BMJ, Adiponektin Pd GDM

8162019 BMJ Adiponektin Pd GDM

httpslidepdfcomreaderfullbmj-adiponektin-pd-gdm 19

Adiponectin and IGFBP-1 in thedevelopment of gestational diabetesin obese mothers

Vanessa I Ramirez1 Evelyn Miller1 Christiane L Meireles1 Jonathan Gelfond2

Debra A Krummel3 Theresa L Powell1

To cite Ramirez VI Miller E

Meireles CL et al

Adiponectin and IGFBP-1 in

the development of

gestational diabetes in obese

mothers BMJ Open Diabetes

Research and Care 20142

e000010 doi101136

bmjdrc-2013-000010

Received 10 December 2013

Revised 5 March 2014

Accepted 7 April 2014

For numbered affiliations see

end of article

Correspondence to

Dr Theresa L Powell

powellt3uthscsaedu

ABSTRACTObjective Gestational diabetes mellitus (GDM) is

more common in pregnancies complicated by obesityand both diseases increase the risk for fetal overgrowthand long-term adverse health consequences for the

mother and child Previous studies have linked lowmaternal serum adiponectin to GDM in normal andoverweight women We hypothesized that lower

adiponectin in particular the high-molecular-weightform and insulin-like growth factor I (IGF-I) and itsbinding protein (IGFBP-1) are associated with GDM in

pregnant obese Hispanic women

Methods 72 obese predominantly Hispanic (92)women were recruited at 24ndash28 weeks of gestationAdiposity was assessed fasting serum samples were

collected and glucose insulin triglyceride cholesterollevels adipokines and hormones associated withobesity and insulin resistance were measured

30 women had been recently diagnosed with GDM

Results Gestational weeks body mass index tricepsskinfold thickness mid-arm circumference serumleptin IGF-I tumor necrosis factor α and interleukin-6

did not differ in the two groups Obese women withGDM had significantly higher fasting glucose A1Ctriglycerides very-low-density lipoprotein cholesterol

and lower high-density lipoprotein cholesteroladiponectin and IGFBP-1 compared to obese womenwithout GDM Homeostasis model assessment of

insulin resistance was positively correlated to IGF-I andnegatively correlated to adiponectin

Conclusions Obese pregnant women with recentlydiagnosed GDM had a significantly exacerbated

metabolic profile low serum adiponectin and IGFBP-1levels at 24ndash28 weeks of gestation as compared towomen with obesity alone Because low adiponectin is

well established to cause insulin resistance anddecreased IGFBP-1 indicates increased IGF-Ibioavailability we propose that these changes are

mechanistically linked to the development of GDM inobese Hispanic women

INTRODUCTIONRecent estimates indicate that 32 of women in reproductive age (20ndash39 years) areobese1 The prevalence of obesity in preg-

nancy has become a signi1047297cant obstetrical

challenge due to the increased risk of preg-nancy complications in these women includ-ing gestational hypertension pre-eclampsiaand gestational diabetes mellitus (GDM) as well as operative and postoperativ e complica-tions following cesarean delivery2 The fetus

can also be negatively affected by high mater-nal adiposity with increased risk for stillbirthprematurity shoulder dystocia and fetalovergrowth3

Obese pregnant women often enter preg-nancy with mild insulin resistance which isassociated with hyperinsulinemia The inci-dence of GDM in obese mothers is nearly double compared with mothers of normalbody mass index (BMI kgm2)4 Advancesin detection and treatment of GDM inrecent years have not alleviated the unfavor-able intrauterine environment for the devel-oping fetus and fetal overgrowth continuesto be a major problem in these pregnan-cies5 6 Large-for-gestational-age childrenhave a higher long-term risk for metabolicand cardiovascular disease7 Pregnancy com-plicated by GDM also increases the risk forthe mother as well as the fetus to developmetabolic and cardiovascular diseases laterin life8

Mexican-American women of reproductiveage (20ndash39) have a greater prevalence of overweight and obesity (69) than non-Hispanic

White women (51)1 The frequency of

Key messages

Obesity in pregnancy is highly prevalent but themechanism underlying the development of ges-tational diabetes mellitus (GDM) in some but notall of these women is unclear

At mid-pregnancy obese mothers with GDM had

significantly lower serum adiponectin and insulin-

like growth factor I binding protein (IGFBP-1)compared with obese non-GDM mothers

We speculate that low maternal adiponectin andIGFBP-1 is mechanistically linked to the develop-ment of GDM by promoting insulin resistance

BMJ Open Diabetes Research and Care 20142e000010 doi101136bmjdrc-2013-000010 1

Open Access Research

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GDM has been reported to be 13 in obese Hispanic women compared with 7 for obese Caucasian women4 9 Therefore babies of Hispanic women are at particular risk of exposure to the adverse intrauterinemetabolic environment associated with maternal obesity and GDM which may predispose them for obesity anddiabetes This may contribute to the very high rate of

childhood and adolescent obesity (21 with BMI gt95thcentile) in Hispanic children and adolescents10

Insulin resistance has been identi1047297ed as a commonunderlying factor for poor pregnancy outcomes11 Theability to diagnose abnormal insulin resistance in preg-nancy is complicated by the natural decrease in insulinresponsiveness that occurs in all pregnant women Adiponectin has well-established insulin sensitizing prop-erties and circulating levels of adiponectin decrease withincreasing BMI contributing to insulin resistance inobese non-pregnant participants In pregnancy low maternal adiponectin levels have been reported in women diagnosed with GDM12ndash23 However maternal

