cortisol is negatively associated with insulin sensitivity ... · cortisol is negatively associated...

J. Clin. Endocrinol. Metab. 2010 95:4729-4735 originally published online Jul 21, 2010; , doi: 10.1210/jc.2010-0322

Christianne J. Lane, Marc J. Weigensberg and Michael I. Goran Tanja C. Adam, Rebecca E. Hasson, Emily E. Ventura, Claudia Toledo-Corral, Kim-Ann Le, Swapna Mahurkar,

Youth

Cortisol Is Negatively Associated with Insulin Sensitivity in Overweight Latino

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Cortisol Is Negatively Associated with InsulinSensitivity in Overweight Latino Youth

Tanja C. Adam, Rebecca E. Hasson, Emily E. Ventura, Claudia Toledo-Corral,Kim-Ann Le, Swapna Mahurkar, Christianne J. Lane, Marc J. Weigensberg,and Michael I. Goran

University of Southern California, Department of Preventive Medicine, Childhood Obesity ResearchCenter, Los Angeles, California 90033

Context and Objective: The purpose of the present study was to investigate the cross-sectional andlongitudinal associations of serum morning cortisol and aspects of insulin action in Latino childrenand adolescents (8–13 yr) at risk for type 2 diabetes.

Design and Participants: The present study includes a cross-sectional analysis in 211 participantsand a longitudinal analysis in a subset of 143 participants.

Results: At baseline, cortisol was negatively associated with fasting glucose (r � 0.23; P � 0.01),�-cell function (disposition index, r � �0.24; P � 0.05), and acute insulin response to glucose (r �

�0.27; P � 0.05). Baseline cortisol was also significantly related to the change in insulin sensitivityover 1 yr (r � �0.23; P � 0.05). These results did not differ by Tanner stage or sex.

Conclusions: Cortisol contributes to the reduction in insulin sensitivity at an early age in Latinochildren and adolescents. Specifically, cortisol is negatively associated with potential compensatorymechanisms for insulin resistance, such as increased �-cell function and increased insulin release toa glucose challenge, by exacerbating the progression toward insulin resistance in this population.The results underline the relevance of glucocorticoid reduction for the prevention of metabolicdisease in Latino children and adolescents. (J Clin Endocrinol Metab 95: 4729–4735, 2010)

Type 2 diabetes has emerged as a significant health issuein American youth, particularly among Latinos, with

an estimated lifetime risk of approximately 50% (1). Theethnic disparity of diabetes risk has not been fully exam-ined but likely includes a combination of insulin resistanceand the inability of pancreatic �-cells to compensatethrough increased insulin secretion (2). Compensatorymechanisms to insulin resistance in children and early ad-olescence appear to be ethnic specific, and previous re-search from our laboratory has reported increased insulinrelease in response to an insulin-modified iv glucose chal-lenge as a compensatory mechanism for insulin resistancein Latinos (3). Although this mechanism may be able tomaintain the already low levels of insulin sensitivity (SI) inLatino youth in the short term, it may eventually lead to

failure of the �-cell and the progression toward type 2diabetes (3).

In addition to nutrition and physical activity, researchhas started to include the role of the social environment,particularly psychosocial stress on adiposity and insulinresistance (4). The physiological stress response leads tothe release of cortisol, a glucocorticoid, from the adrenalglands. Designed to increase energy availability in theshort term, cortisol acutely impairs insulin secretion andincreases hepatic glucose output. An environment of pro-longed glucocorticoid exposure, i.e. chronic stress, exertsdiabetogenic effects by interfering with insulin action onseveral different levels (5–7), including a direct inhibitionof insulin secretion from pancreatic �-cells (8), impairedinsulin-mediated glucose uptake (9), and disruption of the

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2010 by The Endocrine Societydoi: 10.1210/jc.2010-0322 Received February 17, 2010. Accepted June 10, 2010.First Published Online July 21, 2010

Abbreviations: AIR, Acute insulin release; AUC, area under the curve; BMI, body mass index;CV, coefficient of variation; DI, disposition index; FSIVGTT, frequently sampled iv glucosetolerance test; HPA, hypothalamus-pituitary-adrenal; IGFBP, IGF binding protein; IVGTT, ivglucose tolerance test; OGTT, oral glucose tolerance test; SI, insulin sensitivity.

O R I G I N A L A R T I C L E

E n d o c r i n e R e s e a r c h

J Clin Endocrinol Metab, October 2010, 95(10):4729–4735 jcem.endojournals.org 4729

insulin signaling cascade in skeletal muscle (10). Healthyadults appear able to compensate for glucocorticoid-in-duced insulin resistance with increased �-cell function orincreased insulin release (11–13). This is evident even un-der rather chronic circumstances. In less insulin sensitiveor obese individuals, however, those compensatory mech-anisms fail to counteract glucocorticoid-induced insulinresistance, resulting in hyperglycemia (12, 13).

