A neglected source of household air pollution: a preliminary, mixed methods study of purposely produced household smoke in Wollo, Ethiopia.

BACKGROUND: Ill health associated with household air pollution (HAP) is increasingly recognized as a public health problem in sub-Saharan Africa. To date, attempts to reduce HAP have focussed on smoke from cooking fires and have ignored traditional cultural practices which generate purposely produced smoke (PPS). This study aimed to investigate PPS prevalence, reasons for use and safety perceptions. METHODS: The study was conducted in Wollo, Ethiopia, and used a mixed methods approach of quantitative surveys (analysed descriptively) and qualitative interviews with householders and healthcare workers (analysed thematically). RESULTS: PPS use was reported by 99% of survey respondents and it was considered a fundamental part of life. Although reasons for use included housekeeping, culture/religion and well-being, coffee ceremony was most commonly cited (44% of respondents). Both householders and healthcare workers appeared to assume PPS is safe, except for people with certain underlying conditions. Healthcare workers felt the lack of evidence of harm from PPS meant there was no justification for intervention. CONCLUSION: This study, the first in-depth study of PPS, has shown its use to be widespread, with many perceived benefits and thus a very important part of local culture in this sample Ethiopian community. Consequently, any public health interventions aimed at reducing HAP in this setting need to consider PPS.

Size at birth, morning cortisol and cardiometabolic risk markers in healthy Indian children.

OBJECTIVE: Prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis may link reduced foetal growth with higher adult chronic disease risk. South Asians have a high prevalence of low birth weight and a thin-fat phenotype, which is associated with subsequent type 2 diabetes and the metabolic syndrome. Altered HPA activity could be one of the pathological processes underlying this link. METHODS: Plasma morning cortisol and corticosteroid-binding globulin (CBG) concentrations were determined in 528 children aged 9·5 years from a prospective birth cohort in India. They had detailed anthropometry at birth, and current measurements of anthropometry, plasma glucose, insulin and lipid concentrations and blood pressure. Insulin resistance (Homeostasis Model Assessment) and insulin secretion (the 30-min insulin increment) were also assessed. RESULTS: None of the birth measurements were associated with cortisol concentrations, but both birth weight (P = 0·03) and length (P = 0·004) were inversely associated with CBG concentrations. Cortisol concentrations were inversely associated with current body mass index (P = 0·02), and positively associated with glucose (fasting: P < 0·001; 30-min: P = 0·002) concentrations, and systolic blood pressure (P = 0·005), but not insulin resistance or the insulin increment. CONCLUSION: Higher morning cortisol is associated with higher cardiometabolic risk markers in Indian children. Although cortisol concentrations did not appear to be related to birth size, small size at birth was associated with higher CBG levels, and may be one of the processes by which foetal undernutrition affects adult health. The findings suggest a need for dynamic testing of HPA axis activity (such as measuring stress responses).

Dietary total antioxidant capacity is related to glucose tolerance in older people: the Hertfordshire Cohort Study.

BACKGROUND AND AIMS: Dietary antioxidants may play a protective role in the aetiology of type 2 diabetes. However, observational studies that examine the relationship between the antioxidant capacity of the diet and glucose metabolism are limited, particularly in older people. We aimed to examine the relationships between dietary total antioxidant capacity (TAC) and markers of glucose metabolism among 1441 men and 1253 women aged 59-73 years who participated in the Hertfordshire Cohort Study, UK. METHODS AND RESULTS: Diet was assessed by food frequency questionnaire. Dietary TAC was estimated using published databases of TAC measured by four different assays: oxygen radical absorbance capacity (ORAC), ferric-reducing ability of plasma (FRAP), total radical-trapping antioxidant parameter (TRAP) and trolox equivalent antioxidant capacity (TEAC). Fasting and 120-min plasma glucose and insulin concentrations were measured during a standard 75-g oral glucose tolerance test. In men, dietary TAC estimated by all four assays was inversely associated with fasting insulin concentration and homoeostasis model assessment of insulin resistance (HOMA-IR); with the exception of ORAC, dietary TAC was also inversely related to 120-min glucose concentration. There were no associations with fasting glucose or 120-min insulin concentrations. In women, with the exception of the association between ORAC and 120-min insulin concentration, dietary TAC estimated by all assays showed consistent inverse associations with fasting and 120-min glucose and insulin concentrations and HOMA-IR. These associations were more marked among women with BMI ≥ 30 kg/m(2). CONCLUSION: These findings suggest dietary TAC may have important protective effects on glucose tolerance, especially in older obese women.