BMI was not consistently accounted for in these reports Adiponectin is found in multimeric forms in the circu-

lation commonly known as high-molecular-weight (HMW) middle-molecular-weight and low-molecular- weight forms Most metabolic ef fects of adiponectin canbe attributed to HMW forms24 and the strongest pre-dictor of insulin sensitivity in non-pregnant individuals isthe HMW adiponectintotal adiponectin ratio In preg-nancy the relationship between HMW adiponectin andinsulin sensitivity appears to be similar with HMW adipo-nectin being positively correlated with insulin sensitivity and HM W forms reported to be reduced in GDM

mothers18 25

Naruse et al

26

observed a decline in HMW adiponectin as gestation progresses In contrastMazaki-Tovi et al

17 reported no change with gestation inany multimeric form Low maternal levels of HMW adi-ponectin have been reported in GDM pregnancies12ndash23

as well as in pregnancies complicated by small-for-gestational-age fetuses27 Mat ernal HMW adipo-nectin is increased in pre-eclampsia28 Interestingly cordserum HMW adiponectin levels are higher than inmaternal serum and are positi vely correlated to birth weight 29ndash31 in most but not all32 studies

Maternal circulating levels of insulin-like growth factorI (IGF-I) and its binding proteins (IGFBP) increase overgestation This is likely due to the effects of placentalgrowth hormone on hepatic IGF-I release33 MaternalIGF-I correlates positively with birth weight and placen-tal weight and maternal IGF-I is signi1047297cantly higher inGDM pregnancies compared with non-diabetic pregnan-cies3 4 3 5 Maternal IGF-I levels are positively correlated with pre-pregnancy BMI fasting insulin and the homeo-stasis model assessment of insulin resistance (HOMA-IR)in individuals with gestational diabetes but not incontrol pregnancies suggesting that elevated IGF-I may contribute to insulin resistance in women with GDM34

One study suggested that early preg nancy IGF-I plasma

levels may be predictive of GDM36 The predominant

IGFBP-isoform 3 is degraded in pregnancy resulting inincreased IGF-I availability37 This data suggests that IGFBP-1 plays an important role in modulating IGF-Ibioavailability during pregnancy IGFBP-1 is negatively correlated with birth size in normal and diabeticpregnancies38 39

Our study was designed to examine maternal meta-

bolic parameters (glucose and lipids) hormones(insulin IGF-I IGFBP-1) and adipokine levels (adipo-nectin leptin interleukin (IL)-6 and tumor necrosisfactor (TNF) α) in obese pregnant women This study was conducted at 24ndash28 weeks of gestation in predomin-antly Hispanic women with pre-pregnancy BMI gt30 withor without recent diagnosis of GDM We hypothesizedthat lower adiponectin in particular the HMW formand IGFBP-1 and higher IGF-I are associated with thediagnosis of GDM in pregnancies complicated by mater-nal obesity

METHODSStudy subjects All participants granted informed consent and approveduse of their protected health information Seventy-twopregnant women were included according to the inclu-sion criteria of high pre-pregnancy or early pregnancy (lt12 weeks) BMI (30ndash45) with singleton pregnanciesand between 18 and 40 years of age Participantsbetween 24 and 28 weeks of gestation were recruitedfrom the University Hospital System prenatal clinics inSouth Central Texas The exclusion criteria were concur-rent in1047298ammatory vascular or metabolic disease

current use of tobacco street drugs or medicationsknown to affect in1047298ammatory markers (including corti-costeroids) excessive weight gain or loss prior to preg-nancy (gt20 lbs) including bariatric surgery in the past year plans to leave the area and inability to travel tostudy visit Of the 72 women 30 were diagnosed withGDM at or within 2 weeks of enrollment GDM is carbo-hydrate intolerance of varying degrees of severity withonset or 1047297rst recognition during pregnancy Diagnosis was con1047297rmed when a 50 g carbohydrate load (1 hglucose challenge test) yielded a blood sugar 1 h latergreater than 130 mgdL and a subsequent 100 g carbo-hydrate load (3 h glucose tolerance test) resulted in ablood sugar greater than 95 (fasting) 180 155 and140 mgdL at 1 2 and 3 h respectively with at least two abnormal values out of four

In order to determine eligibility ( pre-pregnant BMIgt30) we calculated BMI (kgm2) based on pre-pregnancy medical records or an estimate of pre-pregnancy BMI was calculated from self-reported weight when pre-pregnant medical records were not availableParticipants visited the 1047297rst outpatient research unit located at University of Texas Health Science CenterSan Antonio (UTHSCSA) after an overnight fast (minimum 8 h) We completed anthropometric mea-

surements reviewed medical history and obtained a

2 BMJ Open Diabetes Research and Care 20142e000010 doi101136bmjdrc-2013-000010

Obesity studies




fasting blood sample After delivery we reviewed themedical records for each participant and recorded infor-mation on pregnancy complications medications birth weight and length

AnthropometricsIn order to calculate total weight gain during pregnancy

we subtracted pre-pregnancy weight from the motherrsquos weight at delivery Maternal weight and height were alsomeasured at 24ndash28 weeks of gestation and regional adi-posity was assessed by measurement of the tricep skin-fold and the arm circumference using the protocol fromthe National Health and Nutrition ExaminationSurvey40 The tricep skinfold was measured using aLange caliper and the mid-arm circumference using anon-stretchable tape measure All measurements weredone in triplicate by the same investigator

After birth the gestational age at delivery and weightlength and head circumference of the neonate were

recorded from the participant rsquo

s medical record andponderal index (PI) was calculated using the formulaPI=birth weighttimes100(crown-heel length)3

Maternal blood sampling A maternal venous fasting blood sample was obtainedand processed immediately for glucose A1C and lipidpanel by standard clinical assays Serum samples were ali-quoted and stored at minus80degC until batch analysisMaternal serum hormone and cytokine levels (insulinleptin total adiponectin IL-6 TNFα and IGF-I) weredetermined by ELISA according to manufacturersrsquoinstructions (RampD Systems) In a subset of serumsamples HMW adiponectin (ALPCO) and IGFBP-1(Diagnostic System Lab) were determined by ELISA