Although research has demonstrated the negative as-sociation between cortisol and SI in adults (14, 15), verylittle research has addressed the question of whether cor-tisol interferes with SI and potential compensatory mech-anisms for insulin resistance in children and adolescents.To assess the effects of cortisol on SI in ethnic minoritiesis of particular interest, because they are exposed togreater chronic stress and life events (16). The hypercor-tisolism associated with chronic stress exposure may fur-ther compromise the already lower SI and exacerbate theprogression to insulin resistance and type 2 diabetes in thispopulation. In support of that idea, previous work fromour laboratory has shown an association between highermorning cortisol and the metabolic syndrome in Latinoyouth (17). Hence, the purpose of the present paper was toinvestigate the relationship of cortisol with SI, �-cell func-tion [disposition index (DI)], and acute insulin release(AIR), as well as their changes over a 1-yr period in asample of Latino youth at risk for type 2 diabetes. Wehypothesized that cortisol is negatively associated withthose variables as well as the change in insulin parametersover a 1-yr period. The results of the present paper willprovide additional insight regarding the relevance of stressreduction as a component of preventive measures againstobesity and type 2 diabetes in minority youth.

Patients and Methods

ParticipantsThe current analysis includes data from the first two annual

visits of 211 participants (119 boys and 92 girls) of the longitu-dinal, observational SOLAR study (Study of Latino Adolescentsat Risk of Diabetes) conducted at the University of SouthernCalifornia (18). Inclusion criteria for participants were Latinoethnicity, a family history of type 2 diabetes, and a body massindex (BMI) at or above the 85th percentile for age and gender.BMI and BMI percentiles for age and gender were based onestablished Centers for Disease Control and Prevention norma-tive curves (19).

Participants were between 8 and 13 yr old at study entry.Exclusionary criteria included major illness and medications ora condition known to affect body composition or SI. The studywas approved by the Institutional Review Board of the Univer-sity of Southern California, and informed consent as well as childassent was obtained before testing from parents and children,respectively. After consenting, children completed an oral glu-cose tolerance test (OGTT) (outpatient visit) to further deter-

mine eligibility for the study by excluding the presence of type 2diabetes. Eligible participants completed an annual frequentlysampled iv glucose tolerance test (FSIVGTT) (inpatient visit)establishing SI, �-cell function (DI), and AIR to a glucose chal-lenge. A detailed description of both procedures are describedbelow.

Oral glucose tolerance testThe annual OGTT was performed after an overnight fast in

the General Clinical Research Center of the University of South-ern California. After arrival at approximately 0800 h, a thor-ough medical history and physical exam were performed andTanner stage was determined (20) by a licensed pediatric health-care provider. Height was measured to the nearest 0.1 cm by awall-mounted stadiometer, and weight was recorded to the near-est 0.1 kg by a balance-beam medical scale. Oral glucose toler-ance was determined with two blood samples taken before (�5min) as well as 2 h (120 min) after ingestion of 1.75 g oral glucosesolution/kg body weight (up to a maximum of 75 g). Blood sam-ples were analyzed for glucose and insulin concentrations. Im-paired glucose tolerance was determined according to guidelinesof the American Diabetes Association (21).

Intravenous glucose tolerance testOne to 2 wk after the OGTT, eligible participants were read-

mitted to the General Clinical Research Center in the afternoon.Total fat mass and total lean tissue mass was determined by whole-body dual-energy x-ray absorptiometry (QDR 4500W; Hologic,Bedford, MA) by a small group of trained research techniciansblinded to patients treatment.

Waist circumference was measured to determine central ad-iposity, and waist-to-hip ratio was calculated. After body com-position measurements were completed, participants wereserved dinner. After a 12-h fasting period, the FSIVGTT startedat 0630 h the following morning. Intravenous catheters wereplaced in an anticubital vein of both arms. Two fasting bloodsamples (�15 and �5 min) were followed by a 0.3 g/kg bodyweight iv glucose administration at time point 0. Blood sampleswere taken at 2, 4, 8, and 19 min. At 20 min, iv insulin (0.02 U/kgbody weight Humulin R; Eli Lilly, Indianapolis, IN) was admin-istered. The remaining blood samples were taken at 22, 30, 40,50, 70, 100, and 180 min. SI, AIR to a glucose challenge, andDI as an indicator for �-cell function was calculated withMINMOD Millenium 2003 (22).

The yr 1 fasting blood draw (�15 min) from the iv glucosetolerance test (IVGTT) also included aliquots for serum cortisol,lipids, IGF-I, IGF binding protein 1 (IGFBP-1), and IGF bindingprotein 3 (IGFBP-3).

