.03for both groups, group difference,P=0.049. Insulin’sability to suppress plasma FFA was significantlylower over time (P=0.025) in the GDM subjectscompared with the pregnant controls.84


receptor-g mRNA and protein concentrationthat was more pronounced in women withGDM. The decrease in peroxisome prolifera-tor-activated receptor-g and the decreases inlipoprotein lipase mRNA are consistent withincreased insulin resistance in late pregnancyand may contribute to the increased lipolysisand decrease in fat mass in late pregnancy.Ultimately, these changes result in increasedFFA concentrations and fat oxidation in lategestation in women who are either obese and/orhave GDM.

SUMMARYThere are significant alterations in maternalglucose and lipid metabolism through gestation.The differences observed between obese/gesta-tional diabetic women as compared withmatched controls in large part are a function ofpregravid metabolic status and are exacerbatedby the metabolic stress of pregnancy.

Note: Following is an abbreviated reference list.The complete reference list is available on line at:www.clinicalobgyn.com

References1. Catalano PM, Tyzbir ED, Roman NM, et al.

Longitudinal changes in insulin release andinsulin resistance in nonobese pregnantwomen. Am J Obstet Gynecol. 1991;165:1667–1672.

2. Catalano PM, Tyzbir ED, Wolfe RR, et al.Longitudinal changes in basal hepatic glucoseproduction and suppression during insulin in-fusion in normal pregnantwomen.AmJObstetGynecol. 1992;167:913–919.

5. Sivan E, Chen X, Homko CJ, et al. Long-itudinal study of carbohydrate metabolism inhealthy 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 metabolismduring pregnancy in obese womenwith normalglucose tolerance and gestational diabetesmellitus. Am J Obstet Gynecol. 1999;180:903–916.

13. Catalano PM, Tyzbir ED, Wolfe RR, et al.Carbohydrate metabolism during pregnancyin control subjects and women with gesta-tional diabetes. Am J Physiol. 1993;264:E60–E67.

18. Buchanan TA, Metzger BE, Freinkel N, et al.Insulin sensitivity and B-cell responsiveness toglucose during late pregnancy in lean andmod-erately obese women with normal glucosetolerance or mild gestational diabetes. Am JObstet Gynecol. 1990;162:1008–1014.

22. Catalano PM, Roman-Drago NM, Amini SB,et al. Longitudinal changes in body composi-tion and energy balance in lean women withnormal and abnormal glucose tolerance duringpregnancy. Am J Obstet Gynecol. 1998;179:156–165.

23. Xiang AH, Peters RK, Trigo E, et al. Multiplemetabolic defects during late pregnancy in wo-men 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: implica-tions for regulation of glucose and lipid meta-bolism. Diabetologia. 2006;49:1677–1685.

70. Homko C, Sivan E, Chen X, et al. Insulinsecretion during and after pregnancy in pa-tients with gestational diabetes mellitus. J ClinEndocrinol Metab. 2001;86:568–573.

71. Harris MI. Gestational diabetes may representdiscovery of preexisting glucose intolerance.Diabetes Care. 1988;11:402–411.

73. Buchanan TA, Xiang AH, Peters RK, et al.Preservation of pancreatic beta-cell functionand prevention of type 2 diabetes by pharma-cological treatment of insulin resistance inhigh-risk Hispanic women. Diabetes. 2002;51:2796–2803.


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