Statistical analysisStudent t test or a χ

2 test were used to evaluate differ-ences in continuous outcomes or categorical variablesbetween the two groups Pearson correlation coef 1047297cients

were used to determine the relationships between mater-nal metabolic parameters To understand the relation-ship between maternal metabolic factors body sizeparameters and insulin sensitivity we combined datafrom all participants and computed Pearson correlationcoef 1047297cients We examined the relationship between pre-pregnancy BMI of the mother and metabolic para-

meters similarly In order to identify clusters of corre-lated factors we computed the full correlation matrixbetween all key variables and this was permuted using hierarchical clustering with average linkage When mul-tiple factors were correlated with key outcomes weapplied linear regression to account for confounding effects Data are expressed as meanplusmnSEM A cut-off of plt005 was considered statistically signi1047297cant Statisticalanalysis was performed using the R V215 (Vienna Austria) statistical package

RESULTS

Table 1 summarizes the demographics of the two study groups at 24ndash28 weeks of gestation Obese participants without GDM were slightly younger (3 years) than theobese mothers with GDM However there was no rela-tionship between maternal age and any of the measuredmetabolic parameters There was also a difference in thegenders of the neonates with 32 of obese mothersdelivering female babies while 57 of GDM mothershad female babies We found no signi1047297cant differencesbetween the two groups for other demographic para-meters including Women Infants Child (WIC) bene1047297t recipients and years of education completed

Pre-pregnancy BMI gestational weight gain birth weight length and PI of the neonates did not differbetween the two groups Maternal BMI triceps skinfoldthickness and mid-arm circumference were similar inboth groups indicating similar levels of adiposity (table 2)

Fasting glucose and A1C in obese GDM mothers wassigni1047297cantly higher compared to obese women without diabetes (table 2) Maternal adipokines (leptin IL-6 or

Table 1 Demographics of the study participants

Variable Obese Obese with GDM p Value

N 42 30Maternal age (years) 281plusmn083 3087plusmn085 002

Pre-pregnancy BMI (kgm2) 3438plusmn058 3407plusmn082 076

Gestational age at study (weeks) 2654plusmn014 2655plusmn015 095

Gestational weight gain (lbs) 657plusmn108 944plusmn229 026

Parity ( primiparous) 14 10 086

Raceethnicity ( Hispanic) 90 93 1

Birth weight (g) 347716plusmn6573 352181plusmn8608 068

Birth length (cm) 5116plusmn031 5133plusmn033 07

Ponderal index (cm2) 259plusmn003 258plusmn005 086

Gender ( female) 32 58 007

WIC recipient () 79 93 017

Education ( HS or higher) 57 50 07

BMI body mass index GDM gestational diabetes mellitus HS high school WIC Women Infant Child


Obesity studies




TNFα see table 2) were not signi1047297cantly different in thetwo groups Insulin (+27 p=007) appeared to be elevated in obese women with GDM but these differences

did not reach statistical signi1047297

cance HOM A-IR scorescalculated according to Catalano and Kirwan41 were sig-ni1047297cantly higher in obese women recently diagnosed with GDM compared with obese women without GDM(1047297gure 1)

Obese pregnant women with GDM demonstrated asigni1047297cant dyslipidemia compared to obese mothers without diabetes As shown in 1047297gure 2 total triglyceridesand very-low-density lipoprotein cholesterol (VLDL-c) were elevated high-density lipoprotein cholesterol(HDL-c) was reduced whereas total cholesterol andLDL-c were not different in obese GDM mothers com-pared to mothers with obesity alone The obese GDM

mothers had markedly lower levels of total adiponectincompared to obese mothers without diabetes and thisdifference was predominantly due to a decrease inHMW adiponectin (1047297gure 3) Total IGF-I levels were not signi1047297cantly different in GDM obese women compared with obesity alone however IGFBP-1 was signi1047297cantly

lower in the GDM group (1047297gure 4) suggesting increasedIGF-I bioavailability

We found that HOMA-IR was negatively correlated to

maternal adiponectin (1047297

gure 5 A) positively correlatedto IGF-I (1047297gure 5B) and negatively correlated toIGFBP-1 (1047297gure 5C) at 24ndash28 weeks of gestation Weobserved the expected strong positive correlationsbetween BMI (as well as other maternal adiposity indica-tors) and fasting glucose insulin leptin and HOMA-IR (see online supplementary 1047297gure S1) Obesity in preg-nancy has been suggest ed to be accompanied by proin-1047298ammatory activation21 42 While we could not addressthis question directly because our study did not includelean mothers there was no correlation between any body size measurements and circulating IL-6 and TNFα(see online supplementary 1047297gure S1) Furthermore

there was no relationship between IL-6 and TNFα andany insulin sensitivity measurements fasting glucoseinsulin or HOMA-IR (see supplementary 1047297gure S1) Weapplied multiple linear regression to HOMA-IR to deter-mine the simultaneous effects of adiponectin (effect minus0158 plt005) plus IGF-I (effect 0015 plt0001) and

Figure 1 Homeostasis model assessment of insulin

resistance (HOMA-IR) scores in obese women and obese

women with gestational diabetes mellitus (GDM) at

approximately 26 weeks of gestation HOMA-IR scores were

significantly increased in GDM women compared with their

obese euglycemic counterparts Values are expressed as

mean+SEM n=42 obese n=30 obeseGDM plt005

Student t test

Figure 2 Obese gestational diabetes mellitus (GDM) women

demonstrate significant dyslipidemia at 26 weeks of gestation

compared to obese women without diabetes Women with

GDM had significantly higher triglycerides (TG)

very-low-density lipoprotein cholesterol (VLDL-c) and lower

high-density lipoprotein cholesterol (HDL-c) than non-diabetic

pregnant women Values are expressed as mean+SEM n=42

obese (open bar) n=29 obeseGDM (closed bars) plt005

analysis of variance

Table 2 Anthropomorphic measurements and biochemical analysis of plasma samples at 24ndash28 weeks of gestation