AssaysGlucose samples from the OGTT were analyzed by the in

vitro hexokinase method (Dade Behring, Deerfield, IL). Bloodsamples from the FSIVGTT were centrifuged for 10 min at 2500rpm, and plasma aliquots were frozen at �80 C until additionalanalysis. Insulin concentrations were measured with a humaninsulin ELISA (Linco, St. Charles, MO) [intraassay coefficient ofvariation (CV), 4.7–7%; interassay CV, 9.1–1%]. Glucose con-centrations were measured with the glucose oxidase technique(Yellow Springs Instrument analyzer; YIS Inc., Yellow Springs,OH). Morning serum cortisol concentrations were measuredwith RIA (Siemens, Deerfield, IL) (intraassay CV, 4.69%; inter-

4730 Adam et al. Cortisol and Insulin Sensitivity J Clin Endocrinol Metab, October 2010, 95(10):4729–4735

assay CV, 6.28% with minimal detection limit of 0.47 �g/dl).Fasting lipids were measured with Vitros Chemistry DT slides(Johnson & Johnson Clinical Diagnostics, Rochester, NY). IGF-I,IGFBP-1, and IGFBP-3 concentrations were determined usingtwo site coated tube immunoradiometric assay kits (ActiveDiagnostic System Laboratories, Webster, TX). Samples wereassayed in duplicate for IGF-I (intraassay CV, 8.2%; interas-say CV, 11.3%), IGFBP-1 (intraassay CV, 6.8%; interassayCV, 11.4%), and IGFBP-3 (intraassay CV, 7.0%; interassayCV, 3.6%).

StatisticsThe total sample size of 211 participants was used for de-

scriptive analysis. Mean differences by Tanner stage were as-sessed with �2 analysis. Differences by sex were determined withANOVA. Effects of sex and Tanner stage on the relationship ofcortisol and changes in SI were assessed with analysis of covari-ance, covarying for fat mass and fat-free mass. AIR was logtransformed to achieve normality before analysis. Zero-ordercorrelations were used to assess the relationship of cortisol withanthropometric measures, parameters of the OGTT [area underthe curve (AUC), impaired fasting glucose, and impaired glucosetolerance], and IVGTT (SI, AIR, DI, and fasted insulin and glu-cose concentrations).

Change scores in parameters of the OGTT and FSIVGTTwere calculated by subtracting yr 1 values from yr 2 values. Atotal of 143 participants (78 boys and 65 girls) had complete datafrom yr 1 and yr 2 and therefore were available for analyses,including change scores.

Zero-order correlations were then used to examine the rela-tionship of yr 1 cortisol with the change in OGTT and IVGTTparameters from yr 1 to yr 2. All correlations and cross-sectionaland change scores were then reexamined with adjusted partial

correlations. Correlations were adjusted for age, sex, total fatmass, and total lean mass. Because of the considerable dropoutbetween yr 1 and yr 2, analyses including change variables wereperformed, including all participants from yr 1 and yr 2, as wellas with participants who had complete data for both years only.

The correlations of cortisol and change scores were addition-ally adjusted for baseline values. Data were analyzed using SPSSfor Windows version 16.0 (SPSS Inc., Chicago, IL). Data in Table1 are presented as means � SDs. A P value of 0.05 was a prioriassigned significance.

Results

The 211 participants included 119 male and 92 femaleparticipants. Table 1 displays subject participant charac-teristics separate for gender stratified by sex in yr 1 and yr2 as well as the change between the two assessments. �2

tests showed that neither cortisol, SI, DI, log AIR, nor thechange from yr 1 to yr 2 were different for Tanner stages,and therefore results are reported for all Tanner stagescombined. Sex differences were observed for fasting insu-lin in yr 1 but not in yr 2 with females having higher fastinginsulin compared with males in yr 1. Fasting insulin con-centrations increased for both sexes between the two as-sessments but the increase was not different. DI was higherin males compared with females in both years. However,the change between the 2 yr was not different by sex.

Changes between yr 1 and yr 2 were different by sex forheight, weight, percentage fat mass, and total lean mass.

