ORIGINAL E n d o c r i n e
ARTICLE R e s e a r c h
Exposure to maternal gestational diabetes is associated with higher cardiovascular responses to stress in adolescent Indians. Ghattu V Krishnaveni1, Sargoor R Veena1, Alexander Jones2, Krishnamachari Srinivasan3, Clive Osmond4, Samuel C Karat1, Anura V Kurpad3, Caroline HD Fall4 1
Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore 570021, India; 2Centre for Cardiovascular Imaging, UCL Institute of Child Health, London, UK; 3 St. John’s Research Institute, St, John’s National Academy of Health Sciences, Bangalore, India; 4 MRC Lifecourse Epidemiology Unit, University of Southampton, UK.
Context: Altered endocrinal and autonomic nervous system responses to stress may link impaired intra-uterine growth with later cardiovascular disease. Objective: To test the hypothesis that offspring of gestational diabetic mothers (OGDM) have high cortisol and cardio-sympathetic responses during the Trier Social Stress Test for Children (TSST-C). Design: Adolescents from a birth cohort in India (N⫽213, mean age:13.5 years) including 26 OGDM, 22 offspring of diabetic fathers (ODF) and 165 offspring of non-diabetic parents (controls) completed five minutes each of public speaking and mental arithmetic tasks in front of two unfamiliar ‘evaluators’ (TSST-C). Salivary cortisol concentrations were measured at baseline and at regular intervals after the TSST-C. Heart rate, blood pressure (BP), stroke volume, cardiac output and total peripheral resistance (TPR) were measured continuously at baseline, during and for 10 minutes after the TSST-C using a finger cuff; the beat-to-beat values were averaged for these periods. Results: Cortisol and cardio-sympathetic parameters increased from baseline during stress (P⬍0.001). OGDM had greater systolic BP (mean difference: 5.6 mmHg), cardiac output (0.5 L/min), and stroke volume (4.0 mL) rises and a lower TPR rise (125 dyn.s/cm5) than controls during stress. ODF had greater systolic BP responses than controls (difference: 4.1 mmHg); there was no difference in other cardio-sympathetic parameters. Cortisol responses were similar in all three groups. Conclusions: Maternal diabetes during pregnancy is associated with higher cardio-sympathetic stress-responses in the offspring, which may contribute to their higher cardiovascular disease risk. Further research may confirm stress-response programming as a predictor of cardiovascular risk in OGDM.
D
ysregulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to increased cortisol concentrations, and altered cardiac sympathetic reactivity to stress have been linked to higher metabolic and cardiovascular
disease risk in humans (1). Fetal exposure to maternal undernutrition and maternal stress or excess of glucocorticoids may permanently alter cortisol and cardio-sympathetic stress-responsiveness, leading to a range of meta-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. This article has been published under the terms of the Creative Commons Attribution License (CC-BY http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the Endocrine Society the exclusive right to publish the article and identify itself as the original publisher. Received August 19, 2014. Accepted December 1, 2014.
Abbreviations:
doi: 10.1210/jc.2014-3239
J Clin Endocrinol Metab
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Maternal diabetes and offspring stress-response
bolic and cardiovascular changes in the offspring (2). This may contribute to the higher risk of type 2 diabetes and cardiovascular disease in low birth weight (LBW) individuals (1). Exposure to maternal overnutrition as in gestational diabetes mellitus (GDM) also increases metabolic and cardiovascular disease risk in the offspring (3). Animal model studies show that these offspring may be at an increased risk of hypertension and cardiovascular abnormalities due to altered vascular reactivity and endothelial dysfunction (4). Limited studies in animals have indicated that higher sympathetic nervous system activity also leads to hypertension in offspring of diabetic mothers (5, 6). However, the role of stress-response programming as a cause of higher cardiovascular disease risk in offspring exposed to intra-uterine hyperglycemia has not been studied in humans. The Mysore Parthenon birth cohort study is at the forefront of investigating the long-term effects of maternal GDM on the offspring in India (7, 8). We showed earlier in this cohort that maternal, but not paternal diabetes was strongly associated with higher cardiovascular risk markers in the offspring during childhood (8). Even in control children, maternal insulin concentrations were associated positively with offspring subscapular skinfold thickness and HOMA-IR. We have now re-examined the cohort in order to test whether offspring of gestational diabetic mothers (OGDM) exhibit exaggerated cortisol and cardio-sympathetic responses to a laboratory induced stressor compared with control offspring and whether similar stress-responses are observed in offspring of diabetic fathers (ODF). Availability of continuous measures of glucose and insulin concentrations in the mothers also enabled us to test whether glucose and insulin concentrations in the absence of diabetes are associated with stress responses in the offspring.
Materials and Methods During 1997–1998, we screened 1539 women booking consecutively into the antenatal clinics of HMH. Of these, 1233 (80%) eligible women (⬍32 weeks gestation at booking, no diabetes before pregnancy, planned delivery at HMH, singleton pregnancy) were invited to undergo detailed anthropometry and a 100 g, 3-hour, oral glucose tolerance test (OGTT) (7). Of the 830 women (67%) who participated, 785 completed the OGTT (49 with GDM). Six hundred and thirty-nine women with known GDM status (81%) delivered at HMH (43 offspring of GDM mothers/ OGDM); 6 babies were stillborn and 3 were born with severe congenital anomalies. The remaining 630 offspring were included for further follow-up (41 OGDM).
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The babies were measured at birth and at 6 –12 monthly postnatal follow-ups. Paternal diabetes status was assessed using fasting glucose at the 5-year follow-up. Offspring of non-GDM mothers and nondiabetic fathers were designated controls. At 13.5 years, 445 adolescent children were available for follow-up. We aimed to perform a standard laboratory based stress-test, the Trier Social Stress Test for Children (TSST-C) (9) in 200 offspring of non-GDM mothers, representing four birth weight categories, and all available OGDM (N ⫽ 32) from those living within Mysore city (N ⫽ 298). Families were approached in the chronological order of the children’s date of birth until the final number was achieved (234; 28 ODM, 23 ODF). TSST-C. The tests were conducted between 2 and 3.30 PM, for one child at a time (10). A baseline (pretest) salivary sample was collected 10 minutes before the test, after they had watched a calming video for 5 minutes in a standing position. The children performed 5 minutes of public speaking (imaginative story telling) and 5 minutes of mental arithmetic standing in front of two unfamiliar adults who pretended to evaluate their performance. Further salivary samples were collected at 0, 10, 20, 30 and 60 minutes after the TSST-C to measure the cortisol response. Children watched another calming video for five minutes, in the standing position, before the final salivary sample was collected. Systolic and diastolic blood pressure (BP), cardiac output, stroke volume, heart rate and total peripheral resistance (TPR) were measured continuously during the pretest video-viewing period (baseline), during the TSST-C, and for 10 minutes after the TSST-C. This was done using a noninvasive, portable hemodynamic monitoring system with appropriately sized finger cuffs (Nexfin, BMeye, Amsterdam, Netherlands). The beat-to-beat values were averaged over 5 minutes for the baseline, story, mental arithmetic and immediate poststressor periods. Detailed anthropometry was performed. Bioimpedance-estimated percentage body fat (fat%) and resting BP were measured as described before (8). A fasting blood sample was collected the following day for measuring plasma glucose, insulin and lipid concentrations. Pubertal growth was assessed as the stage of breast development in girls and genital development in boys using Tanner’s method (11). The socio-economic status (SES) of the family was determined using the Standard of Living Index designed by the National Family Health Survey-2 (12). Physical activity was measured using Actigraph accelerometers (AM7164/GT1M; MTI) which measure movement in the vertical plane as counts. Children’s energy, fat and protein intakes were measured using a purpose-designed food frequency questionnaire at 9.5 years of age. Laboratory assays were carried out at the Diabetes Unit, KEM Hospital Research center, Pune, India. Salivary cortisol concentrations were measured using an ELISA method (Alpco Diagnostics, Salem, NH) as per the manufacturer’s instructions. The assay sensitivity was 1 ng/ml; interand intra-assay coefficients of variation were 10.0% and 6.6% respectively. Plasma glucose, insulin, and fasting lipid concentrations were measured as described elsewhere (8, 13). Insulin resistance was estimated using the Homeostasis Model Assessment for insulin resistance (HOMA-IR) equation (14), as this was the method
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doi: 10.1210/jc.2014-3239
used in previous follow-ups. Reassuringly, there were high correlations between these values and HOMA-IR calculated using the online HOMA calculator (r ⫽ 0.99) (15). Area-underthecurve measures were calculated using the trapezoid rule for maternal plasma glucose (GAUC) and insulin (IAUC) (16). The TSST-C judges and the laboratory staff were not aware of parental diabetes status. The HMH ethics committee gave approval for the study; informed written consent from parents and assent from children were obtained. Statistical methods. Children’s salivary cortisol and insulin concentrations and HOMA-IR distributions were skewed, and were log-transformed for analysis. Differences between OGDM and controls, and ODF and controls in anthropometry, risk factors, and cortisol and cardio-sympathetic parameters at baseline were analyzed using independent t-tests or 2 tests. The above differences were adjusted for age, sex, socio-economic status and children’s current weight by including these variables as covariates in multiple linear or logistic regression models. We performed linear mixed-model analysis to examine the associations of maternal GDM and paternal diabetes with repeated measures of outcome variables to account for within group correlations. Salivary cortisol concentrations at all time points, and averaged cardio-sympathetic parameters at different test stages, respectively were included in the models to examine the change from baseline over time, adjusted for age, sex and socio-economic status. The cardiac parameters are all related to body size. Traditionally cardiac output, stroke volume and TPR are indexed on body surface area (BSA). We explored which body size parameters (weight, height, higher order terms of these) best explained the variability in the above cardiovascular outcomes. Body weight alone was the best and this was also adjusted for in all regressions by including this variable as a covariate. Analyses were also repeated using indexed variables, and after adjusting for other measures of body size such as BMI and fat% instead of weight. Analyses were done using SPSS v 21 and STATA v 12.