N 42 30

BMI (kgm2) 355plusmn054 3567plusmn085 087

Gestational age at study (week) 2654plusmn014 2655plusmn015 095

Triceps skinfold (mm) 369plusmn084 3663plusmn101 083

Mid-arm circumference (cm) 3572plusmn055 3589plusmn066 084

Fasting glucose (mgdL) 7931plusmn09 8993plusmn295 15e-03Fasting insulin (microIDmL) 1297plusmn094 1641plusmn183 01

A1C () 539plusmn004 559plusmn008 004

Leptin (ngmL) 5233plusmn368 4545plusmn342 018

TNFα (pgmL) 238plusmn035 169plusmn021 009

IL-6 (pgmL) 185plusmn028 147plusmn019 027

BMI body mass index GDM gestational diabetes mellitus IL interleukin TNF tumor necrosis factor


Obesity studies




we found that both parameters are independently asso-ciated with HOMA-IR

DISCUSSIONOur study evaluated pregnant women at the time inpregnancy when most women have an oral glucose toler-ance test for diagnosis of GDM 24ndash28 weeks Ourobjective was to study women in which body sizecharacteristics including weight height skinfold thick-ness and mid-arm circumference were similar so that GDM was the relevant difference between the groups

rather than degree of adiposity Maternal age was differ-ent between the two groups but this did not in1047298uencethe metabolic parameters measured and therefore donot account for the differences in adiponectin and tri-glycerides between the two groups Selecting obese women based on BMI proved to be a good method forobtaining two groups of equivalent body size The

anthropomorphic measures and the 1047297nding of no sig-ni1047297cant difference in leptin levels indicate that we weresuccessful in achieving our recruitment goalMetabolically obese women with recent diagnosis of GDM differed from those who were obese without dia-betes by having a greater degree of insulin resistance(higher fasting glucose A1C and HOMA-IR scores) sig-

ni1047297

cantly lower adiponectin and IGFBP-1 as well as a sig-ni1047297cant dyslipidemia with higher triglycerides VLDL-cand lower HDL-c

Owing to its insulin sensitizing action in peripheraltissues the reduction in circulating adiponectin withincreasing adiposity is considered to be an important component of the insulin resistance associated with weight gain43 Adiponectin levels in pregnancy havebeen reported to be increased not changed or reducedover the course of gestation17 26 A potential role for adi-ponectin as a factor in modulating insulin sensitivity inpregnancy has been previously addressed18 25 One study indicated that early (11ndash13 weeks) low adiponectin levels

may be predictive for later development of GDM44

Obese pregnant women have more pronounced insulinresistance and glucose int olerance than pregnant women with normal BMI11 however the underlying mechanisms remain elusive The role of adipose tissueand circulating adipokines in regulating maternalglucose homeostasis has been recently recognized as animportant component in the development of glucoseintolerance and insulin resistance Dyslipidemia and adi-pokine le vels associated with GDM have been previously reported45 but BMI and other body size parameters were not carefully controlled in many early studies

Therefore identifying a de1047297nitive role of adipokinessuch as adiponectin in the insulin resistance of obeseGDM mothers was dif 1047297cult in those studies We foundsigni1047297cantly lower circulating adiponectin levels in par-ticular the HMW form in those women recently diag-nosed with GDM compared with euglycemic obese women matched for body sizeadiposity This is consist-ent with the possibility that adiponectin is a major con-tributor to the loss of insulin sensitivity in obese mothers who develop GDM The nearly 50 reduction in totaladiponectin was for the most part due to reduction inHMW form of adiponectin however the underlying mechanism for reduced HMW adiponectin release fromadipocytes in some obese women but not others is cur-rently unclear Likewise it is unknown whether the dif-ferences in adiponectin preceded pregnancy ordeveloped during pregnancy These are clear considera-tions for further investigation

In addition to adiponectin our data suggest that IGF-Iand IGFBP-1 are determinants of maternal insulin sensi-tivity and altered IGF-I and IGFBP-1 levels may contrib-ute to the development of GDM IGF-I has beenpreviously implicated as an important factor for meta-bolic health in pregnancy Qui et al

36 found that freeIGF-I and IGFBP-1 measured at 13 weeks were inversely

correlated with GDM risk Likewise lower amniotic 1047298uid

Figure 3 Serum adiponectin is significantly lower in obese

gestational diabetes mellitus (GDM) women compared with

obese women at 26 weeks of gestation Total (n=42 obese

n=25 obeseGDM) and high-molecular-weight (HMW n=18

obese n=19 obeseGDM) adiponectin were significantly

decreased in obese GDM women compared with non-diabetic

obese women Open bars obese closed bars obeseGDM

Values are expressed as mean+SEM plt0005 Student

t test

Figure 4 Decreased insulin-like growth factor I binding

protein (IGFBP-1) in serum from obese women with

gestational diabetes mellitus (GDM) at 26 weeks of gestation

IGFBP-1 was significantly lower in obese GDM women (n=14

closed bars) compared to obese women without GDM (n=20

open bars) Total IGF-I serum levels were not different

between the two groups (n=42 obese n=26 obeseGDM)

