Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia.

AIMS/HYPOTHESIS: We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations. METHODS: A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants. RESULTS: Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16-25 and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10-7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans. CONCLUSIONS/INTERPRETATION: The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.

Type 1 Diabetes in a Resource-Poor Setting: Malnutrition Related, Malnutrition Modified, or Just Diabetes?

PURPOSE OF REVIEW: Very little is known about the occurrence of type 1 diabetes (T1DM) in resource-poor countries and particularly in their rural hinterlands. RECENT FINDINGS: Studies of the epidemiology of T1DM in Ethiopia and similar countries in sub-Saharan Africa show that the pattern of presenting disease differs substantially from that in the West. Typically, the peak age of onset of the disease is more than a decade later with a male excess and a low prevalence of indicators of islet-cell autoimmunity. It is also associated with markers of undernutrition. These findings raise the question as to whether the principal form of T1DM seen in these resource-poor communities has a different pathogenesis. Whether the disease is a direct result of malnutrition or whether malnutrition may modify the expression of islet-cell autoimmunity is unclear. However, the poor prognosis in these settings underlines the urgent need for detailed clinical and epidemiological studies.

Prenatal Undernutrition and Autonomic Function in Adulthood.

OBJECTIVES: Early-life adversity has been shown to be associated with cardiovascular disease and mortality in later life, but little is known about the mechanisms that underlie this association. Prenatal undernutrition, a severe early-life stressor, is associated with double the risk of coronary heart disease and increased blood pressure responses to psychological stress. In the present study, we tested the hypothesis that prenatal undernutrition induces alterations in the autonomic nervous system, which may increase the risk of developing heart disease. METHODS: We studied autonomic function in 740 men and women (mean [SD] age, 58 [0.9] years) who were members of the Dutch famine birth cohort. We compared those exposed to famine during early (n = 64), mid (n = 107), or late gestation (n = 127) to those unexposed to famine in utero (n = 442). Participants underwent a series of 3 psychological stressors (Stroop, mirror tracing, and speech) while their blood pressure and heart rate were recorded continuously. RESULTS: Data had sufficient quality in 602 participants for derivation of autonomic function indices by spectral analysis. The stress protocol led to significant sample-level changes in systolic blood pressure, heart rate, and all cardiovascular control measures (all p values < .001). None of the autonomic function parameters, at rest or in response to stress, differed significantly (all p values > .050) according to prenatal famine exposure. CONCLUSIONS: Prenatal undernutrition was not associated with autonomic function in late adulthood. We conclude that altered autonomic function does not seem to explain our previous findings of increased coronary heart disease risk among those exposed to famine prenatally.

Early-life factors are associated with nocturnal cortisol and glucose effectiveness in Afro-Caribbean young adults.

CONTEXT: Early-life factors (including intrauterine growth retardation) may influence the development of type 2 diabetes. We postulated that birth size is associated with cortisol levels, which itself could alter serum adipomyokines (i.e. adiponectin, IGF-I, myostatin) and glucose metabolism. DESIGN: An observational study with 60 Afro-Caribbean young adults from a birth cohort. MEASUREMENTS: Fasting blood was drawn for serum adiponectin, IGF-I and myostatin. A frequently sampled intravenous glucose tolerance test measured insulin sensitivity (SI), acute insulin response (AIRg), disposition index (DI) and glucose effectiveness (Sg). Body composition was assessed by dual-energy X-ray absorptiometry. Salivary cortisol was collected at home at 0800 and 2300 h. Sex-adjusted correlations were used to explore the relationships between birth size, cortisol and the metabolic variables. RESULTS: The participants were 55% male, mean age 23·1 ± 0·5 years. Birth weight correlated positively with 2300-h cortisol (P = 0·04), although not after adjusting for gestational age. Gestational age was correlated with 2300 h cortisol (r = 0·38, P = 0·03), even after adjusting for birth weight (P = 0·02). 2300 h cortisol was not associated with adiponectin, IGF-I, myostatin, SI, AIRg or DI, but was negatively correlated with Sg (r = -0·30, P = 0·05) even after adjusting for birth and adult anthropometry. Adiponectin, IGF-I and myostatin were unrelated to glucose metabolism. CONCLUSIONS: Gestational age is associated with higher nocturnal cortisol, which in turn is associated with lower glucose effectiveness in adulthood. Higher glucose effectiveness could therefore be a compensatory mechanism to improve glucose uptake.