TABLE 1. Subject characteristics at baseline yr 1 and yr 2 (data presented as means � SD)

Boys Girls

Year 1(n � 119)

Year 2(n � 78) Change

Year 1(n � 92)

Year 2(n � 65) Change

Tanner stage (1/2/3/4/5) 85/62/18/30/17 27/26/9/10/6 33/42/15/32/23 6/15/6/21/17Age (yr) 11.1 � 1 12.1 � 1 1.0 10.8 � 1 11.8 � 1 1.0Height (cm) 149 � 11.4 156 � 11.3a 6.6 � 2.1 147.7 � 11.9 152.9 � 10.3a 5.0 � 2.7c

Weight (kg) 63.2 � 19.1 72.6 � 20.4a 9.7 � 4.9 62.9 � 20.7 70.6 � 20.9a 7.6 � 4.2c

BMI (kg/m2) 27.6 � 5 29.3 � 5a 3.1 � 10.1 28.0 � 5.5 29.6 � 5.7a 5.6 � 21.2Total fat mass (kg) 23.35 � 9.7 25.7 � 9.4a 2.5 � 2.8 25.0 � 10.6 28.1 � 11.1a 3.1 � 3.0Fat mass (%) 37.5 � 7 36.0 � 6.6 �0.91 � 2.8 39.8 � 5.4 39.5 � 5.1 0.32 � 2.3c

Total lean mass (kg) 36.9 � 9.5 43.0 � 11.2a 6.26 � 3.1 35.7 � 10.3 39.8 � 10.2a 4.0 � 2.3c

Cortisol (�g/dl) 9.3 � 3.2 9.7 � 3.1 0.38 � 3.9 9.2 � 3.2 9.6 � 3.3 0.44 � 3.4IGF-I 432.7 � 263 590.1 � 285 159 � 198a 533.6 � 269 661 � 256 82.3 � 199IGFBP-1 18 � 15.2 11.3 � 11 �6.7 � 8.4 14.8 � 15.8 8.9 � 10.6 �4.6 � 6.3IGFBP-3 3871 � 745 4509 � 801 622 � 715 4123 � 848 4659 � 716 509 � 605Fasting insulin (�U/ml) 17.2 � 8.7b 23.7 � 12.9a 6.7 � 11.2 21.3 � 13.1 27.3 � 17.2a 5.8 � 9.4Fasting glucose (mg/dl) 93.2 � 5.9 93.8 � 5.5 0.27 � 6.4 92.4 � 5.8 92.1 � 6.0 1.7 � 6.3Insulin AUC (�U/ml) 261.2 � 138.7b 300.9 � 191.2a,b 50.0 � 154 361.6 � 246 371.7 � 247 11.3 � 216Glucose AUC (mg/dl) 260.3 � 29.4 257.9 � 27.9 �2.8 � 26 267.5 � 32 264.4 � 37.2 �2.2 � 33.1SI �(�10�4/min�1)/

(�U/ml)�2.3 � 1.6 1.8 � 1.2a �0.48 � 0.96 2.1 � 1.4 1.6 � 1.0a �0.47 � 0.81

DI (�10�4/min�1) 2795 � 1235b 2688 � 1215b �49.0 � 1010 2231 � 980 2023 � 994a �226 � 864AIR (�U/ml) 1663 � 1233 1935 � 1293a 281 � 840 1604 � 1213 1681 � 1236 72.4 � 763a Difference between yr 1 and yr 2 for boys or girls significant at P � 0.05.b Difference between gender in the same year significant at P � 0.05.c Change scores are significantly different for gender at P � 0.05.


None of the changes in insulin-related parameters wasdifferent by sex. Therefore, additional analysis was con-ducted for the whole group with sex as a covariate. Neithercortisol at yr 1 and yr 2 nor the change in cortisol wasdifferent by sex. Status of menarche had no effect on base-line SI, cortisol, or change in SI in females.

Cross-sectional analysis of baseline dataFrom the OGTT, cortisol was negatively associated

with the 2-h AUC for glucose (r � 0.15; P � 0.05) but notwith the 2-h insulin AUC. Cortisol was significantly higherin those participants with impaired fasting glucose com-pared with normal fasting glucose (10.9 � 3.1 vs. 9.1 �3.1 �g/dl, respectively; P � 0.05; n � 26 vs. n � 185,respectively) and in those with impaired glucose tolerance(10.4 � 3.7 vs. 9.0 � 2.9 �g/dl, respectively, P � 0.01; n �53 vs. n � 158, respectively).

During the IVGTT, cortisol concentrations were asso-ciated with fasting glucose concentrations (r � 0.23;P � 0.01) but were not associated with fasting insulinconcentrations, lipid concentrations, or SI. Cortisol wasnegatively associated with DI (r � �0.24; P � 0.05) (Fig.1)and log AIR (r � �0.27; P � 0.05) (Fig. 1B) in yr 1. Ananalysis of covariance showed no main effect of sex orTanner stage for these associations.

Longitudinal analysisChange scores for OGTT parameters were not different

by sex or Tanner stage. Insulin AUC significantly increased

from yr 1 to yr 2 in males but not in females. Glucose AUCdid not change from yr 1 to yr 2. Cortisol was not related tothe change in insulin AUC.