Values are expressed as mean+SEM plt005 Student t test


Obesity studies




IGFBP-1 has been described in women prior to GDMdiagnosis46 Contrary to some studies we found no dif-ference in total IGF-I in obese w omen with GDM whencompared with obese women39 We did not measure

free IGF-I which we assume would have been signi1047297-cantly increased There was a highly signi1047297cant positivecorrelation between IGF-I and HOMA-IR when datafrom all participants were combined suggesting that IGF-I may be involved in regulating maternal insulin sen-sitivity in mid-pregnancy IGFBP-1 was signi1047297cantly reduced in the GDM group and was inversely related toHOMA-IR in all women studied Given the role of IGFBP-1 in regulating IGF-I bioavailability the reducedIGFBP-1 levels in women recently diagnosed with GDMmay be an important contributor to the development of insulin resistance in obese pregnancies through

increased IGF-I bioavailability Adipose tissue in1047298ammation associated with obesity

leads to the release of proin1047298ammatory cytokines to thecirculation and obese pregnant women have beenreported to have approximately a doubling of circulating proin1047298ammatory cytokine levels42 However a recent sys-tematic review concluded that the published studies todate do not support an increase in proin1047298ammatory cytokines in pregnancies complicated by GDM47 In thecurrent study we did not 1047297nd a difference in circulating IL-6 and TNFα between obese mothers with and without GDM Because no lean mothers were included in thisstudy we cannot clearly determine whether the cyto-kines of obese Hispanic mothers were elevated but GDM did not alter cytokine levels compared with obesity alone even though insulin resistance was increased Wefound no relationship between these proin1047298ammatory cytokines and insulin sensitivity (fasting glucose insulinor HOMA-IR) at 26 weeks of gestation This is contrary to previously published studies at term that indicate that cytokines are a major contributor to insulin resistanceTNFα has been linked to insulin resistance by serinephosphorylation of insulin receptor substrate 1 whichcauses a reduction in the responsiveness to insulin48

Maternal TNFα and IL-6 have also been strongly linked

to fetal size42

These discrepant 1047297ndings may re1047298ect

ethnic differences in the in1047298ammatory response toobesity andor pregnancy Nevertheless our data indi-cate that elevated circulating levels of proin1047298ammatory cytokines are unlikely to explain the high rate of GDM

in Hispanic womenThe strength of this study is the use of two groups of

women with similar degrees of adiposity allowing for dis-tinction of factors speci1047297cally associated with diabetesThe limitations of the study are the small sample sizeand lack of a lean control group The purpose of thisstudy was to de1047297ne metabolic parameters associated withmaternal obesity that would lead to GDM Metabolicchanges associated with maternal obesity compared withlean or normal BMI women have been previously described49 Therefore we focused on delineating factors in obese women with GDM compared with

BMI-matched mothers who remained euglycemicthroughout pregnancy

Obese women are more likely to develop GDM with asigni1047297cantly greater prevalence in Hispanic mothers9

Importantly the majority of obese pregnant women donot develop GDM and there is a clear lack of early diag-nostic tools to identify those obese women who willdevelop GDM prior to the occurrence of hyperglycemiaafter mid-gestation GDM is associated with increasedshort-term and long-term risks for the mother as well asher developing fetus therefore early detection could aidin reducing the negative outcomes associated with thiscondition Women who have been diagnosed with GDMhave a hig h probability to develop type 2 diabetes inlater life50 and the children of these pregnancies arealso at greater risk to de velop metabolic syndrome inthe 1047297rst 6ndash11 years of life51 GDM may be a window of opportunity to identify mothers and babies at risk andto intervene in pregnancy to improve the in utero envir-onment and contribute to reducing the negative out-comes Our study suggests that in a subset of women themetabolic response to pregnancy results in dyslipidemiareduced levels of HMW forms of adiponectin anddecreased IGFBP-1 leading to increased IGF-I bioavail-ability These factors likely contribute to the exacerba-

tion of insulin resistance leading to glucose intolerance

Figure 5 Homeostasis model assessment of insulin resistance (HOMA-IR) correlates strongly with serum adiponectin (ADPN)

insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGFBP-1) HOMA-IR values from obese and obesegestational

diabetes mellitus groups had (A) a significant inverse relationship between adiponectin (plt0001) (B) a strong positive

correlation with IGF-1 (plt00001) and (C) a significant inverse relationship between IGFBP-1 (plt0042) Pearson


Obesity studies




the hallmark of diabetes in pregnancy A commonmechanism linking low adiponectin and dyslipidemiamay be altered adipose tissue function and we speculatethat obese women who develop GDM in pregnancy havemore pronounced adipose tissue dysfunction than those who do not Two studies suggest that early pregnancy may provide a useful diagnostic window for women at

risk because adiponectin levels measured in early gesta-tion were signi1047297cantly lower in those women who w erelater diagnosed with GDM compared with controls23 52

However the substantial variability in maternal adipo-nectin levels in early pregnancy may limit the usefulnessof low adiponectin as a single predictive biomarker forlater GDM Adipose dysfunction in women who developGDM may precede pregnancy because pre-pregnancy adiponectin levels have also been reported to be lowerin women who were later diagnosed with GDM53

Obese pregnant women with recently diagnosed GDMhad a signi1047297cantly exacerbated metabolic pro1047297le low serum adiponectin and IGFBP-1 levels at 24ndash28 weeks of

gestation as compared to women with obesity aloneBecause low adiponectin is well established to causeinsulin resistance and decreased IGFBP-1 indicatesincreased IGF-I bioavailability we propose that thesechanges are mechanistically linked to the development of GDM in obese Hispanic women Several studies in non-pregnant individuals have demonstrated that adiponectinlevels can be improved by moderate exercise lowering caloric intake increasing ω-3 fatty acid intake andincreasing dietary 1047297ber54 This is consistent with the possi-bility that a modi1047297cation in 1047297ber and 1047297sh intake andmoderate exercise may improve outcomes in obese preg-

nant women with low adiponectin levels Improving adi-ponectin levels in obese mothers may contribute toimproved insulin sensitivity and perinatal outcomesFuture studies are needed to establish a causal link between adiponectin andor IGFBP-1 and insulin sensi-tivity in pregnancy and to develop effective interventions

Author affiliations1Department of Obstetrics and Gynecology Center for Pregnancy and