The developmental origins of chronic rheumatic heart disease.

OBJECTIVES: Programming is the phenomenon whereby the body's structures and functions are permanently set by nutrition and other influences during early development. There is increasing evidence that programming in utero initiates cardiovascular disease. We hypothesized that susceptibility to developing chronic rheumatic heart disease on exposure to Streptococcus pyogenes is programmed. METHODS: We studied hospital admissions and deaths from chronic rheumatic heart disease in 20,431 people born in Helsinki, Finland, during 1924-1944. One hundred and one people, 56 men, and 45 women, had chronic rheumatic heart disease. RESULTS: The disease was not associated with body or placental size at birth. It was, however, associated with a long umbilical cord so that the hazard ratio for the disease was 1.23 (95% CI 1.04-1.45, P = 0.02) for every 10 cm increase in cord length. This association was present in people with mitral valve disease, hazard ratio 1.5 (1.20-1.89, P < 0.0001), but not in people with aortic valve disease, hazard ratio 1.0 (0.76-1.33, P = 0.97). Growing up in large households increased the risk of rheumatic heart disease. CONCLUSION: Longer umbilical cords have more spirals and a greater density of spirals per unit of length. Increased spiraling will increase the resistance to flow and the pressure load on the fetal heart. This could affect the development of the heart's valves and make them more vulnerable to the autoimmune process initiated by Streptococcus pyogenes. The mitral valve may be more vulnerable than the aortic valve because the valve leaflets are larger and therefore have greater wall stress.

Type 1 diabetes mellitus in the context of high levels of rural deprivation: differences in demographic and anthropometric characteristics between urban and rural cases in NW Ethiopia.

Background: While there is increasing evidence for an altered clinical phenotype of Type 1 diabetes in several low-and middle-income countries, little is known about urban-rural differences and how the greater poverty of rural environments may alter the pattern of disease. Objective: Investigation of urban-rural differences in demographic and anthropometric characteristics of type 1 diabetes in a resource-poor setting. Research design and methods: Analysis of a unique case register, comprising all patients (rural and urban) presenting with Type 1 diabetes over a 20 yr. period in a poor, geographically defined area in northwest Ethiopia. The records included age, sex, place of residence, together with height and weight at the clinical onset. Results: A total of 1682 new cases of Type 1 diabetes were registered with a mean age of onset of 31.2 (SD 13.4) yr. The patients were thin with 1/3 presenting with a body mass index (BMI) <17kg/m2. There was a striking male predominance of cases when clinical onset was between 20 and 35 yr., this was more marked in the very poor rural dwellers compared to the urban population. While most patients with Type 1 diabetes presented with low BMIs and reduced height, stunting preferentially affected rural men. Conclusions: These data have led to the hypothesis that complex interactions among poor socioeconomic conditions in early life affect both pancreatic function and the development of autoimmunity and provide a possible explanation of the unusual phenotype of Type 1 diabetes in this very poor community.

The "Cairo Accord"- Towards the Eradication of RHD: An Update.

Rheumatic heart disease (RHD) is the most common cause of acquired heart disease in children and young adults. It continues to be prevalent in many low- and middle-income countries where it causes significant morbidity and mortality. Following the 2017 Cairo conference "Rheumatic Heart Disease: from Molecules to the Global Community," experts from 21 countries formulated an approach for addressing the problem of RHD: "The Cairo Accord on Rheumatic Heart Disease." The Accord attempts to set policy priorities for the eradication of acute rheumatic fever (ARF) and RHD and builds on a recent series of policy initiatives and calls to action. We present an update on the recommendations of the Cairo Accord and discuss recent progress toward the eradication of RHD, including contributions from our own Aswan Rheumatic Heart Disease Registry (ARGI).

Community-based prevalence of rheumatic heart disease in rural Ethiopia: Five-year follow-up.