Change scores for IVGTT parameters were not differ-ent by sex or by Tanner stage. Although fasting glucose didnot increase significantly from yr 1 to yr 2, fasting insulinconcentrations did increase significantly from yr 1 to yr 2.Cortisol, however, was not associated with the change infasting insulin. SI decreased significantly from yr 1 to yr 2for both sexes individually and for the whole group (2.2 �1.4 compared with 1.7 � 1.1; respectively; P � 0.01). AIRincreased significantly from yr 1 to yr 2 (1640 � 1262compared with 1817 � 1277, respectively; P � 0.05) formales only. DI significantly decreased between the twoannual assessments for females only. However, althoughthe change in DI between the two assessments was notdifferent by sex, DI was significantly higher in sex in yr 1and yr 2.

Baseline cortisol concentrations were negatively asso-ciated with change in SI from yr 1 to yr 2 (r � �0.23; P �0.05) (Fig. 2). No relationship was observed between cor-tisol and the change in log AIR and DI. IGFs were notdifferent for Tanner stage at baseline. Female participantshad significantly higher concentrations of IGF-I andIGFBP-3 compared with male participants (432.1 � 263vs. 534.1 � 270, P � 0.01 and 3871 � 745 vs. 4120 � 852,P � 0.05, respectively).

In adjusted correlations, cortisol was negatively asso-ciated with IGF-I (r � �0.15; P � 0.05) and IGFBP-3 (r �0.18; P � 0.05) and positively with IGFBP-1 (r � �0.18;P � 0.05).

Zero-order and partial correlation coefficients for corti-sol, the dependent variables from OGTT and FSIVGTT, aswell as changes in the variables from yr 1 to yr 2 are sum-marizedinTable2.Analysesonly includingparticipantswithcomplete data from both years (n � 143) were comparedwith analyses including all participants from yr 1 (n � 211).Results for both groups were the same. Most relevant, cor-tisol was still significantly associated with the decline in SI

FIG. 2. Zero-order correlation of cortisol with change scores of SI (�SI)(r � �0.23; P � 0.01).

FIG. 1. A, B, Zero-order correlation of cortisol with DI (A) (r � �0.13;P � 0.05) and AIR (B) (r � �0.16; P � 0.05).


from yr 1 to yr 2, considering participants with measure-ments from both years only (r � �0.18; P � 0.05).

Discussion

The present paper demonstrates that serum cortisol is as-sociated with increased fasting glucose concentrations anddecreased AIR and �-cell function in overweight Latinoyouth. Moreover, we found that higher baseline cortisolwas related to a greater decrease in SI over a 1-yr follow-upperiod. Although it has been demonstrated that cortisolaffects SI in adults (7, 23), the current study shows thatcortisol may interfere with SI during adolescence as well.

The relationship between SI and insulin secretion hasbeen described as hyperbolic (22, 24). This means thatindividuals with lower SI compensate with higher insulinsecretion to maintain normal glucose tolerance (13, 24).Indeed, our laboratory has shown both increased AIR andDI as potential compensatory mechanisms for decreasedSI in minority youths (3).

The current study suggests that cortisol may be asso-ciated with the decrease in SI in children and adolescentsthrough decreasing �-cell function and the acute insulinresponse to a glucose stimulus, thus affecting the compen-satory route for insulin resistance described above. Thisfinding is further supported by results from research in

adult individuals, showing a lack of adaption of islet func-tion in response to a glucocorticoid-induced reduction inSI, specifically in individuals with low inherent SI, com-parable with the Latino youths in our study (13). Bothdecreased AIR and decreased function of the � cell maythen contribute to the decrease in SI in our study popula-tion, as evidenced in the negative association of cortisoland the change in SI after 1 yr. The present study is, to thebest of our knowledge, the first report linking relative hy-percortisolemia with indices of SI and a longitudinalchange in SI in Latino youth.

Epidemiological and clinical studies in adults haveshown that obesity, especially visceral obesity, and relatedmetabolic comorbidities are associated with stress-relatedconditions (25–27). Our laboratory has found a signifi-cant relationship between the number of features of themetabolic syndrome and cortisol concentrations in Latinoyouth (17), suggesting that obesity and the related meta-bolic disturbances such as insulin resistance may in partresult from a maladaptive physiological reaction to envi-ronmental stress factors in susceptible individuals (28). De-spite the fact that differences in exposure to stress defined byethnicity and socioeconomic status are systematically under-estimated (16), very little research has addressed differencesin the physiological stress reaction and their consequencesfor health in ethnic minorities.