Newborn Research University of Texas Health Science Center at San Antonio

San Antonio Texas USA2Department of Biostatistics and Epidemiology University of Texas Health

Science Center at San Antonio San Antonio Texas USA3Department of Nutritional Sciences University of Cincinnati Academic Health

Center Cincinnati Ohio USA

Contributors VIR DAK and TLP were involved in conception and design of

the experiments carried out at University of Texas Health Science Center at

San Antonio (UTHSCSA) VIR EM CLM and TLP were involved in collection

analysis and interpretation of data JG was involved in statistical analysis VIR

and TLP were involved in drafting the article or revising it critically for

important intellectual content All authors approved the final version of the

manuscript

Funding This study was generously supported by the National Institutes of

Health National Heart Lung Blood Institute (1R21HL093532) the National

Center for Research Resources Clinical and Translational Science Award

(CTSA) grant to UTHSCSA (8UL1TR000149) and the Mike Hogg Fund

Competing interests None

Ethics approval This study was approved by the UTHSCSA institutional

review board (IRB)

Provenance and peer review Not commissioned externally peer reviewed

Data sharing statement No additional data are available

Open Access This is an Open Access article distributed in accordance with

the Creative Commons Attribution Non Commercial (CC BY-NC 30) license

which permits others to distribute remix adapt build upon this work non-

commercially and license their derivative works on different terms providedthe original work is properly cited and the use is non-commercial See http

creativecommonsorglicensesby-nc30

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trends in the distribution of body mass index among US adults1999ndash2010 JAMA 2012307491ndash7

2 Mission JF Marshall NE Caughey AB Obesity in pregnancy a bigproblem and getting bigger Obstet Gynecol Surv 201368389ndash99

3 Galliano D Bellver J Female obesity short- and long-termconsequences on the offspring Gynecol Endocrinol 201329626ndash31

4 Baci Y Ustuner I Keskin HL et al Effect of maternal obesity andweight gain on gestational diabetes mellitus Gynecol Endocrinol

201329133ndash

65 Black MH Sacks DA Xiang AH et al The relative contribution ofprepregnancy overweight and obesity gestational weight gain andIADPSG-defined gestational diabetes mellitus to fetal overgrowthDiabetes Care 20133656ndash62

6 Henriksen T The macrosomic fetus a challenge in currentobstetrics Acta Obstet Gynecol Scand 200887134ndash45

7 Marshall NE Spong CY Obesity pregnancy complications andbirth outcomes Semin Reprod Med 201230465ndash71

8 Yessoufou A Moutairou K Maternal diabetes in pregnancy earlyand long-term outcomes on the offspring and the concept oflsquometabolic memoryrsquo Exp Diabetes Res 20112011218598

9 Shah A Stotland NE Cheng YW et al The association betweenbody mass index and gestational diabetes mellitus varies by race ethnicity Am J Perinatol 201128515ndash20

10 Ogden CL Carroll MD Kit BK et al Prevalence of obesity andtrends in body mass index among US children and adolescents1999ndash2010 JAMA 2012307483ndash90

11 Catalano PM Obesity insulin resistance and pregnancy outcomeReproduction 2010140365ndash71

12 Retnakaran R Hanley AJ Raif N et al Adiponectin and beta celldysfunction in gestational diabetes pathophysiological implicationsDiabetologia 200548993ndash1001

13 Kinalski M Telejko B Kuzmicki M et al Tumor necrosis factor alphasystem and plasma adiponectin concentration in women withgestational diabetes Horm Metab Res 200537450ndash4

14 Altinova AE Toruner F Bozkurt N et al Circulating concentrationsof adiponectin and tumor necrosis factor-alpha in gestationaldiabetes Gynecol Endocrinol 200723161ndash5

15 Georgiou HM Lappas M Georgiou GM et al Screening for biomarkers predictive of gestational diabetes mellitus Acta Diabetol 200845157ndash65

16 Lain KY Daftary AR Ness RB et al First trimester adipocytokineconcentrations and risk of developing gestational diabetes later inpregnancy Clin Endocrinol (Oxf) 200869407ndash11

17 Mazaki-Tovi S Romero R Kusanovic JP et al Adiponectinmultimers in maternal plasma J Matern Fetal Neonatal Med 200821796ndash815

18 Mazaki-Tovi S Romero R Vaisbuch E et al Maternal serumadiponectin multimers in gestational diabetes J Perinat Med 200937637ndash50

19 Soheilykhah S Mohammadi M Mojibian M et al Maternal serumadiponectin concentration in gestational diabetes Gynecol Endocrinol 200925593ndash6

20 Thyfault JP Hedberg EM Anchan RM et al Gestational diabetes isassociated with depressed adiponectin levels J Soc Gynecol Investig 20051241ndash5

21 Lowe LP Metzger BE Lowe WL Jr et al Inflammatory mediatorsand glucose in pregnancy results from a subset of theHyperglycemia and Adverse Pregnancy Outcome (HAPO) StudyJ Clin Endocrinol Metab 2010955427ndash34

22 Vitoratos N Valsamakis G Mastorakos G et al Pre-and earlypost-partum adiponectin and interleukin-1beta levels in women with

and without gestational diabetes Hormones 20087230ndash6


Obesity studies




23 Ferreira AF Rezende JC Vaikousi E et al Maternal serum visfatinat 11ndash13 weeks of gestation in gestational diabetes mellitus Clin Chem 201157609ndash13

24 Lara-Castro C Fu Y Chung BH et al Adiponectin and themetabolic syndrome mechanisms mediating risk for metabolic andcardiovascular disease Curr Opin Lipidol 200718263ndash70

25 Retnakaran R Connelly PW Maguire G et al Decreasedhigh-molecular-weight adiponectin in gestational diabetesimplications for the pathophysiology of type 2 diabetes Diabet Med 200724245ndash52