BACKGROUND: As little is known about the prevalence and clinical progression of subclinical (latent) rheumatic heart disease (RHD) in sub-Saharan Africa, we report the results of a 5 year follow-up of a community based, echocardiographic study of the disease, originally carried out in a rural area around Jimma, Ethiopia. METHODS: Individuals with evidence of RHD detected during the baseline study as well as controls and their family members were screened with a short questionnaire together with transthoracic echocardiography. RESULTS: Of 56 individuals with RHD (37 definite and 19 borderline) in the original study, 36 (26 definite and 10 borderline) were successfully located 57.3 (range 44.9-70.7) months later. At follow-up two thirds of the definite cases still had definite disease; while a third had regressed. Approximately equal numbers of the borderline cases had progressed and regressed. Features of RHD had appeared in 5 of the 60 controls. There was an increased risk of RHD in the family relatives of borderline and definite cases (3.8 and 4.0 times respectively), notably among siblings. Compliance with penicillin prophylaxis was very poor. CONCLUSIONS: We show the persistence of echocardiographically demonstrable RHD in a rural sub-Saharan population. Both progression and regression of the disease were found; however, the majority of the individuals who had definite features of RHD had evidence of continuing RHD lesions five years later. There was an increased risk of RHD in the family relatives of borderline and definite cases, notably among siblings. The findings highlight the problems faced in addressing the problem of RHD in the rural areas of sub-Saharan Africa. They add to the evidence that community-based interventions for RHD will be required, together with appropriate ways of identifying active disease, achieving adequate penicillin prophylaxis and developing vaccines for primary prevention.

Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients Attending the Diabetic Clinic of the University of Gondar Hospital, Northwest Ethiopia.

OBJECTIVE: To investigate the level of diabetic retinopathy in type 2 diabetes (T2DM) patients attending the University of Gondar Hospital (UGH) Diabetic Clinic, Northwest Ethiopia. METHODS: An audit was carried out involving a total of 739 T2DM patients attending at the diabetic clinic of UGH. They represented approximately 90% and 50% of all T2DM patients under regular review at the urban and rural diabetic clinics of UGH, respectively. All were supervised by the same clinical team for a long period. Eye examinations were performed for visual acuity, cataract, and retinal changes (retinal photography and slit-lamp biomicroscopy). Body mass index (BMI) and HbA1c levels were measured. The presence or absence of hypertension was recorded. RESULTS: Men constituted 41.5% of the group, the mean age at diagnosis of T2DM was 50.4 years, and 50.2% were hypertensive. The BMI was 25.0 ± 4.1 kg/m2, and HbA1c was 7.75 ± 1.63% (61.2 ± 17.8 mmol/mol) (mean ± SD, for BMI and HbA1c)). Severe visual impairment/blindness was reported in 10.6%, 15.2% had cataract, 16.0% had retinopathy, and 11.1% had maculopathy. The prevalence of retinopathy increased with time from diagnosis of T2DM (chi-square for trend, p < 0.001) and with increasing HbA1c level (chi-square for trend, p=0.03). CONCLUSION: These results compare well with the most recent results in well-equipped, wealthier regions of the world and show the importance of stable healthcare infrastructure for chronic-disease management.

The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria.

BACKGROUND: Polycystic ovary syndrome (PCOS) is considered to be the most common endocrine disorder in women of reproductive age, yet debate over appropriate diagnostic criteria and design limitations with sampling methodology have left some doubt as to the actual prevalence in the community. The objective of this study was to create a representative prevalence estimate of PCOS in the community under the National Institutes of Health (NIH) criteria and the more recent Rotterdam consensus criteria and Androgen Excess Society (AES) criteria. METHODS: A retrospective birth cohort study was carried out in which 728 women born during 1973-1975 in a single maternity hospital were traced and interviewed in adulthood (age = 27-34 year; n = 728). Symptoms of PCOS (hyperandrogenism, menstrual dysfunction and polycystic ovaries) were identified by examination and the presence of polycystic ovaries in those that did not consent to the ultrasound were imputed. RESULTS: The estimated prevalence of PCOS in this birth cohort using the NIH criteria was 8.7 +/- 2.0% (with no need for imputation). Under the Rotterdam criteria, the prevalence was 11.9 +/- 2.4% which increased to 17.8 +/- 2.8% when imputed data were included. Under the AES recommendations, PCOS prevalence was 10.2 +/- 2.2%, and 12.0 +/- 2.4% with the imputed data. Of the women with PCOS, 68-69% did not have a pre-existing diagnosis. CONCLUSIONS: The Rotterdam and AES prevalence estimates were up to twice that obtained with the NIH criteria in this, as well other prevalence studies. In addition, this study also draws attention to the issue of many women with PCOS in the community remaining undiagnosed.

Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring.

BACKGROUND: Maternal nutrition during pregnancy has been linked with fetal brain development and psychopathology in the offspring. We examined for associations of maternal folate status and dietary intake during pregnancy with brain growth and childhood behavioural difficulties in the offspring. METHODS: In a prospective cohort study, maternal red blood cell folate (RCF) was measured at 14 weeks of pregnancy and total folate intake (TFI) from food and supplements was assessed in early and late pregnancy. The offspring's head circumference and body weight were measured at birth and in infancy, and 100 mothers reported on children's behavioural difficulties at a mean age of 8.75 years using the Strengths and Difficulties Questionnaire. RESULTS: Lower maternal RCF and TFI in early pregnancy were associated with higher childhood hyperactivity (RCF: beta = -.24; p = .013; TFI: beta = -.24; p = .022) and peer problems scores (RCF: beta = -.28; p = .004; TFI: beta = -.28; p = .009) in the offspring. Maternal gestational RCF was positively associated with head circumference at birth (adjusted for gestational age), and mediation analyses showed significant inverse indirect associations of RCF with hyperactivity/inattention and peer problems via fetal brain growth. Adjustment for mother's smoking and drinking alcohol during pregnancy did not change the results. CONCLUSIONS: Although the associations are small and residual confounding is possible, our data provide preliminary support for the hypothesis that lower folate status in early pregnancy might impair fetal brain development and affect hyperactivity/inattention and peer problems in childhood.

Fetal origins of mental health: evidence and mechanisms.

The concept of fetal programming states that changes in the fetal environment during sensitive periods of organ development may cause long-lasting changes in the structure and functioning of these organs later in life and influence the risk for chronic diseases such as coronary heart disease and type 2 diabetes. Fetal growth is a summary marker of the fetal environment and is reflected by relatively easy-to-obtain measures of size at birth such as birth weight. In the last two decades, a body of evidence emerged linking fetal growth with behavioural and mental health outcomes later in life. Cognitive functioning and behavioural problems in childhood, in particular inattention/hyperactivity, have been shown to be inversely related to fetal growth. Although results are mixed, risk for personality disorders and schizophrenia seems to be linked with fetal growth and adversity, while the evidence for mood disorders is weak. Vulnerability for psychopathology may also be influenced by prenatal adversity. There is evidence for associations of fetal growth with temperament in childhood as well as stress reactivity and distress. The associations of fetal growth with mental health later in life are potentially caused by specific prenatal factors such as maternal smoking, alcohol, toxins/drugs, nutrition, psychosocial stress and infection during pregnancy. The mechanisms likely involve changes in neurodevelopment and in the set point of neuroendocrine systems, and there is evidence that prenatal adversity interacts with genetic and postnatal environmental factors. Future studies should examine the effects of specific prenatal factors and attempt to disentangle genetic and prenatal environmental effects.

Sex-specific programming of cardiovascular physiology in children.

AIMS: Increasing evidence suggests that adverse prenatal environments, as indicated by low birth weight, cause long-term changes in cardiovascular physiology that predispose to circulatory disease. The mechanisms are poorly understood, most human studies have been carried out in adults and little is known about early pathophysiological changes. Therefore, we have assessed the relationship between birth weight and cardiovascular physiology in children. METHODS AND RESULTS: In 140 healthy boys and girls (aged 7-9 years), born at term and followed prospectively, we continuously recorded blood pressure, electrocardiograms and cardiac impedance before, during, and after 10 min of psychosocial stress (Trier Social Stress Test for Children). In boys, an association of lower birth weight with higher resting systemic arterial pressure (ß = -6.8 mmHg/kg, P= 0.03) and a trend towards higher vascular resistance (ß = -87 dyne s/cm(5)/kg, ns) were substantially strengthened following stress (ß = -9.5 mmHg/kg, P= 0.003 and ß = -139 dyne s/cm(5)/kg, P = 0.02, respectively). In girls, lower birth weight was associated with a shorter pre-ejection period (ß = 8.0 ms/kg, P = 0.005) and corrected QT interval (ß = 11.9 ms/kg, P = 0.003) at rest and little changed by stress. CONCLUSION: Smaller size at birth is associated with sex-specific alterations in cardiac physiology; boys had higher systemic vascular resistance and girls had increased cardiac sympathetic activation.

Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function.

The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo-pituitary-adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1-35 (early restriction; ER), or 36-70 (late restriction; LR). Female offspring (F(1)) were mated and fed ad libitum to create second generation (F(2)) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F(1) and F(2) offspring. ER(F1) males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ER(F2) offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.

Effortful control mediates associations of fetal growth with hyperactivity and behavioural problems in 7- to 9-year-old children.

BACKGROUND: Inverse associations of fetal growth with behavioural problems in childhood have been repeatedly reported, suggesting long-term effects of the prenatal developmental environment on behaviour later in life. However, no study so far has examined effects on temperament and potential developmental pathways. Temperamental traits may be particularly susceptible to neurodevelopmental alterations, and they are linked to behavioural problems. Therefore, we tested for associations of fetal growth with behavioural problems in children and tested if temperament mediated such effects. METHODS: One hundred and thirty-nine mother-child pairs were recruited in early pregnancy.Weight, head circumference and gestational age were measured at birth, and the mother reported on their child's behavioural problems and temperament at age 7 to 9 years. RESULTS: Birth weight and head circumference at birth adjusted for gestational age (i.e., fetal growth) were inversely associated with hyperactivity and total behavioural problems, and positively associated with the temperamental trait Effortful Control. Path analyses showed that Effortful Control mediated the effects of fetal growth on hyperactivity and total behavioural problems. CONCLUSIONS: Our results suggest that an adverse fetal environment is associated with behavioural problems in childhood, in particular in those children that show a low capacity for attentional and behavioural regulation. An adverse fetal environment might induce vulnerability for behavioural problems, or it might induce changes in temperament and behavioural problems independently, representing a common cause. Pathways are likely to be based on long-lasting neurodevelopmental alterations due to prenatal adversity.

Evaluating the long-term consequences of air pollution in early life: geographical correlations between coal consumption in 1951/1952 and current mortality in England and Wales.

OBJECTIVE: To evaluate associations between early life air pollution and subsequent mortality. DESIGN: Geographical study. SETTING: Local government districts within England and Wales. EXPOSURE: Routinely collected geographical data on the use of coal and related solid fuels in 1951-1952 were used as an index of air pollution. MAIN OUTCOME MEASURES: We evaluated the relationship between these data and both all-cause and disease-specific mortality among men and women aged 35-74 years in local government districts between 1993 and 2012. RESULTS: Domestic (household) coal consumption had the most powerful associations with mortality. There were strong correlations between domestic coal use and all-cause mortality (relative risk per SD increase in fuel use 1.124, 95% CI 1.123 to 1.126), and respiratory (1.238, 95% CI 1.234 to 1.242), cardiovascular (1.138, 95% CI 1.136 to 1.140) and cancer mortality (1.073, 95% CI 1.071 to 1.075). These effects persisted after adjustment for socioeconomic indicators in 1951, current socioeconomic indicators and current pollution levels. CONCLUSION: Coal was the major cause of pollution in the UK until the Clean Air Act of 1956 led to a rapid decline in consumption. These data suggest that coal-based pollution, experienced over 60 years ago in early life, affects human health now by increasing mortality from a wide variety of diseases.

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Stress responsiveness in adult life: influence of mother's diet in late pregnancy.