Research in non-Latino white adults has linked obesityand insulin resistance with increased morning cortisolconcentrations (29), whereas studies performed in Latinoand African-American youth have shown lower morningcortisol and a flatter diurnal cortisol slope compared withtheir non-Latino white counterparts (4). Because of theone-time sampling of cortisol in the present study, we can-not draw conclusions regarding the overall stress levels inLatino children. It is possible that a maladaptive hypo-thalamus-pituitary-adrenal (HPA) axis physiology in cor-tisol slopes across the day may have not been observed inthe present study as a result of one-time sampling in themorning. There is no uniformly accepted way of expressingHPAaxisactivity, andeachwayhas inherent limitations.Wepreviously found that, in obese Latino adolescents aged14–17 yr, serum cortisol correlates with salivary cortisolawakening response (r � 0.42; P � 0.05) (Weigensberg M.J., E. Bomberg, C. J. Lane, S. Nguyen-Rodriguez, M. I.Goran, Z. Shoar, T. Wright, T. C. Adam, D. Spruijt-Metz,unpublished data), a frequently used measure of HPA activ-ity in the psychoneuroendocrinology literature (for over-view, see 30). Findings in the literature suggest that even asingle morning measurement of serum cortisol, althoughimperfect, reflects overall HPA activity (31) and justify ourconclusions of this relationship, albeit with the stated lim-itations of a single cortisol measure.

TABLE 2. Zero order and partial correlations forcortisol, anthropometric, and metabolic parameters

Cortisol(zero order)

Cortisol(partial)

BaselineDiastolic blood pressure 0.19 0.24Systolic blood pressure 0.19 0.35*Weight (kg) �0.12 0.08BMI (kg/m2) �0.10 0.06Total fat mass (kg) �0.12 0.0Total lean mass (kg) �0.11 �0.08Waist circumference �0.11 �0.03Hip circumference �0.09 0.01Fasting insulin (�U/ml) �0.03 �0.05Fasting glucose (mg/dl) 0.23* 0.25*IGF-I (ng/ml) �0.19* �0.15*IGFBP-1 (ng/ml) 0.15* 0.18*IGFBP-3 (ng/ml) �0.18* �0.18*SI �(�10�4/min�1)/(�U/ml)� 0.10 0.03DI (�10�4/min�1) �0.13* �0.21*Log AIR (�U/ml) �0.16* �0.13*

Change (� yr 1–yr 2)�SI �(�10�4/min�1)/(�U/ml)� �0.23** �0.17*�DI (�10�4/min�1) 0.08 0.06�AIR (�U/ml) 0.13 0.12

Shown are zero-order and partial correlations for cortisol. Partialcorrelations were adjusted for age, gender, Tanner stage, fat mass,and fat-free mass. Correlations with change variables (�) wereadditionally adjusted for baseline values. *, P � 0.05; **, P � 0.01.


Because cortisol has been generally associated with vis-ceral fat accumulation (17, 32), it is of interest that we didnot find a relationship between cortisol and indices ofvisceral fat accumulation in our group of participants.This might be attributable to the age group or to the ho-mogeneity of the group in terms of ethnicity and bodyweight. Visceral fat accumulation may be a consequenceof prolonged glucocorticoid exposure, and the relation-ship may be present in somewhat older adolescents (33).Cortisol was negatively associated with IGF-I in thepresent study. IGF-I is an insulin sensitizer and has suc-cessfully been used as a surrogate to estimate GH secretion(26) based on the negative feedback relationship betweenthe two. Epidemiological studies have shown that peoplewith low IGF concentrations have a 2-fold increased riskof developing glucose intolerance or type 2 diabetes (34).Considering the physiological changes in the GH/IGF-Iaxis during puberty, the lack of difference in IGF-I be-tween Tanner stages indicates a derangement of the GH/IGF-I axis in obesity. Our result is supportive of literaturereporting an inhibitory effect of obesity on GH secretion,including peripheral factors such as IGF-I (35). IGF-I ismainly derived from the liver, which also is the sole site ofsplanchnic cortisol production, a fact that suggests a closeinteraction between cortisol and IGF-I. Although IGF hasgained clinical significance predominantly as a mechanismlinking obesity to cancer (36), in the present paper it is ofparticular interest because of its representation of GH con-centrations. GH is greatly reduced in obesity and is par-ticularly associated with visceral fat accumulation (32).The present paper would support work suggesting thatlow GH and high cortisol act in concert to reduce insulinresistance in adolescents (33).

Because of the correlational nature of the present study,we also cannot draw conclusions regarding the directionof the relationship between cortisol and our insulin pa-rameters. However, we do have evidence that chronicstress and the related altered HPA activity are associatedwith features of the metabolic syndrome in adolescents(37). Elegant animal models have shown a direct inhibi-tory effect of glucocorticoids on insulin release (38). Acausative effect of cortisol on several parameters relevantto SI is also substantiated by research investigating indi-viduals with primary pathological hypercortisolism, e.g.Cushing’s disease (39).