Results Two hundred and thirty-one of the 234 participants completed the TSST-C. Adequate pre- and post-test salivary samples and complete cardio-sympathetic responses were available for 213 children including 26 OGDM, 22 ODF and 165 controls. Birth weight, current BMI and socioeconomic status did not differ significantly between participants and nonparticipants. In all children, the TSST-C resulted in significant cortisol (Supplemental Figure 1) and cardio-sympathetic responses (Figure 1), indicated by a significant effect of time in mixed model analysis (P ⬍ .001 for all). There was a high degree of correlation between mean cardio-sympathetic parameters during the story and mental arithmetic tasks (r ⬎ 0.9 for all except TPR, for TPR r ⫽ 0.8).
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OGDM General characteristics of OGDM in comparison to control offspring at 13.5 years of age are presented in Table 1. Offspring of mothers with GDM were heavier, more adipose, had a higher prevalence of overweight/obesity and higher fasting insulin and insulin resistance (HOMA-IR) than control children, even after controlling for age, sex and socio-economic status in multiple regression analyses. In both sexes, OGDM had similar pubertal stages to control children. There were no differences in resting BP or fasting glucose and lipid concentrations between the two groups. They were also similar to control children in physical activity counts. TSST-C. At baseline, there were no differences between OGDM and control children in salivary cortisol concentrations and cardio-sympathetic parameters (Table 1). There was no significant association between maternal GDM and cortisol responses to TSST-C (Supplemental Figure 1). Mixed-model analysis showed that, in OGDM, there was an increase in systolic BP from baseline by about 5– 6 mmHg more than that in controls, after adjusting for age, sex, socioeconomic status and current weight (Table 2, Figure 1). Similarly, there was a significantly greater increase in cardiac output and stroke volume, but a lesser increase in TPR in OGDM compared to controls during the TSST-C (Figure 1, Table 2). These associations were similar during public speaking and mental arithmetic tasks (Table 2), and remained statistically significant after adjustment for current BMI or fat% instead of weight, and after additionally adjusting for activity and dietary intake (data not shown). The findings were also robust to further adjustment of cardiac output (P ⬍ .001), stroke volume (P ⫽ .001) and TPR (P ⫽ .02) for BSA. The associations were similar in boys and girls, and there were no interactions with sex for these outcomes after complete adjustment (P ⱖ .2). ODF At 13.5 years, after adjustment for age, sex and socioeconomic status, ODF tended to have higher HOMA-IR than control children (Table 1). Pubertal stage in male and female ODF was similar to control boys and girls respectively. There were no differences between ODF and controls in anthropometry and cardiovascular risk markers. TSST-C. Pretest systolic BP was significantly higher in ODF than control offspring (Table 1). Mixed-model analysis showed that there was also a significant increment in systolic BP from baseline during TSST-C compared to controls (Figure 1); the association was little changed after adjustment for age, sex, socioeconomic status and current
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Maternal diabetes and offspring stress-response
J Clin Endocrinol Metab
Discussion
6
140
4
§
*
130
Maths
Maths
Post-test
Story
Story
Post-test
Pre-test
Post-test
Post-test
Total peripheral resistance (dyn.s/cm5)
Pre-test
4.5
Post-test
Post-test
2000
Post-test
Post-test
1800
Maths
Maths
1600
Story
Story
1400
Pre-test
Pre-test
55
50
45
40
Stroke volume (ml)
*
Cardiac output (L/min) 5 5.5
120 110
100
Systolic BP (mmHg)
In a sample of healthy adolescent children from a birth cohort in India, * offspring of mothers who had GDM exhibited greater cardio-sympathetic responses to a standard stress test than control offspring. Off* spring of diabetic fathers also had greater stress-induced systolic BP compared to controls; there were no apparent differences from controls in the other stress-response parameters. Cortisol responses to stress were similar in all three groups. As far as we know this is the first study to report neuroendocrine stress-responsiveness in relation to parental * * * diabetes status. As observed during the previous follow-ups of the same cohort, OGDM and ODF had higher insulin resistance (HOMA-IR) com* * pared to control children. Our study has demonstrated the first evidence of exaggerated cardiosympathetic stress-responses in OGDM. It has been proposed that altered HPAA and autonomic nervous system responses to psychologControls ical stress increase susceptibility to OGDM ODF cardiovascular disease (1). Using a Figure 1. Stress-induced cardio-sympathetic response in offspring of GDM mothers (OGDM), offspring of diabetic fathers (ODF) and controls. Values represent mean values (95% confidence well-validated stress test, we showed intervals) in OGDM, ODF and controls at different time points relative to the stress-test. Values that ODGM develop higher systolic derived using linear mixed model analysis, adjusting for age, sex, socio-economic status and BP, cardiac output and stroke volcurrent weight. *: P ⬍ .05 for the difference between OGDM and controls; §: P ⬍ .05 for the ume than control children under difference between ODF and controls stressful situation. These responses weight (Table 2). There were no associations between pa- were independent of their body size, BSA or fat%. TPR ternal diabetes status, and cortisol (Supplemental Figure response to stress was lower than in control children; this 1) or other cardio-sympathetic responses to stress (Table may be due to the reciprocal actions of cardiac output and 2). TPR in the regulation of BP, especially in stress, in which an increase in one of these parameters is compensated for Control children by a decrease in the other (17). Though there was also a Even in the control offspring, higher maternal insulin greater stress-response in ODF compared to controls, sugconcentrations (IAUC) were associated with higher regesting gene interactions, it was not as strong as in OGDM sponses for diastolic BP (0.0001 mmHg per pmol.h/L change in maternal IAUC, 95% CI: 0.00002– 0.0001 and was apparent only with systolic BP. However, we mmHg, P ⫽ .02) and TPR during the TSST-C (0.002 cannot rule out stress-responses in other cardiovascular dyn.s/cm5 per pmol.h/L change in maternal IAUC, 95% parameters such as arterial compliance in ODF, which our CI: 0.001– 0.003 dyn.s/cm5, P ⬍ .01, adjusted). Maternal study did not measure. There was also some evidence of IAUC was not associated with cortisol and other cardio- higher cardio-sympathetic stress responses in association sympathetic responses to stress. There was no association with higher maternal insulin concentrations even in the between maternal glucose concentrations (GAUC) and absence of parental diabetes. However, our study does not stress-responses in the control offspring (data not shown). provide conclusive evidence for altered stress responses in *
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doi: 10.1210/jc.2014-3239
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Table 1. Anthropometry, cardiometabolic risk factors, and baseline cortisol concentrations and cardio-sympathetic parameters in offspring of gestational diabetic mothers (OGDM), controls, and offspring of diabetic fathers (ODF) who participated in the TSST-C at 13.5 yr.