26 Naruse K Noguchi T Sado T et al Chemokine and free fatty acidlevels in insulin-resistant state of successful pregnancy apreliminary observation Mediators Inflamm 20122012432575

27 Mazaki-Tovi S Romero R Vaisbuch E et al Maternal serumadiponectin multimers in patients with a small-for-gestational-agenewborn J Perinat Med 200937623ndash35

28 Fasshauer M Waldeyer T Seeger J et al Circulatinghigh-molecular-weight adiponectin is upregulated in preeclampsiaand is related to insulin sensitivity and renal function Eur J Endocrinol 2008158197ndash201

29 Inoue M Itabashi K Nakano Y et al High-molecular-weightadiponectin and leptin levels in cord blood are associated withanthropometric measurements at birth Horm Res 200870268ndash72

30 Basu S Laffineuse L Presley L et al In utero gender dimorphism ofadiponectin reflects insulin sensitivity and adiposity of the fetusObesity (Silver Spring) 2009171144ndash9

31 Ballesteros M Simon I Vendrell J et al Maternal and cord bloodadiponectin multimeric forms in gestational diabetes mellitus

a prospective analysis Diabetes Care 2011342418ndash2332 Ong GK Hamilton JK Sermer M et al Maternal serum adiponectin

and infant birthweight the role of adiponectin isoform distributionClin Endocrinol (Oxf) 200767108ndash14

33 McIntyre HD Zeck W Russell A Placental growth hormone fetalgrowth and the IGF axis in normal and diabetic pregnancy Curr Diabetes Rev 20095185ndash9

34 Matuszek B Lenart-Lipinska M Burska A et al Increased seruminsulin-like growth factor-1 levels in women with gestationaldiabetes Adv Med Sci 201156200ndash6

35 Luo ZC Nuyt AM Delvin E et al Maternal and fetal IGF-I and IGF-IIlevels fetal growth and gestational diabetes J Clin Endocrinol Metab 2012971720ndash8

36 Qiu C Vadachkoria S Meryman L et al Maternal plasmaconcentrations of IGF-1 IGFBP-1 and C-peptide in early pregnancyand subsequent risk of gestational diabetes mellitus Am J Obstet Gynecol 20051931691ndash7

37 Sakai K Iwashita M Takeda Y Profiles of insulin-like growth factor binding proteins and the protease activity in the maternal circulationand its local regulation between placenta and decidua Endocr J 199744409ndash17

38 El-Masry SA El-Ganzoury MM El-Farrash RA et al Size at birth andinsulin-like growth factor-I and its binding protein-1 among infants ofdiabetic mothers J Matern Fetal Neonatal Med 2013265ndash9

39 Olausson H Lof M Brismar K et al Maternal serum concentrationsof insulin-like growth factor (IGF)-I and IGF binding protein-1 beforeand during pregnancy in relation to maternal body weight andcomposition and infant birth weight Br J Nutr 2010104842ndash8

40 Committee on Nutritional Anthropometry Food and Nutrition BoardNational Research Council Recommendations concerning bodymeasurements for the characterization of nutritional status In BrozekJ ed Body Measurements Detroit Wayne University Press 1956

41 Catalano PM Kirwan JP Clinical utility and appraoches for estimating insulin sensitivity in pregnancy Semin Perinatol 200226181ndash89

42 Kirwan JP Hauguel-de Mouzon S Lepercq J et al TNF-alpha is apredictor of insulin resistance in human pregnancy Diabetes 2002512207ndash13

43 Kadowaki T Yamauchi T Kubota N et al Adiponectin andadiponectin receptors in insulin resistance diabetes and themetabolic syndrome J Clin Invest 20061161784ndash92

44 Nanda S Savvidou M Syngelaki A et al Prediction of gestationaldiabetes mellitus by maternal factors and biomarkers at 11 to 13weeks Prenat Diagn 201131135ndash41

45 Herrera E Ortega-Senovilla H Disturbances in lipid metabolism indiabetic pregnancymdashare these the cause of the problem Best Pract Res Clin Endocrinol Metab 201024515ndash25

46 Tisi DK Burns DH Luskey GW et al Fetal exposure to alteredamniotic fluid glucose insulin and insulin-like growth factor-bindingprotein 1 occurs before screening for gestational diabetes mellitusDiabetes Care 201134139ndash44

47 Gomes CP Torloni MR Gueuvoghlanian-Silva BY et al Cytokine

levels in gestational diabetes mellitus a systematic review of theliterature Am J Reprod Immunol 201369545ndash57

48 Capurso C Capurso A From excess adiposity to insulinresistance the role of free fatty acids Vascul Pharmacol 20125791ndash7

49 Jansson N Nilsfelt A Gellerstedt M et al Maternal hormoneslinking maternal body mass index and dietary intake to birth weightAm J Clin Nutr 2008871743ndash9

50 Retnakaran R Glucose tolerance status in pregnancy a window tothe future risk of diabetes and cardiovascular disease in youngwomen Curr Diabetes Rev 20095239ndash44

51 Boney CM Verma A Tucker R et al Metabolic syndrome inchildhood association with birth weight maternal obesity andgestational diabetes Pediatrics 2005115e290ndash6

52 Lacroix M Battista MC Doyon M et al Lower adiponectin levels atfirst trimester of pregnancy are associated with increased insulinresistance and higher risk of developing gestational diabetesmellitus Diabetes Care 2013361577ndash83

53 Hedderson MM Darbinian J Havel PJ et al Low prepregnancyadiponectin concentrations are associated with a marked increase inrisk for development of gestational diabetes mellitus Diabetes Care 2013363930ndash7

54 Silva FM de Almeida JC Feoli AM Effect of diet on adiponectinlevels in blood Nutr Rev 201169599ndash612


Obesity studies




of gestational diabetes in obese mothersAdiponectin and IGFBP-1 in the development