In conclusion, the present study suggests that cross-sectionally, cortisol may affect SI through increased glu-cose concentrations, decreased �-cell function, decreasedAIR, and IGF-I at an early age, contributing to a long-termdecrease in SI. These results reinforce the fact that cortisolmay play a permissive role for health disparities in meta-bolic diseases in ethnic minorities. Additional research is

necessary to examine possible ethnic-specific stress expo-sure and more specifically the acute HPA responses tostress in African-American and Latino youth. Results fromthe present study underline the importance of preventionof chronic glucocorticoid exposure in minority childrenand adolescents as an additional preventive measure formetabolic disease.

Acknowledgments

Address all correspondence and requests for reprints to: MichaelI. Goran, University of Southern California, Department of Pre-ventive Medicine, 2250 Alcazar Street, Clinical Sciences Center,Los Angeles, California 90033. E-mail: [email protected].

ThisworkwassupportedbyNational InstitutesofHealth(NIH)Grant R01-DK-59211, the General Research Center, NationalCenter for Research Resources/NIH Grant M01 RR 00043, and a2009–2011 Fellowship in Health Disparities award from Pfizer’sMedical and Academic Partnership program.

Disclosure Summary: The authors have nothing to disclose.

References

1. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, WilliamsonDF 2003 Lifetime risk for diabetes mellitus in the United States.JAMA 290:1884–1890

2. Goran MI, Lane C, Toledo-Corral C, Weigensberg MJ 2008 Per-sistence of pre-diabetes in overweight and obese Hispanic children:association with progressive insulin resistance, poor �-cell functionand increasing visceral fat. Diabetes 57:3007–3012

3. Goran MI, Bergman RN, Cruz ML, Watanabe R 2002 Insulin re-sistance and associated compensatory responses in African-Ameri-can and Hispanic children. Diabetes Care 25:2184–2190

4. DeSantis AS, Adam EK, Doane LD, Mineka S, Zinbarg RE, CraskeMG 2007 Racial/ethnic differences in cortisol diurnal rhythms in acommunity sample of adolescents. J Adolesc Health 41:3–13

5. Adam TC, Epel ES 2007 Stress, eating and the reward system.Physiol Behav 91:449–458

6. Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES,Scribner KA, Smith M 1993 Feast and famine: critical role of glu-cocorticoids with insulin in daily energy flow. Front Neuroendocri-nol 14:303–347

7. Rosmond R 2003 Stress induced disturbances of the HPA axis: apathway to Type 2 diabetes? Med Sci Monit 9:RA35–RA39

8. Lambillotte C, Gilon P, Henquin JC 1997 Direct glucocorticoidinhibition of insulin secretion. An in vitro study of dexamethasoneeffects in mouse islets. J Clin Invest 99:414–423

9. Coderre L, Vallega GA, Pilch PF, Chipkin SR 1996 In vivo effects ofdexamethasone and sucrose on glucose transport (GLUT-4) proteintissue distribution. Am J Physiol 271:E643–E648

10. van Raalte DH, Ouwens DM, Diamant M 2009 Novel insights intoglucocorticoid-mediated diabetogenic effects: towards expansion oftherapeutic options? Eur J Clin Invest 39:81–93

11. Beard JC, Halter JB, Best JD, Pfeifer MA, Porte Jr D 1984 Dexa-methasone-induced insulin resistance enhances B cell responsivenessto glucose level in normal men. Am J Physiol 247:E592–E596

12. Grill V, Pigon J, Hartling SG, Binder C, Efendic S 1990 Effects ofdexamethasone on glucose-induced insulin and proinsulin release inlow and high insulin responders. Metabolism 39:251–258

13. Larsson H, Ahren B 1999 Insulin resistant subjects lack islet adap-


tation to short-term dexamethasone-induced reduction in insulinsensitivity. Diabetologia 42:936–943

14. Bjorntorp P 1997 Neuroendocrine factors in obesity. J Endocrinol155:193–195

15. Bjorntorp P, Rosmond R 2000 Obesity and cortisol. Nutrition 16:924–936

16. Turner RJ, Avison WR 2003 Status variations in stress exposure:implications for the interpretation of research on race, socioeco-nomic status, and gender. J Health Soc Behav 44:488–505

17. Weigensberg MJ, Toledo-Corral CM, Goran MI 2008 Associationbetween the metabolic syndrome and serum cortisol in overweightLatino youth. J Clin Endocrinol Metab 93:1372–1378

18. Goran MI, Bergman RN, Avila Q, Watkins M, Ball GD, Shaibi GQ,Weigensberg MJ, Cruz ML 2004 Impaired glucose tolerance andreduced �-cell function in overweight Latino children with a positivefamily history for type 2 diabetes. J Clin Endocrinol Metab 89:207–212