Age (yr)a Boys/girls (N)a BMI (kg/m2) Height (cm) Subscapular skinfolds (mm) Fat% Overweight/ obesity (N) Physical activity (counts/min) Energy intake (Kcal/day) Fat intake (g/day ) Protein intake ( g/day) Socioeconomic status (score)a Maternal GAUC (mmol) Maternal IAUC (pmol) Resting parameters Systolic BP (mmHg)b Diastolic BP (mmHg)b Triglycerides (mmol/liter) Total cholesterol ( mmol/liter) HDL cholesterol ( mmol/liter) Glucose (mmol/liter) Insulin (pmol/liter) Insulin resistance (HOMA-IR) TSST-C parameters Cortisol concentrations (ng/mL) Systolic BP (mmHg)c Diastolic BP (mmHg)c Heart rate (bpm) Cardiac output (L/min)d Stroke volume (mL) d TPR (dyn.s/cm5) d
OGDM (n ⴝ 26)
P1
Control (n ⴝ 165)
ODF (n ⴝ 22)
13.5 (0.1) 8/18 (31/69) 20.1 (3.4) 154.9 (7.6) 17.4 (14.3,25.3) 26.4 (8.0) 8 (30.8%) 447.5 (150.6) 2426 (658) 77 (30) 58 (18) 38.5 (6.7) 1708 (545) 80 404 (35 782)
0.8 0.03 ⬍0.001 0.5 ⬍0.001 0.02 0.008 0.6 0.7 0.8 0.9 1.0 ⬍0.001 0.001
13.6 (0.1) 89/76 (54/46) 17.4 (2.6) 154.1 (7.4) 12.1 (8.2,15.8) 21.3 (7.5) 15 (9.1%) 470.3 (176.4) 2561 (844) 82 (33) 59 (20) 38.6 (6.7) 1121 (149) 58 018 (30 633)
0.2 0.7 0.6 0.8 0.4 0.8 0.5 0.1 0.7 0.8 0.6 0.6 0.8 1.0
13.5 (0.1) 11/11 (50/50) 17.5 (2.5) 154.9 (7.0) 9.8 (8.1,20.0) 22.1 (7.6) 1 (4.5%) 413.3 (124.7) 2565 (1150) 77 (41) 60 (26) 39.3 (5.9) 1115 (167) 59 230 (40 832)
110.5 (8.1) 61.7 (6.5) 0.83 (0.4) 3.7 (0.7) 1.08 (0.2) 5.1 (0.4) 54.3 (37.0,73.3) 2.0 (1.5,2.6)
0.1 0.3 0.9 0.3 0.7 0.7 0.02 0.02
109.0 (8.3) 61.4 (7.0) 0.82 (0.4) 3.6 (0.6) 1.10 (0.2) 5.1 (0.5) 42.5 (30.7, 53.2) 1.6 (1.1,2.0)
0.1 0.4 0.3 0.3 0.3 0.6 0.09 0.1
111.5 (8.0) 62.3 (7.0) 0.91 (0.4) 3.4 (0.6) 1.03 (0.3) 5.0 (0.5) 49.6 (38.9,63.5) 1.8 (1.5,2.2)
5.9 (5.2,8.3) 101.2 (9.3) 68.6 (5.9) 106.7 (13.9) 4.8 (0.9) 45.6 (8.1) 1414 (208)
0.6 0.6 0.9 0.7 0.8 0.7 0.8
6.6 (4.6,9.1) 100.1 (11.9) 69.1 (8.0) 107.1 (12.1) 4.6 (0.8) 43.1 (7.9) 1494 (305)
0.2 0.02 0.003 0.4 0.8 0.8 0.1
7.9 (7.1,9.0) 106.3 (12.1) 74.3 (7.6) 109.5 (13.0) 4.6 (0.7) 42.9 (7.8) 1565 (220)
P2
BP: Blood pressure; HOMA-IR: Homeostasis Model Assessment insulin resistance; TPR: Total peripheral resistance Values are mean (SD), median (IQR) or N (%) a b c
Unadjusted P values Resting BP: measured using automated BP machine at the arm level in sitting position TSST-C BP: Measured over five-minutes using figure cuff, in standing position
P values derived using linear or logistic regression analysis, adjusted for age, sex, socio-economic status and d current weight. P1:for the difference between OGDM and controls; P2: for the difference between ODF and controls.
Table 2.
Association between parents’ diabetes status and offspring cardiovascular responses to stress. Systolic BP (mmHg)
Cardiac output (L/min)
Stroke volume (ml)
TPR (dyn.s/cm5)
Systolic BP (mmHg)
Public speaking Maternal GDM Model 1  (95% CI) 5.96 (2.10,9.82) P 0.002 Model 2  (95% CI) 5.96 (2.10,9.82) P 0.002 Paternal diabetes Model 1  (95% CI) 4.70 (0.54,8.85) P 0.03 Model 2  (95% CI) 4.70 (0.54,8.84) P 0.03
Cardiac output (L/min)
Stroke volume (ml)
TPR (dyn.s/cm5)
Mental arithmetic
0.49 (0.26,0.72) ⬍0.001
3.98 (2.00,5.97) ⬍0.001
⫺114 (-220,-9) 0.03
5.23 (1.37,9.10) 0.008
0.50 (0.27,0.73) ⬍0.001
4.10 (2.12,6.09) ⬍0.001
⫺136 (-241,-30) 0.01
0.49 (0.26,0.72) ⬍0.001
3.98 (2.00,5.97) ⬍0.001
⫺114 (-220,-9) 0.03
5.23 (1.37,9.10) 0.008
0.50 (0.27,0.73) ⬍0.001
4.10 (2.12,6.09) ⬍0.001
⫺136 (-241,-30) 0.01
0.09 (-0.16,0.34) 0.5
0.09 (-2.05,2.22) 0.9
97 (-17 211) 0.09
3.47 (-0.68,7.62) 0.1
0.15 (-0.10,0.40) 0.2
0.22 (-1.92,2.35) 0.8
⫺1 (-115 112) 1.0
0.09 (-0.16,0.34) 0.5
0.09 (-2.05,2.22) 0.9
97 (-17 211) 0.09
3.47 (-0.68,7.62) 0.1
0.15 (-0.10,0.40) 0.2
0.22 (-1.92,2.35) 0.8
⫺1 (-115 112) 1.0
The beat-to-beat outcome values were averaged over 5 min for baseline, story, mental arithmetic and immediate post-stressor periods for analysis;
 and P values derived using linear mixed model analysis, using offspring outcomes as continuous variable and parental diabetes status as ‘yes/ no’ categories;  represents unit change in the outcome variable in the offspring of GDM mothers/ diabetic fathers from baseline in excess of that in controls. Model 1: Adjusted for children’s age and sex; Model2: Model 1 ⫹ socio-economic status and children’s current weight
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Maternal diabetes and offspring stress-response
relation to variations in maternal glycemia within the normal range in control offspring. Studies show that OGDM are at an increased risk of obesity, type 2 diabetes and cardiovascular disease in later life (3, 18, 19, 20). The Mysore Parthenon study had previously observed higher subcutaneous adiposity, insulin resistance (HOMA-IR) and systolic BP in OGDM during childhood, more strongly than ODF, compared to control offspring (8). Our current investigations show that these children continue to have higher metabolic risk markers even during early adolescence. The mechanism underlying higher cardiovascular and metabolic risks in OGDM is not well understood. Although genetic transmission may offer a partial explanation, studies among Pima Indians, showing a higher risk of obesity and type 2 diabetes in OGDM than ODF (18), and in siblings born after the mother became diabetic compared to those born before (21), suggest an incremental role of intrauterine hyperglycaemia. Intrauterine hyperinsulinemia, resulting from increased glucose transfer from the mother, is thought to play a major role in promoting long-term adverse outcomes. Apart from the anabolic properties of insulin, contributing to increased size, hyperinsulinaemia and/or leptin resistance in OGDM may also alter hypothalamic appetite regulation, resulting in increased food intake and obesity (22). Shared maternal lifestyle habits, such as higher energy intake, may also be important (23). Dysfunctional endothelial systems leading to impaired vascular dilatation may result in hypertension and cardiovascular abnormalities (4). Our current findings indicate that altered physiological stress responses may also be a contributing factor. A few studies have shown an association between LBW, a proxy for impaired fetal growth, and higher cortisol (24, 25) and cardio-sympathetic stress-responses (26, 27) suggesting a mechanistic link between early growth and later cardiovascular disease in humans. Though maternal GDM also influences fetal growth adversely, studies examining stress-responsiveness in OGDM are sparse. In an earlier study from the UK, 24-hour urinary glucocorticoid metabolite excretion was higher in both low and high birth weight children (28). The researchers speculated that the latter association may be due to altered HPAA activity in babies born to mothers with glucose intolerance during pregnancy. Studies exploring autonomic stress responses in OGDM are also very few. Limited data from animal studies suggest altered sympathetic activity in OGDM (5, 6). In a rat model, pups born to mothers with streptozotocin induced diabetes had higher renal sympathetic activity and developed hypertension later in life (5). In another study, norepinephrine levels were increased, at 22 and 64 days postnatally, in the heart tissue of rat pups born to diabetic mothers (6). These studies, however, did not
J Clin Endocrinol Metab
explore the effect of stress on sympathetic activity. Our study significantly extends this limited literature on the role of neuroendocrine development in the early origins of adult chronic disease. We do not know the mechanism for altered cardiosympathetic stress responses in our OGDM population. This may be related to a direct effect of glucose and insulin concentrations on the autonomic nervous system. Though, cardiovascular autonomic dysfunction is a known complication of uncontrolled hyperglycemia in diabetic individuals (29), this is unlikely in our healthy children born to GDM mothers, whose glucose concentrations were within the normal range and were not different from that of the control children. Hyperinsulinaemia, which is a feature in the OGDM in our cohort, may also increase their sympathetic activity (30); however cardiosympathetic parameters were similar in OGDM and controls in an unstressed state in our study. Another possible explanation is that perinatal hyperinsulinemia in OGDM results in altered neuro-behavioral development (31). An animal model study showed that rat pups born to diabetic mothers demonstrated greater anxiety in stressful situations (32). Diabetic model studies in animals show that maternal hyperglycemia and/or hyperinsulinemia during fetal development permanently alter the development of the hypothalamic structure and function, including that of paraventricular nucleus, which regulates anterior pituitary and autonomic nervous system functions (31). It is suggested that intra-uterine hyperglycemia induces oxidative stress in the developing brain cells leading to cell inflammation, which may underlie the hypothalamic developmental aberrations in OGDM (31, 33). Alternatively, in our cohort, OGDM had higher cognitive ability than controls at 9 –10 years of age (34), which may have resulted in altered stress perception. Interestingly, OGDM did not show altered cortisol responsiveness. This may be related to inadequate power due to our small GDM group. Cortisol response to stress has shown to be gender specific and apparent only in male offspring in studies examining birth weight associations of stress (24). It is possible that it is also true in OGDM, and since we have very few boys in the OGDM group the cortisol responses may not be apparent. However, it is beyond the scope of our study to determine the mechanism for our findings. Strengths and weaknesses. This is the first study to use a well-established stress test to compare stress responses of OGDM and ODF with controls in humans. Continuous measures of maternal glucose and insulin concentrations were examined in association with the above responses even in control children. This is also one of few prospective non-Pima Indian studies to examine the long-term risks of
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doi: 10.1210/jc.2014-3239
intra-uterine exposure to diabetes in comparison with paternal diabetes in children. A limitation was the relatively small numbers of OGDMs. Another limitation was that the TSST-C was conducted only in those children living within the Mysore city. As cognitive performance was better in urban children compared to rural children in our cohort (34), their orientation towards stressful situations may have differed too. However, as most our OGDM were from an urban background, selection bias is unlikely. Fathers’ diabetes status was not measured during the index pregnancy, and was determined using only fasting glucose concentrations. In contrast to OGDM, ODF were not overselected. These factors may have reduced the power of any association between paternal diabetes and offspring stress response. In conclusion, our findings indicate that OGDM are not only exposed to higher adiposity and insulin resistance but are also susceptible to higher stress reactivity. Although it is not known if the higher cardiovascular reactivity in relation to a laboratory stressor in OGDM predicts future disease risk, a recent meta-analysis showed that greater reactivity to laboratory induced stress was associated with an increased risk of future negative cardiovascular outcomes (35). As individuals who have greater reactivity to a laboratory stressor are also more likely to have higher cardiovascular reactivity to everyday stressors (35), these differences in OGDM from normal controls may combine to increase long-term risk of disease substantially. More studies in OGDMs from different populations are required to substantiate the findings from our study.