Gelfond Debra A Krummel and Theresa L PowellVanessa I Ramirez Evelyn Miller Christiane L Meireles Jonathan

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GDM has been reported to be 13 in obese Hispanic women compared with 7 for obese Caucasian women4 9 Therefore babies of Hispanic women are at particular risk of exposure to the adverse intrauterinemetabolic environment associated with maternal obesity and GDM which may predispose them for obesity anddiabetes This may contribute to the very high rate of

childhood and adolescent obesity (21 with BMI gt95thcentile) in Hispanic children and adolescents10

Insulin resistance has been identi1047297ed as a commonunderlying factor for poor pregnancy outcomes11 Theability to diagnose abnormal insulin resistance in preg-nancy is complicated by the natural decrease in insulinresponsiveness that occurs in all pregnant women Adiponectin has well-established insulin sensitizing prop-erties and circulating levels of adiponectin decrease withincreasing BMI contributing to insulin resistance inobese non-pregnant participants In pregnancy low maternal adiponectin levels have been reported in women diagnosed with GDM12ndash23 However maternal

BMI was not consistently accounted for in these reports Adiponectin is found in multimeric forms in the circu-

lation commonly known as high-molecular-weight (HMW) middle-molecular-weight and low-molecular- weight forms Most metabolic ef fects of adiponectin canbe attributed to HMW forms24 and the strongest pre-dictor of insulin sensitivity in non-pregnant individuals isthe HMW adiponectintotal adiponectin ratio In preg-nancy the relationship between HMW adiponectin andinsulin sensitivity appears to be similar with HMW adipo-nectin being positively correlated with insulin sensitivity and HM W forms reported to be reduced in GDM

mothers18 25

Naruse et al

26

observed a decline in HMW adiponectin as gestation progresses In contrastMazaki-Tovi et al

17 reported no change with gestation inany multimeric form Low maternal levels of HMW adi-ponectin have been reported in GDM pregnancies12ndash23

as well as in pregnancies complicated by small-for-gestational-age fetuses27 Mat ernal HMW adipo-nectin is increased in pre-eclampsia28 Interestingly cordserum HMW adiponectin levels are higher than inmaternal serum and are positi vely correlated to birth weight 29ndash31 in most but not all32 studies

Maternal circulating levels of insulin-like growth factorI (IGF-I) and its binding proteins (IGFBP) increase overgestation This is likely due to the effects of placentalgrowth hormone on hepatic IGF-I release33 MaternalIGF-I correlates positively with birth weight and placen-tal weight and maternal IGF-I is signi1047297cantly higher inGDM pregnancies compared with non-diabetic pregnan-cies3 4 3 5 Maternal IGF-I levels are positively correlated with pre-pregnancy BMI fasting insulin and the homeo-stasis model assessment of insulin resistance (HOMA-IR)in individuals with gestational diabetes but not incontrol pregnancies suggesting that elevated IGF-I may contribute to insulin resistance in women with GDM34

One study suggested that early preg nancy IGF-I plasma

levels may be predictive of GDM36 The predominant

IGFBP-isoform 3 is degraded in pregnancy resulting inincreased IGF-I availability37 This data suggests that IGFBP-1 plays an important role in modulating IGF-Ibioavailability during pregnancy IGFBP-1 is negatively correlated with birth size in normal and diabeticpregnancies38 39

Our study was designed to examine maternal meta-

bolic parameters (glucose and lipids) hormones(insulin IGF-I IGFBP-1) and adipokine levels (adipo-nectin leptin interleukin (IL)-6 and tumor necrosisfactor (TNF) α) in obese pregnant women This study was conducted at 24ndash28 weeks of gestation in predomin-antly Hispanic women with pre-pregnancy BMI gt30 withor without recent diagnosis of GDM We hypothesizedthat lower adiponectin in particular the HMW formand IGFBP-1 and higher IGF-I are associated with thediagnosis of GDM in pregnancies complicated by mater-nal obesity

METHODSStudy subjects All participants granted informed consent and approveduse of their protected health information Seventy-twopregnant women were included according to the inclu-sion criteria of high pre-pregnancy or early pregnancy (lt12 weeks) BMI (30ndash45) with singleton pregnanciesand between 18 and 40 years of age Participantsbetween 24 and 28 weeks of gestation were recruitedfrom the University Hospital System prenatal clinics inSouth Central Texas The exclusion criteria were concur-rent in1047298ammatory vascular or metabolic disease

current use of tobacco street drugs or medicationsknown to affect in1047298ammatory markers (including corti-costeroids) excessive weight gain or loss prior to preg-nancy (gt20 lbs) including bariatric surgery in the past year plans to leave the area and inability to travel tostudy visit Of the 72 women 30 were diagnosed withGDM at or within 2 weeks of enrollment GDM is carbo-hydrate intolerance of varying degrees of severity withonset or 1047297rst recognition during pregnancy Diagnosis was con1047297rmed when a 50 g carbohydrate load (1 hglucose challenge test) yielded a blood sugar 1 h latergreater than 130 mgdL and a subsequent 100 g carbo-hydrate load (3 h glucose tolerance test) resulted in ablood sugar greater than 95 (fasting) 180 155 and140 mgdL at 1 2 and 3 h respectively with at least two abnormal values out of four

In order to determine eligibility ( pre-pregnant BMIgt30) we calculated BMI (kgm2) based on pre-pregnancy medical records or an estimate of pre-pregnancy BMI was calculated from self-reported weight when pre-pregnant medical records were not availableParticipants visited the 1047297rst outpatient research unit located at University of Texas Health Science CenterSan Antonio (UTHSCSA) after an overnight fast (minimum 8 h) We completed anthropometric mea-

surements reviewed medical history and obtained a


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BMJ, Adiponektin Pd GDM

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