19. 1998 Clinical guidelines on the identification, evaluation, andtreatment of overweight and obesity in adults: executive sum-mary. Expert Panel on the Identification, Evaluation, and Treat-ment of Overweight in Adults. Am J Clin Nutr 68:899 –917

20. Tanner JM 1981 Growth and maturation during adolescence. NutrRev 39:43–55

21. 2000 Type 2 diabetes in children and adolescents. American Dia-betes Association. Pediatrics 105:671–680

22. Bergman RN, Phillips LS, Cobelli C 1981 Physiologic evaluation offactors controlling glucose tolerance in man: measurement of insulinsensitivity and �-cell glucose sensitivity from the response to intra-venous glucose. J Clin Invest 68:1456–1467

23. Amatruda JM, Livingston JN, Lockwood DH 1985 Cellular mech-anisms in selected states of insulin resistance: human obesity, glu-cocorticoid excess, and chronic renal failure. Diabetes Metab Rev1:293–317

24. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN,Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al.1993 Quantification of the relationship between insulin sensitivityand �-cell function in human subjects. Evidence for a hyperbolicfunction. Diabetes 42:1663–1672

25. Overgaard D, Gyntelberg F, Heitmann BL 2004 Psychologicalworkload and body weight: is there an association? A review of theliterature. Occup Med (Lond) 54:35–41

26. Rosmond R, Dallman MF, Bjorntorp P 1998 Stress-related cortisolsecretion in men: relationships with abdominal obesity and endo-crine, metabolic and hemodynamic abnormalities. J Clin EndocrinolMetab 83:1853–1859

27. Rosmond R, Lapidus L, Bjorntorp P 1996 The influence of occu-pational and social factors on obesity and body fat distribution inmiddle-aged men. Int J Obes Relat Metab Disord 20:599–607

28. Bjorntorp P 1993 Visceral obesity: a “civilization syndrome.” ObesRes 1:206–222

29. Vicennati V, Pasquali R 2000 Abnormalities of the hypothalamic-pituitary-adrenal axis in nondepressed women with abdominal obe-sity and relations with insulin resistance: evidence for a central anda peripheral alteration. J Clin Endocrinol Metab 85:4093–4098

30. Pasquali R, Vicennati V, Cacciari M, Pagotto U 2006 The hypo-thalamic-pituitary-adrenal axis activity in obesity and the metabolicsyndrome. Ann NY Acad Sci 1083:111–128

31. Dorn LD, Lucke JF, Loucks TL, Berga SL 2007 Salivary cortisolreflects serum cortisol: analysis of circadian profiles. Ann Clin Bio-chem 44:281–284

32. Scacchi M, Pincelli AI, Cavagnini F 1999 Growth hormone in obe-sity. Int J Obes Relat Metab Disord 23:260–271

33. Misra M, Bredella MA, Tsai P, Mendes N, Miller KK, Klibanski A2008 Lower growth hormone and higher cortisol are associated withgreater visceral adiposity, intramyocellular lipids, and insulin resis-tance in overweight girls. Am J Physiol Endocrinol Metab 295:E385–E392

34. Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB,Wareham NJ 2002 Circulating concentrations of insulin-likegrowth factor-I and development of glucose intolerance: a prospec-tive observational study. Lancet 359:1740–1745

35. Kreitschmann-Andermahr I, Suarez P, Jennings R, Evers N, BrabantG 2010 GH/IGF-I regulation in obesity—mechanisms and practicalconsequences in children and adults. Horm Res Paediatr 73:153–160

36. Toledo-Corral CM, Roberts CK, Shaibi GQ, Lane CJ, Higgins PB,Davis JN, Weigensberg MJ, Goran MI 2008 Insulin-like growthfactor-I is inversely related to adiposity in overweight Latino chil-dren. J Pediatr Endocrinol Metab 21:855–864

37. Ravaja N, Keltikangas-Jarvinen L, Viikari J 1996 Life changes, locusof control and metabolic syndrome precursors in adolescents andyoung adults: a three-year follow-up. Soc Sci Med 43:51–61

38. Delaunay F, Khan A, Cintra A, Davani B, Ling ZC, Andersson A,Ostenson CG, Gustafsson J, Efendic S, Okret S 1997 Pancreatic �

cells are important targets for the diabetogenic effects of glucocor-ticoids. J Clin Invest 100:2094–2098

39. Pivonello R, Faggiano A, Lombardi G, Colao A 2005 The metabolicsyndrome and cardiovascular risk in Cushing’s syndrome. Endocri-nol Metab Clin North Am 34:327–339, viii


cortisol is negatively associated with insulin sensitivity ... · cortisol is negatively associated...

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