Acknowledgments We are grateful to the families and hospital staff, the research team, the staff of MRC Lifecourse Epidemiology Unit, and Sneha-India for their support. We thank Prof. D Hellhammer (University of Trier, Germany) for guidance on the TSST-C. Our sincere thanks to KEM Hospital, Pune, for biochemical assays and Sneha-India for its support. GVK acknowledges the mentoring in non communicable disease epidemiology supported by the Fogarty International Center and the Eunice Kennedy Shriver National Institute of Child Health & Human Development at the National Institutes of Health (grant no. 1 D43 HD065249). Part of this study was presented in abstract form at the eighth World Congress on Developmental Origins of Health and Disease, Singapore, 17 –20 November, 2013, and has appeared in the conference supplement of the Journal of Developmental Origins of Health and Disease 2013: 4 (suppl 2): S157. Address all correspondence and requests for reprints to: Dr Krishnaveni GV, Epidemiology Research Unit, Holdsworth Memorial Hospital, Post Box no. 38, Mandi Mohalla, Mysore
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570 021, India. Phone: 0091– 821–2 521 651. Fax: 0091– 821– 2 565 607. E-mail: [email protected]. Disclosure: Authors have no conflict of interest to disclose This work was supported by Parthenon Trust, Switzerland; Wellcome Trust, UK; Medical Research Council, UK.
References 1. Phillips DI, Jones A, Goulden PA. Birthweight, stress and the metabolic syndrome in adult life. Ann NY Acad Sci. 2006;1083:28 –36. 2. Maniam J, Antoniadis C, Morris MJ. Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes. Front Endocrinol (Lausanne). 2014;5:1–17. 3. Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabetes Care. 2007;30(Suppl 2):S169 –S174. 4. Katkhuda R, Peterson ES, Roghair RD, Norris AW, Scholz TD, Segar JL. Sex-specific programming of hypertension in offspring of late gestation diabetic rats. Pediatr Res. 2012;72:352–361. 5. de Almeida Chaves Rodrigues AF, de Lima IL, Bergamaschi CT, Campos RR, Hirata AE, Schoorlemmer GH, Gomes GN. Increased renal sympathetic nerve activity leads to hypertension and renal dysfunction in offspring from diabetic mothers. Am J Physiol Renal Physiol. 2013;304:F189 –F197. 6. Young JB, Morrison SF. Effects of fetal and neonatal environment on sympathetic nervous system development. Diabetes Care. 1998; 21(Suppl):B156 –B160. 7. Hill JC, Krishnaveni GV, Annamma I, Leary SD, Fall CHD. Glucose tolerance in pregnancy in South India: Relationships to neonatal anthropometry. Acta Obstet Gynecol Scand. 2005;84:159 –165. 8. Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, Fall CH. Intra-uterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care. 2010;33:402– 404. 9. Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C, Rauh W, Hellhammer D. Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med. 1997;59: 419 – 426. 10. Krishnaveni GV, Veena SR, Jones A, Bhat DS, Malathi MP, Hellhammer D, Srinivasan K, Upadya H, Kurpad AV, Fall CHD. Trier’s Social Stress Test for Indian adolescents. Indian Pediatrics. 2014; 51:463– 467. 11. Tanner JM. Growth in adolescence. 2nd edition, Oxford, England, Blackwell Scientific Publications, 1962. 12. International Institute for Population Sciences (IIPS) and Operations Research Centre (ORC) Macro 2001. National Family Health Survey (NFHS-2), India 1998 –1999. IIPS: Maharashtra, Mumbai. 13. Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH. Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia. 2014;57:110 – 121. 14. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting glucose and insulin concentrations in man. Diabetologia. 1985;28:412– 419. 15. HOMA calculator. Available from http://www.dtu.ox.ac.uk/index.php?maindocⴝ/homa/. Accessed 21 February 2014. 16. Tai MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes care. 1994;17:152–154. 17. Gregg ME, Matyas TA, James JE. A new model of individual differences in hemodynamic profile and blood pressure reactivity. Psychophysiology. 2002;39:64 –72. 18. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH, Knowler WC. Congenital susceptibility to NIDDM: Role of intrauterine environment. Diabetes. 1988;37:622– 628.
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19. Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, Richards GE, Metzger BE. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes. 1991;40(Suppl):121–125. 20. Aceti A, Santhakumaran S, Logan KM, Philipps LH, Prior E, Gale C, Hyde MJ, Modi N. The diabetic pregnancy and offspring blood pressure in childhood: a systematic review and meta-analysis. Diabetologia. 2012;55:3114 –3127. 21. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: A study of discordant sibships. Diabetes. 2000;49:2208 –2211. 22. Plagemann A, Harder T, Melchior K, Rake A, Rhode W, Dorner G. Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. Neuroreport. 1999;10:3211–3216. 23. Gluck ME, Venti CA, Lindsay RS, Knowler WC, Salbe AD, Krakoff J. Maternal influence, not diabetic intrauterine environment, predicts children’s energy intake. Obesity. 2009;17:772–777. 24. Jones A, Godfrey KM, Wood P, Osmond C, Goulden P, Philips DIW. Fetal growth and the adrenocortical response to psychological stress. J Clin Endocrinol Metab. 2006;91:1868 –1871. 25. Wust S, Entringer S, Federenko IS, Schlotz W, Hellhammer DH. Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology. 2005;30: 591–598. 26. Jones A, Beda A, Osmond C, Godfrey KM, Simpson DM, Phillips DIW. Sex-specific programming of cardiovascular physiology in children. Eur Heart J. 2008;29:2164 –2170. 27. Feldt K, Räikkönen K, Pyhälä R, Jones A, Phillips DI, Eriksson JG, Pesonen AK, Heinonen K, Järvenpää AL, Strandberg TE, Kajantie E. Body size at birth and cardiovascular response to and recovery from mental stress in children. J Hum Hypertens. 2011;25:231–240.
J Clin Endocrinol Metab
28. Clarke PM, Hindmarsh PC, Shiell AW, Law CM, Honour JW, Barker DJ. Size at birth and adrenocortical function in childhood. Clin Endocrinol (Oxf). 1996;45:721–726. 29. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, PopBusui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011. doi: 10.1002/dmrr. 1239. (Epub ahead of print) 30. Scherrer U, Sartori C. Insulin as a Vascular and Sympathoexcitatory Hormone Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity. Circulation. 1997;96: 4104 – 4113. 31. Steculorum SM, Vogt MC, Brüning JC. Perinatal programming of metabolic diseases role of insulin in the development of hypothalamic neurocircuits. Endocrinol Metab Clin N Am. 2013;42:149 – 164. 32. Ramanathan M, Jaiswal AK, Bhattacharya SK. Hyperglycaemia in pregnancy: effects on the offspring behaviour with special reference to anxiety paradigms. Indian J Exp Biol. 2000;38:231–236. 33. Van Lieshout RJ, Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms 34. Veena SR, Krishnaveni GV, Srinivasan K, Kurpad AV, Muthayya S, Hill JC, Kiran KN, Fall CHD. Childhood cognitive ability: relationship to gestational diabetes mellitus in India. Diabetologia. 2010; 53:2134 –2138. 35. Chida Y and Steptoe A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status. Hypertension 2014 (Epub ahead of print).