CONTEXT: Men and women whose mothers ate an unbalanced high-protein, low-carbohydrate diet in late pregnancy have raised blood pressure. We recently showed that they also have raised fasting plasma cortisol concentrations. Because raised fasting cortisol concentrations probably reflect a greater response to the stress of fasting and venesection, we suspected that this diet may have led to increased stress responsiveness in the adult offspring. OBJECTIVE: The aim was to determine whether an unbalanced high-protein diet during pregnancy is associated with increased cortisol secretion in response to psychological stress in the offspring. DESIGN AND PARTICIPANTS: Salivary cortisol concentrations were measured during a modified Trier Social Stress Test in 70 men and women aged 36.3 yr whose mothers had taken part in a dietary intervention in which they were advised to eat 1 pound (0.45 kg) of red meat daily during pregnancy and to avoid carbohydrate-rich foods. RESULTS: The offspring of women who reported greater consumption of meat and fish in the second half of pregnancy had higher cortisol concentrations during the Trier Test. Compared with the offspring of mothers who had reported eating no more than 13 meat/fish portions per week, the average cortisol concentrations were raised by 22% (95% confidence interval, 13 to 71%) and 46% (5 to 103%) in the offspring of those eating 14-16 and at least 17 portions per week, respectively. CONCLUSIONS: These findings provide the first human evidence that an unbalanced high protein maternal diet during late pregnancy leads to increased cortisol secretion in response to psychological stress in the offspring.

Body size at birth predicts hypothalamic-pituitary-adrenal axis response to psychosocial stress at age 60 to 70 years.

BACKGROUND: Studies in humans and animals have suggested intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA) function as an important mechanism in linking fetal life conditions with adult disease. OBJECTIVE: Our aim was to assess how body size at birth, a marker of intrauterine conditions, is associated with hypothalamic-pituitary-adrenal axis response to psychosocial stress in late adulthood. DESIGN AND SETTING: We conducted a clinical study in the Helsinki Birth Cohort. PARTICIPANTS: Two hundred eighty-seven men and women born between 1934 and 1944 whose birth measurements and gestational age came from hospital records participated in the study. MEASUREMENTS: We measured salivary cortisol and, for 215 individuals, plasma cortisol and ACTH concentrations in conjunction with a standardized psychosocial stressor (Trier Social Stress Test). RESULTS: There was a linear relationship between low birth weight and low plasma ACTH but no linear relationship with cortisol. There were, however, quadratic relationships between birth weight and salivary (mixed model P = 0.001) and plasma cortisol (P = 0.005) but not with plasma ACTH (P = 0.1). The lowest peak salivary cortisol concentrations were seen in the lowest third of birth weights (adjusted for gestational age and sex): 12.9 nmol/liter (95% confidence interval of mean 11.2-15.0), compared with 17.1 nmol/liter (14.8-19.8) in the middle and 14.1 nmol/liter (12.6-15.7) in the highest third of birth weights. Corresponding figures for plasma cortisol were 418 nmol/liter (380-459), 498 nmol/liter (455-545), and 454 nmol/liter (428-482), and for plasma ACTH 8.17 pmol/liter (6.98-9.57), 12.42 pmol/liter (10.64-14.51), and 11.50 (10.06-13.14), respectively. Results for areas under the curve were similar. CONCLUSIONS: We found an inverse U-shaped relationship between birth weight and cortisol concentrations during psychosocial stress. The lowest cortisol and ACTH concentrations were seen in subjects with the lowest birth weights. These results support the hypothesis that both hyper- and hypocortisolism may be programmed during the fetal period.

Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system.

OBJECTIVES: Leptin, an important hormonal regulator of body weight, has been shown to stimulate the sympathetic nervous system (SNS) in vitro although the physiological relevance remains unclear. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and an increased cardiovascular risk. We have therefore investigated the relationship between leptin, insulin resistance and cardiac autonomic activity in healthy young adults. 130 healthy men and women age 20.9 years were studied. Insulin sensitivity was assessed using the IVGTT and minimal model with simultaneous measures of leptin. Cardiac autonomic activity was assessed using spectral analysis of heart rate variability. RESULTS: Women showed significantly higher fasting leptin, heart rate and cardiac sympathetic activity, and lower insulin sensitivity. Men showed inverse correlations between insulin resistance and heart rate, and between insulin resistance and cardiac sympatho-vagal ratio. Women, in contrast, showed no SNS relationship with insulin resistance, but rather an inverse correlation between leptin and the sympatho-vagal ratio, suggesting that leptin in women is associated with SNS activity. The correlation remained significant after adjustment for BMI and waist-to-hip ratio (beta=-0.33 and p=0.008). CONCLUSION: Insulin resistance and SNS activity appear to be linked, although the relationship showed marked gender differences, and the direction of causality was unclear from this cross-sectional study. Leptin appears to exert a greater effect on the SNS in women, possibly because of their greater fat mass.