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ARTICLE R e s e a r c h
Exposure to maternal gestational diabetes is associated with higher cardiovascular responses to stress in adolescent Indians. Ghattu V Krishnaveni1, Sargoor R Veena1, Alexander Jones2, Krishnamachari Srinivasan3, Clive Osmond4, Samuel C Karat1, Anura V Kurpad3, Caroline HD Fall4 1
Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore 570021, India; 2Centre for Cardiovascular Imaging, UCL Institute of Child Health, London, UK; 3 St. John’s Research Institute, St, John’s National Academy of Health Sciences, Bangalore, India; 4 MRC Lifecourse Epidemiology Unit, University of Southampton, UK.
Context: Altered endocrinal and autonomic nervous system responses to stress may link impaired intra-uterine growth with later cardiovascular disease. Objective: To test the hypothesis that offspring of gestational diabetic mothers (OGDM) have high cortisol and cardio-sympathetic responses during the Trier Social Stress Test for Children (TSST-C). Design: Adolescents from a birth cohort in India (N⫽213, mean age:13.5 years) including 26 OGDM, 22 offspring of diabetic fathers (ODF) and 165 offspring of non-diabetic parents (controls) completed five minutes each of public speaking and mental arithmetic tasks in front of two unfamiliar ‘evaluators’ (TSST-C). Salivary cortisol concentrations were measured at baseline and at regular intervals after the TSST-C. Heart rate, blood pressure (BP), stroke volume, cardiac output and total peripheral resistance (TPR) were measured continuously at baseline, during and for 10 minutes after the TSST-C using a finger cuff; the beat-to-beat values were averaged for these periods. Results: Cortisol and cardio-sympathetic parameters increased from baseline during stress (P⬍0.001). OGDM had greater systolic BP (mean difference: 5.6 mmHg), cardiac output (0.5 L/min), and stroke volume (4.0 mL) rises and a lower TPR rise (125 dyn.s/cm5) than controls during stress. ODF had greater systolic BP responses than controls (difference: 4.1 mmHg); there was no difference in other cardio-sympathetic parameters. Cortisol responses were similar in all three groups. Conclusions: Maternal diabetes during pregnancy is associated with higher cardio-sympathetic stress-responses in the offspring, which may contribute to their higher cardiovascular disease risk. Further research may confirm stress-response programming as a predictor of cardiovascular risk in OGDM.
D
ysregulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to increased cortisol concentrations, and altered cardiac sympathetic reactivity to stress have been linked to higher metabolic and cardiovascular
disease risk in humans (1). Fetal exposure to maternal undernutrition and maternal stress or excess of glucocorticoids may permanently alter cortisol and cardio-sympathetic stress-responsiveness, leading to a range of meta-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. This article has been published under the terms of the Creative Commons Attribution License (CC-BY http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the Endocrine Society the exclusive right to publish the article and identify itself as the original publisher. Received August 19, 2014. Accepted December 1, 2014.
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doi: 10.1210/jc.2014-3239
J Clin Endocrinol Metab
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Maternal diabetes and offspring stress-response
bolic and cardiovascular changes in the offspring (2). This may contribute to the higher risk of type 2 diabetes and cardiovascular disease in low birth weight (LBW) individuals (1). Exposure to maternal overnutrition as in gestational diabetes mellitus (GDM) also increases metabolic and cardiovascular disease risk in the offspring (3). Animal model studies show that these offspring may be at an increased risk of hypertension and cardiovascular abnormalities due to altered vascular reactivity and endothelial dysfunction (4). Limited studies in animals have indicated that higher sympathetic nervous system activity also leads to hypertension in offspring of diabetic mothers (5, 6). However, the role of stress-response programming as a cause of higher cardiovascular disease risk in offspring exposed to intra-uterine hyperglycemia has not been studied in humans. The Mysore Parthenon birth cohort study is at the forefront of investigating the long-term effects of maternal GDM on the offspring in India (7, 8). We showed earlier in this cohort that maternal, but not paternal diabetes was strongly associated with higher cardiovascular risk markers in the offspring during childhood (8). Even in control children, maternal insulin concentrations were associated positively with offspring subscapular skinfold thickness and HOMA-IR. We have now re-examined the cohort in order to test whether offspring of gestational diabetic mothers (OGDM) exhibit exaggerated cortisol and cardio-sympathetic responses to a laboratory induced stressor compared with control offspring and whether similar stress-responses are observed in offspring of diabetic fathers (ODF). Availability of continuous measures of glucose and insulin concentrations in the mothers also enabled us to test whether glucose and insulin concentrations in the absence of diabetes are associated with stress responses in the offspring.
Materials and Methods During 1997–1998, we screened 1539 women booking consecutively into the antenatal clinics of HMH. Of these, 1233 (80%) eligible women (⬍32 weeks gestation at booking, no diabetes before pregnancy, planned delivery at HMH, singleton pregnancy) were invited to undergo detailed anthropometry and a 100 g, 3-hour, oral glucose tolerance test (OGTT) (7). Of the 830 women (67%) who participated, 785 completed the OGTT (49 with GDM). Six hundred and thirty-nine women with known GDM status (81%) delivered at HMH (43 offspring of GDM mothers/ OGDM); 6 babies were stillborn and 3 were born with severe congenital anomalies. The remaining 630 offspring were included for further follow-up (41 OGDM).
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The babies were measured at birth and at 6 –12 monthly postnatal follow-ups. Paternal diabetes status was assessed using fasting glucose at the 5-year follow-up. Offspring of non-GDM mothers and nondiabetic fathers were designated controls. At 13.5 years, 445 adolescent children were available for follow-up. We aimed to perform a standard laboratory based stress-test, the Trier Social Stress Test for Children (TSST-C) (9) in 200 offspring of non-GDM mothers, representing four birth weight categories, and all available OGDM (N ⫽ 32) from those living within Mysore city (N ⫽ 298). Families were approached in the chronological order of the children’s date of birth until the final number was achieved (234; 28 ODM, 23 ODF). TSST-C. The tests were conducted between 2 and 3.30 PM, for one child at a time (10). A baseline (pretest) salivary sample was collected 10 minutes before the test, after they had watched a calming video for 5 minutes in a standing position. The children performed 5 minutes of public speaking (imaginative story telling) and 5 minutes of mental arithmetic standing in front of two unfamiliar adults who pretended to evaluate their performance. Further salivary samples were collected at 0, 10, 20, 30 and 60 minutes after the TSST-C to measure the cortisol response. Children watched another calming video for five minutes, in the standing position, before the final salivary sample was collected. Systolic and diastolic blood pressure (BP), cardiac output, stroke volume, heart rate and total peripheral resistance (TPR) were measured continuously during the pretest video-viewing period (baseline), during the TSST-C, and for 10 minutes after the TSST-C. This was done using a noninvasive, portable hemodynamic monitoring system with appropriately sized finger cuffs (Nexfin, BMeye, Amsterdam, Netherlands). The beat-to-beat values were averaged over 5 minutes for the baseline, story, mental arithmetic and immediate poststressor periods. Detailed anthropometry was performed. Bioimpedance-estimated percentage body fat (fat%) and resting BP were measured as described before (8). A fasting blood sample was collected the following day for measuring plasma glucose, insulin and lipid concentrations. Pubertal growth was assessed as the stage of breast development in girls and genital development in boys using Tanner’s method (11). The socio-economic status (SES) of the family was determined using the Standard of Living Index designed by the National Family Health Survey-2 (12). Physical activity was measured using Actigraph accelerometers (AM7164/GT1M; MTI) which measure movement in the vertical plane as counts. Children’s energy, fat and protein intakes were measured using a purpose-designed food frequency questionnaire at 9.5 years of age. Laboratory assays were carried out at the Diabetes Unit, KEM Hospital Research center, Pune, India. Salivary cortisol concentrations were measured using an ELISA method (Alpco Diagnostics, Salem, NH) as per the manufacturer’s instructions. The assay sensitivity was 1 ng/ml; interand intra-assay coefficients of variation were 10.0% and 6.6% respectively. Plasma glucose, insulin, and fasting lipid concentrations were measured as described elsewhere (8, 13). Insulin resistance was estimated using the Homeostasis Model Assessment for insulin resistance (HOMA-IR) equation (14), as this was the method
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doi: 10.1210/jc.2014-3239
used in previous follow-ups. Reassuringly, there were high correlations between these values and HOMA-IR calculated using the online HOMA calculator (r ⫽ 0.99) (15). Area-underthecurve measures were calculated using the trapezoid rule for maternal plasma glucose (GAUC) and insulin (IAUC) (16). The TSST-C judges and the laboratory staff were not aware of parental diabetes status. The HMH ethics committee gave approval for the study; informed written consent from parents and assent from children were obtained. Statistical methods. Children’s salivary cortisol and insulin concentrations and HOMA-IR distributions were skewed, and were log-transformed for analysis. Differences between OGDM and controls, and ODF and controls in anthropometry, risk factors, and cortisol and cardio-sympathetic parameters at baseline were analyzed using independent t-tests or 2 tests. The above differences were adjusted for age, sex, socio-economic status and children’s current weight by including these variables as covariates in multiple linear or logistic regression models. We performed linear mixed-model analysis to examine the associations of maternal GDM and paternal diabetes with repeated measures of outcome variables to account for within group correlations. Salivary cortisol concentrations at all time points, and averaged cardio-sympathetic parameters at different test stages, respectively were included in the models to examine the change from baseline over time, adjusted for age, sex and socio-economic status. The cardiac parameters are all related to body size. Traditionally cardiac output, stroke volume and TPR are indexed on body surface area (BSA). We explored which body size parameters (weight, height, higher order terms of these) best explained the variability in the above cardiovascular outcomes. Body weight alone was the best and this was also adjusted for in all regressions by including this variable as a covariate. Analyses were also repeated using indexed variables, and after adjusting for other measures of body size such as BMI and fat% instead of weight. Analyses were done using SPSS v 21 and STATA v 12.
Results Two hundred and thirty-one of the 234 participants completed the TSST-C. Adequate pre- and post-test salivary samples and complete cardio-sympathetic responses were available for 213 children including 26 OGDM, 22 ODF and 165 controls. Birth weight, current BMI and socioeconomic status did not differ significantly between participants and nonparticipants. In all children, the TSST-C resulted in significant cortisol (Supplemental Figure 1) and cardio-sympathetic responses (Figure 1), indicated by a significant effect of time in mixed model analysis (P ⬍ .001 for all). There was a high degree of correlation between mean cardio-sympathetic parameters during the story and mental arithmetic tasks (r ⬎ 0.9 for all except TPR, for TPR r ⫽ 0.8).
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OGDM General characteristics of OGDM in comparison to control offspring at 13.5 years of age are presented in Table 1. Offspring of mothers with GDM were heavier, more adipose, had a higher prevalence of overweight/obesity and higher fasting insulin and insulin resistance (HOMA-IR) than control children, even after controlling for age, sex and socio-economic status in multiple regression analyses. In both sexes, OGDM had similar pubertal stages to control children. There were no differences in resting BP or fasting glucose and lipid concentrations between the two groups. They were also similar to control children in physical activity counts. TSST-C. At baseline, there were no differences between OGDM and control children in salivary cortisol concentrations and cardio-sympathetic parameters (Table 1). There was no significant association between maternal GDM and cortisol responses to TSST-C (Supplemental Figure 1). Mixed-model analysis showed that, in OGDM, there was an increase in systolic BP from baseline by about 5– 6 mmHg more than that in controls, after adjusting for age, sex, socioeconomic status and current weight (Table 2, Figure 1). Similarly, there was a significantly greater increase in cardiac output and stroke volume, but a lesser increase in TPR in OGDM compared to controls during the TSST-C (Figure 1, Table 2). These associations were similar during public speaking and mental arithmetic tasks (Table 2), and remained statistically significant after adjustment for current BMI or fat% instead of weight, and after additionally adjusting for activity and dietary intake (data not shown). The findings were also robust to further adjustment of cardiac output (P ⬍ .001), stroke volume (P ⫽ .001) and TPR (P ⫽ .02) for BSA. The associations were similar in boys and girls, and there were no interactions with sex for these outcomes after complete adjustment (P ⱖ .2). ODF At 13.5 years, after adjustment for age, sex and socioeconomic status, ODF tended to have higher HOMA-IR than control children (Table 1). Pubertal stage in male and female ODF was similar to control boys and girls respectively. There were no differences between ODF and controls in anthropometry and cardiovascular risk markers. TSST-C. Pretest systolic BP was significantly higher in ODF than control offspring (Table 1). Mixed-model analysis showed that there was also a significant increment in systolic BP from baseline during TSST-C compared to controls (Figure 1); the association was little changed after adjustment for age, sex, socioeconomic status and current
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Maternal diabetes and offspring stress-response
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Discussion
6
140
4
§
*
130
Maths
Maths
Post-test
Story
Story
Post-test
Pre-test
Post-test
Post-test
Total peripheral resistance (dyn.s/cm5)
Pre-test
4.5
Post-test
Post-test
2000
Post-test
Post-test
1800
Maths
Maths
1600
Story
Story
1400
Pre-test
Pre-test
55
50
45
40
Stroke volume (ml)
*
Cardiac output (L/min) 5 5.5
120 110
100
Systolic BP (mmHg)
In a sample of healthy adolescent children from a birth cohort in India, * offspring of mothers who had GDM exhibited greater cardio-sympathetic responses to a standard stress test than control offspring. Off* spring of diabetic fathers also had greater stress-induced systolic BP compared to controls; there were no apparent differences from controls in the other stress-response parameters. Cortisol responses to stress were similar in all three groups. As far as we know this is the first study to report neuroendocrine stress-responsiveness in relation to parental * * * diabetes status. As observed during the previous follow-ups of the same cohort, OGDM and ODF had higher insulin resistance (HOMA-IR) com* * pared to control children. Our study has demonstrated the first evidence of exaggerated cardiosympathetic stress-responses in OGDM. It has been proposed that altered HPAA and autonomic nervous system responses to psychologControls ical stress increase susceptibility to OGDM ODF cardiovascular disease (1). Using a Figure 1. Stress-induced cardio-sympathetic response in offspring of GDM mothers (OGDM), offspring of diabetic fathers (ODF) and controls. Values represent mean values (95% confidence well-validated stress test, we showed intervals) in OGDM, ODF and controls at different time points relative to the stress-test. Values that ODGM develop higher systolic derived using linear mixed model analysis, adjusting for age, sex, socio-economic status and BP, cardiac output and stroke volcurrent weight. *: P ⬍ .05 for the difference between OGDM and controls; §: P ⬍ .05 for the ume than control children under difference between ODF and controls stressful situation. These responses weight (Table 2). There were no associations between pa- were independent of their body size, BSA or fat%. TPR ternal diabetes status, and cortisol (Supplemental Figure response to stress was lower than in control children; this 1) or other cardio-sympathetic responses to stress (Table may be due to the reciprocal actions of cardiac output and 2). TPR in the regulation of BP, especially in stress, in which an increase in one of these parameters is compensated for Control children by a decrease in the other (17). Though there was also a Even in the control offspring, higher maternal insulin greater stress-response in ODF compared to controls, sugconcentrations (IAUC) were associated with higher regesting gene interactions, it was not as strong as in OGDM sponses for diastolic BP (0.0001 mmHg per pmol.h/L change in maternal IAUC, 95% CI: 0.00002– 0.0001 and was apparent only with systolic BP. However, we mmHg, P ⫽ .02) and TPR during the TSST-C (0.002 cannot rule out stress-responses in other cardiovascular dyn.s/cm5 per pmol.h/L change in maternal IAUC, 95% parameters such as arterial compliance in ODF, which our CI: 0.001– 0.003 dyn.s/cm5, P ⬍ .01, adjusted). Maternal study did not measure. There was also some evidence of IAUC was not associated with cortisol and other cardio- higher cardio-sympathetic stress responses in association sympathetic responses to stress. There was no association with higher maternal insulin concentrations even in the between maternal glucose concentrations (GAUC) and absence of parental diabetes. However, our study does not stress-responses in the control offspring (data not shown). provide conclusive evidence for altered stress responses in *
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Table 1. Anthropometry, cardiometabolic risk factors, and baseline cortisol concentrations and cardio-sympathetic parameters in offspring of gestational diabetic mothers (OGDM), controls, and offspring of diabetic fathers (ODF) who participated in the TSST-C at 13.5 yr.
Age (yr)a Boys/girls (N)a BMI (kg/m2) Height (cm) Subscapular skinfolds (mm) Fat% Overweight/ obesity (N) Physical activity (counts/min) Energy intake (Kcal/day) Fat intake (g/day ) Protein intake ( g/day) Socioeconomic status (score)a Maternal GAUC (mmol) Maternal IAUC (pmol) Resting parameters Systolic BP (mmHg)b Diastolic BP (mmHg)b Triglycerides (mmol/liter) Total cholesterol ( mmol/liter) HDL cholesterol ( mmol/liter) Glucose (mmol/liter) Insulin (pmol/liter) Insulin resistance (HOMA-IR) TSST-C parameters Cortisol concentrations (ng/mL) Systolic BP (mmHg)c Diastolic BP (mmHg)c Heart rate (bpm) Cardiac output (L/min)d Stroke volume (mL) d TPR (dyn.s/cm5) d
OGDM (n ⴝ 26)
P1
Control (n ⴝ 165)
ODF (n ⴝ 22)
13.5 (0.1) 8/18 (31/69) 20.1 (3.4) 154.9 (7.6) 17.4 (14.3,25.3) 26.4 (8.0) 8 (30.8%) 447.5 (150.6) 2426 (658) 77 (30) 58 (18) 38.5 (6.7) 1708 (545) 80 404 (35 782)
0.8 0.03 ⬍0.001 0.5 ⬍0.001 0.02 0.008 0.6 0.7 0.8 0.9 1.0 ⬍0.001 0.001
13.6 (0.1) 89/76 (54/46) 17.4 (2.6) 154.1 (7.4) 12.1 (8.2,15.8) 21.3 (7.5) 15 (9.1%) 470.3 (176.4) 2561 (844) 82 (33) 59 (20) 38.6 (6.7) 1121 (149) 58 018 (30 633)
0.2 0.7 0.6 0.8 0.4 0.8 0.5 0.1 0.7 0.8 0.6 0.6 0.8 1.0
13.5 (0.1) 11/11 (50/50) 17.5 (2.5) 154.9 (7.0) 9.8 (8.1,20.0) 22.1 (7.6) 1 (4.5%) 413.3 (124.7) 2565 (1150) 77 (41) 60 (26) 39.3 (5.9) 1115 (167) 59 230 (40 832)
110.5 (8.1) 61.7 (6.5) 0.83 (0.4) 3.7 (0.7) 1.08 (0.2) 5.1 (0.4) 54.3 (37.0,73.3) 2.0 (1.5,2.6)
0.1 0.3 0.9 0.3 0.7 0.7 0.02 0.02
109.0 (8.3) 61.4 (7.0) 0.82 (0.4) 3.6 (0.6) 1.10 (0.2) 5.1 (0.5) 42.5 (30.7, 53.2) 1.6 (1.1,2.0)
0.1 0.4 0.3 0.3 0.3 0.6 0.09 0.1
111.5 (8.0) 62.3 (7.0) 0.91 (0.4) 3.4 (0.6) 1.03 (0.3) 5.0 (0.5) 49.6 (38.9,63.5) 1.8 (1.5,2.2)
5.9 (5.2,8.3) 101.2 (9.3) 68.6 (5.9) 106.7 (13.9) 4.8 (0.9) 45.6 (8.1) 1414 (208)
0.6 0.6 0.9 0.7 0.8 0.7 0.8
6.6 (4.6,9.1) 100.1 (11.9) 69.1 (8.0) 107.1 (12.1) 4.6 (0.8) 43.1 (7.9) 1494 (305)
0.2 0.02 0.003 0.4 0.8 0.8 0.1
7.9 (7.1,9.0) 106.3 (12.1) 74.3 (7.6) 109.5 (13.0) 4.6 (0.7) 42.9 (7.8) 1565 (220)
P2
BP: Blood pressure; HOMA-IR: Homeostasis Model Assessment insulin resistance; TPR: Total peripheral resistance Values are mean (SD), median (IQR) or N (%) a b c
Unadjusted P values Resting BP: measured using automated BP machine at the arm level in sitting position TSST-C BP: Measured over five-minutes using figure cuff, in standing position
P values derived using linear or logistic regression analysis, adjusted for age, sex, socio-economic status and d current weight. P1:for the difference between OGDM and controls; P2: for the difference between ODF and controls.
Table 2.
Association between parents’ diabetes status and offspring cardiovascular responses to stress. Systolic BP (mmHg)
Cardiac output (L/min)
Stroke volume (ml)
TPR (dyn.s/cm5)
Systolic BP (mmHg)
Public speaking Maternal GDM Model 1  (95% CI) 5.96 (2.10,9.82) P 0.002 Model 2  (95% CI) 5.96 (2.10,9.82) P 0.002 Paternal diabetes Model 1  (95% CI) 4.70 (0.54,8.85) P 0.03 Model 2  (95% CI) 4.70 (0.54,8.84) P 0.03
Cardiac output (L/min)
Stroke volume (ml)
TPR (dyn.s/cm5)
Mental arithmetic
0.49 (0.26,0.72) ⬍0.001
3.98 (2.00,5.97) ⬍0.001
⫺114 (-220,-9) 0.03
5.23 (1.37,9.10) 0.008
0.50 (0.27,0.73) ⬍0.001
4.10 (2.12,6.09) ⬍0.001
⫺136 (-241,-30) 0.01
0.49 (0.26,0.72) ⬍0.001
3.98 (2.00,5.97) ⬍0.001
⫺114 (-220,-9) 0.03
5.23 (1.37,9.10) 0.008
0.50 (0.27,0.73) ⬍0.001
4.10 (2.12,6.09) ⬍0.001
⫺136 (-241,-30) 0.01
0.09 (-0.16,0.34) 0.5
0.09 (-2.05,2.22) 0.9
97 (-17 211) 0.09
3.47 (-0.68,7.62) 0.1
0.15 (-0.10,0.40) 0.2
0.22 (-1.92,2.35) 0.8
⫺1 (-115 112) 1.0
0.09 (-0.16,0.34) 0.5
0.09 (-2.05,2.22) 0.9
97 (-17 211) 0.09
3.47 (-0.68,7.62) 0.1
0.15 (-0.10,0.40) 0.2
0.22 (-1.92,2.35) 0.8
⫺1 (-115 112) 1.0
The beat-to-beat outcome values were averaged over 5 min for baseline, story, mental arithmetic and immediate post-stressor periods for analysis;
 and P values derived using linear mixed model analysis, using offspring outcomes as continuous variable and parental diabetes status as ‘yes/ no’ categories;  represents unit change in the outcome variable in the offspring of GDM mothers/ diabetic fathers from baseline in excess of that in controls. Model 1: Adjusted for children’s age and sex; Model2: Model 1 ⫹ socio-economic status and children’s current weight
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6
Maternal diabetes and offspring stress-response
relation to variations in maternal glycemia within the normal range in control offspring. Studies show that OGDM are at an increased risk of obesity, type 2 diabetes and cardiovascular disease in later life (3, 18, 19, 20). The Mysore Parthenon study had previously observed higher subcutaneous adiposity, insulin resistance (HOMA-IR) and systolic BP in OGDM during childhood, more strongly than ODF, compared to control offspring (8). Our current investigations show that these children continue to have higher metabolic risk markers even during early adolescence. The mechanism underlying higher cardiovascular and metabolic risks in OGDM is not well understood. Although genetic transmission may offer a partial explanation, studies among Pima Indians, showing a higher risk of obesity and type 2 diabetes in OGDM than ODF (18), and in siblings born after the mother became diabetic compared to those born before (21), suggest an incremental role of intrauterine hyperglycaemia. Intrauterine hyperinsulinemia, resulting from increased glucose transfer from the mother, is thought to play a major role in promoting long-term adverse outcomes. Apart from the anabolic properties of insulin, contributing to increased size, hyperinsulinaemia and/or leptin resistance in OGDM may also alter hypothalamic appetite regulation, resulting in increased food intake and obesity (22). Shared maternal lifestyle habits, such as higher energy intake, may also be important (23). Dysfunctional endothelial systems leading to impaired vascular dilatation may result in hypertension and cardiovascular abnormalities (4). Our current findings indicate that altered physiological stress responses may also be a contributing factor. A few studies have shown an association between LBW, a proxy for impaired fetal growth, and higher cortisol (24, 25) and cardio-sympathetic stress-responses (26, 27) suggesting a mechanistic link between early growth and later cardiovascular disease in humans. Though maternal GDM also influences fetal growth adversely, studies examining stress-responsiveness in OGDM are sparse. In an earlier study from the UK, 24-hour urinary glucocorticoid metabolite excretion was higher in both low and high birth weight children (28). The researchers speculated that the latter association may be due to altered HPAA activity in babies born to mothers with glucose intolerance during pregnancy. Studies exploring autonomic stress responses in OGDM are also very few. Limited data from animal studies suggest altered sympathetic activity in OGDM (5, 6). In a rat model, pups born to mothers with streptozotocin induced diabetes had higher renal sympathetic activity and developed hypertension later in life (5). In another study, norepinephrine levels were increased, at 22 and 64 days postnatally, in the heart tissue of rat pups born to diabetic mothers (6). These studies, however, did not
J Clin Endocrinol Metab
explore the effect of stress on sympathetic activity. Our study significantly extends this limited literature on the role of neuroendocrine development in the early origins of adult chronic disease. We do not know the mechanism for altered cardiosympathetic stress responses in our OGDM population. This may be related to a direct effect of glucose and insulin concentrations on the autonomic nervous system. Though, cardiovascular autonomic dysfunction is a known complication of uncontrolled hyperglycemia in diabetic individuals (29), this is unlikely in our healthy children born to GDM mothers, whose glucose concentrations were within the normal range and were not different from that of the control children. Hyperinsulinaemia, which is a feature in the OGDM in our cohort, may also increase their sympathetic activity (30); however cardiosympathetic parameters were similar in OGDM and controls in an unstressed state in our study. Another possible explanation is that perinatal hyperinsulinemia in OGDM results in altered neuro-behavioral development (31). An animal model study showed that rat pups born to diabetic mothers demonstrated greater anxiety in stressful situations (32). Diabetic model studies in animals show that maternal hyperglycemia and/or hyperinsulinemia during fetal development permanently alter the development of the hypothalamic structure and function, including that of paraventricular nucleus, which regulates anterior pituitary and autonomic nervous system functions (31). It is suggested that intra-uterine hyperglycemia induces oxidative stress in the developing brain cells leading to cell inflammation, which may underlie the hypothalamic developmental aberrations in OGDM (31, 33). Alternatively, in our cohort, OGDM had higher cognitive ability than controls at 9 –10 years of age (34), which may have resulted in altered stress perception. Interestingly, OGDM did not show altered cortisol responsiveness. This may be related to inadequate power due to our small GDM group. Cortisol response to stress has shown to be gender specific and apparent only in male offspring in studies examining birth weight associations of stress (24). It is possible that it is also true in OGDM, and since we have very few boys in the OGDM group the cortisol responses may not be apparent. However, it is beyond the scope of our study to determine the mechanism for our findings. Strengths and weaknesses. This is the first study to use a well-established stress test to compare stress responses of OGDM and ODF with controls in humans. Continuous measures of maternal glucose and insulin concentrations were examined in association with the above responses even in control children. This is also one of few prospective non-Pima Indian studies to examine the long-term risks of
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doi: 10.1210/jc.2014-3239
intra-uterine exposure to diabetes in comparison with paternal diabetes in children. A limitation was the relatively small numbers of OGDMs. Another limitation was that the TSST-C was conducted only in those children living within the Mysore city. As cognitive performance was better in urban children compared to rural children in our cohort (34), their orientation towards stressful situations may have differed too. However, as most our OGDM were from an urban background, selection bias is unlikely. Fathers’ diabetes status was not measured during the index pregnancy, and was determined using only fasting glucose concentrations. In contrast to OGDM, ODF were not overselected. These factors may have reduced the power of any association between paternal diabetes and offspring stress response. In conclusion, our findings indicate that OGDM are not only exposed to higher adiposity and insulin resistance but are also susceptible to higher stress reactivity. Although it is not known if the higher cardiovascular reactivity in relation to a laboratory stressor in OGDM predicts future disease risk, a recent meta-analysis showed that greater reactivity to laboratory induced stress was associated with an increased risk of future negative cardiovascular outcomes (35). As individuals who have greater reactivity to a laboratory stressor are also more likely to have higher cardiovascular reactivity to everyday stressors (35), these differences in OGDM from normal controls may combine to increase long-term risk of disease substantially. More studies in OGDMs from different populations are required to substantiate the findings from our study.
Acknowledgments We are grateful to the families and hospital staff, the research team, the staff of MRC Lifecourse Epidemiology Unit, and Sneha-India for their support. We thank Prof. D Hellhammer (University of Trier, Germany) for guidance on the TSST-C. Our sincere thanks to KEM Hospital, Pune, for biochemical assays and Sneha-India for its support. GVK acknowledges the mentoring in non communicable disease epidemiology supported by the Fogarty International Center and the Eunice Kennedy Shriver National Institute of Child Health & Human Development at the National Institutes of Health (grant no. 1 D43 HD065249). Part of this study was presented in abstract form at the eighth World Congress on Developmental Origins of Health and Disease, Singapore, 17 –20 November, 2013, and has appeared in the conference supplement of the Journal of Developmental Origins of Health and Disease 2013: 4 (suppl 2): S157. Address all correspondence and requests for reprints to: Dr Krishnaveni GV, Epidemiology Research Unit, Holdsworth Memorial Hospital, Post Box no. 38, Mandi Mohalla, Mysore
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570 021, India. Phone: 0091– 821–2 521 651. Fax: 0091– 821– 2 565 607. E-mail: [email protected]. Disclosure: Authors have no conflict of interest to disclose This work was supported by Parthenon Trust, Switzerland; Wellcome Trust, UK; Medical Research Council, UK.
References 1. Phillips DI, Jones A, Goulden PA. Birthweight, stress and the metabolic syndrome in adult life. Ann NY Acad Sci. 2006;1083:28 –36. 2. Maniam J, Antoniadis C, Morris MJ. Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes. Front Endocrinol (Lausanne). 2014;5:1–17. 3. Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabetes Care. 2007;30(Suppl 2):S169 –S174. 4. Katkhuda R, Peterson ES, Roghair RD, Norris AW, Scholz TD, Segar JL. Sex-specific programming of hypertension in offspring of late gestation diabetic rats. Pediatr Res. 2012;72:352–361. 5. de Almeida Chaves Rodrigues AF, de Lima IL, Bergamaschi CT, Campos RR, Hirata AE, Schoorlemmer GH, Gomes GN. Increased renal sympathetic nerve activity leads to hypertension and renal dysfunction in offspring from diabetic mothers. Am J Physiol Renal Physiol. 2013;304:F189 –F197. 6. Young JB, Morrison SF. Effects of fetal and neonatal environment on sympathetic nervous system development. Diabetes Care. 1998; 21(Suppl):B156 –B160. 7. Hill JC, Krishnaveni GV, Annamma I, Leary SD, Fall CHD. Glucose tolerance in pregnancy in South India: Relationships to neonatal anthropometry. Acta Obstet Gynecol Scand. 2005;84:159 –165. 8. Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, Fall CH. Intra-uterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care. 2010;33:402– 404. 9. Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C, Rauh W, Hellhammer D. Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med. 1997;59: 419 – 426. 10. Krishnaveni GV, Veena SR, Jones A, Bhat DS, Malathi MP, Hellhammer D, Srinivasan K, Upadya H, Kurpad AV, Fall CHD. Trier’s Social Stress Test for Indian adolescents. Indian Pediatrics. 2014; 51:463– 467. 11. Tanner JM. Growth in adolescence. 2nd edition, Oxford, England, Blackwell Scientific Publications, 1962. 12. International Institute for Population Sciences (IIPS) and Operations Research Centre (ORC) Macro 2001. National Family Health Survey (NFHS-2), India 1998 –1999. IIPS: Maharashtra, Mumbai. 13. Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH. Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia. 2014;57:110 – 121. 14. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting glucose and insulin concentrations in man. Diabetologia. 1985;28:412– 419. 15. HOMA calculator. Available from http://www.dtu.ox.ac.uk/index.php?maindocⴝ/homa/. Accessed 21 February 2014. 16. Tai MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes care. 1994;17:152–154. 17. Gregg ME, Matyas TA, James JE. A new model of individual differences in hemodynamic profile and blood pressure reactivity. Psychophysiology. 2002;39:64 –72. 18. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH, Knowler WC. Congenital susceptibility to NIDDM: Role of intrauterine environment. Diabetes. 1988;37:622– 628.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2015. at 23:30 For personal use only. No other uses without permission. . All rights reserved.
8
Maternal diabetes and offspring stress-response
19. Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, Richards GE, Metzger BE. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes. 1991;40(Suppl):121–125. 20. Aceti A, Santhakumaran S, Logan KM, Philipps LH, Prior E, Gale C, Hyde MJ, Modi N. The diabetic pregnancy and offspring blood pressure in childhood: a systematic review and meta-analysis. Diabetologia. 2012;55:3114 –3127. 21. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: A study of discordant sibships. Diabetes. 2000;49:2208 –2211. 22. Plagemann A, Harder T, Melchior K, Rake A, Rhode W, Dorner G. Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. Neuroreport. 1999;10:3211–3216. 23. Gluck ME, Venti CA, Lindsay RS, Knowler WC, Salbe AD, Krakoff J. Maternal influence, not diabetic intrauterine environment, predicts children’s energy intake. Obesity. 2009;17:772–777. 24. Jones A, Godfrey KM, Wood P, Osmond C, Goulden P, Philips DIW. Fetal growth and the adrenocortical response to psychological stress. J Clin Endocrinol Metab. 2006;91:1868 –1871. 25. Wust S, Entringer S, Federenko IS, Schlotz W, Hellhammer DH. Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology. 2005;30: 591–598. 26. Jones A, Beda A, Osmond C, Godfrey KM, Simpson DM, Phillips DIW. Sex-specific programming of cardiovascular physiology in children. Eur Heart J. 2008;29:2164 –2170. 27. Feldt K, Räikkönen K, Pyhälä R, Jones A, Phillips DI, Eriksson JG, Pesonen AK, Heinonen K, Järvenpää AL, Strandberg TE, Kajantie E. Body size at birth and cardiovascular response to and recovery from mental stress in children. J Hum Hypertens. 2011;25:231–240.
J Clin Endocrinol Metab
28. Clarke PM, Hindmarsh PC, Shiell AW, Law CM, Honour JW, Barker DJ. Size at birth and adrenocortical function in childhood. Clin Endocrinol (Oxf). 1996;45:721–726. 29. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, PopBusui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011. doi: 10.1002/dmrr. 1239. (Epub ahead of print) 30. Scherrer U, Sartori C. Insulin as a Vascular and Sympathoexcitatory Hormone Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity. Circulation. 1997;96: 4104 – 4113. 31. Steculorum SM, Vogt MC, Brüning JC. Perinatal programming of metabolic diseases role of insulin in the development of hypothalamic neurocircuits. Endocrinol Metab Clin N Am. 2013;42:149 – 164. 32. Ramanathan M, Jaiswal AK, Bhattacharya SK. Hyperglycaemia in pregnancy: effects on the offspring behaviour with special reference to anxiety paradigms. Indian J Exp Biol. 2000;38:231–236. 33. Van Lieshout RJ, Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms 34. Veena SR, Krishnaveni GV, Srinivasan K, Kurpad AV, Muthayya S, Hill JC, Kiran KN, Fall CHD. Childhood cognitive ability: relationship to gestational diabetes mellitus in India. Diabetologia. 2010; 53:2134 –2138. 35. Chida Y and Steptoe A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status. Hypertension 2014 (Epub ahead of print).
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