Insulin-requiring diabetes in rural Ethiopia: should we reopen the case for malnutrition-related diabetes?

AIMS/HYPOTHESIS: We evaluated the incidence of insulin-requiring diabetes in a rural area of sub-Saharan Africa. METHODS: Health surveillance data from a chronic disease programme in two zones of Ethiopia, Gondar and Jimma, were studied. The two zones have a population of more than 5,000,000 people. RESULTS: In Gondar Zone (1995-2008) and Jimma Zone (2002-2008) 2,280 patients presented with diabetes, of whom 1,029 (45%) required insulin for glycaemic control at diagnosis. The annual incidence of insulin-requiring diabetes was 2.1 (95% CI 2.0-2.2) per 100,000 and was twice as high in men (2.9 per 100,000) as in women (1.4 per 100,000). In both sexes incidence rates peaked at the age of 25 to 29 years. Incidence rates in the urban areas of Gondar and Jimma were five times higher than in the surrounding rural areas. Patients with insulin-requiring diabetes from rural and urban areas had a very low BMI and most were subsistence farmers or unemployed. CONCLUSIONS/INTERPRETATION: The typical patient with diabetes in rural Ethiopia is an impoverished, young adult male with severe symptoms requiring insulin for glycaemic control. The low incidence rates in rural compared with urban areas suggest that many cases of this disease remain undiagnosed. The disease phenotype encountered in this area of Africa is very different from the classical type 1 diabetes seen in the West and most closely resembles previous descriptions of malnutrition-related diabetes, a category not recognised in the current WHO Diabetes Classification. We believe that the case for this condition should be reopened.

The relationship between depression and diabetes mellitus: findings from the Hertfordshire Cohort Study.

AIMS: To assess the relationship between depression scores and diabetes, glucose and insulin in a cross-sectional population-based study. METHODS: One thousand, five hundred and seventy-nine men and 1418 women from the Hertfordshire Cohort Study were assessed for diabetes. Plasma glucose and insulin concentrations were measured at 0, 30 and 120 min during a standard 75-g oral glucose tolerance test. Depressive and anxiety symptoms were measured using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Overall, 431 (14.6%) were diagnosed with diabetes [232 men (14.9%) and 199 women (14.3%)]. One hundred and eight (47%) men and 74 (37%) women had known diabetes. The remainder were previously undiagnosed. Fifty-nine (3.7%) men and 65 (4.6%) women had possible depression (HAD-D scores 8-10) and 17 (1.1%) men and 20 (1.4%) women had probable depression (HAD-D scores > or = 11). Probable depression was associated with an adjusted odds ratio for diabetes of 3.89 [95% confidence interval (CI) 1.28-11.88] in men and 1.51 (95% CI 0.47-4.84) in women. In men without previously diagnosed diabetes, fasting insulin (P = 0.035), 2-h glucose concentrations (P = 0.028) and insulin resistance (P = 0.032) were significantly associated with HAD-D scores. With the exception of 2-h glucose concentrations (P = 0.034), the associations were not significant in women. CONCLUSIONS: These data support the hypothesis that depression may increase the risk for diabetes. The relationship between depression score and metabolic variables extends across the whole population and is not confined to those with either diagnosed depression or diabetes. This relationship should lead clinicians to consider screening for diabetes in those with depression and vice versa.

Non-communicable disease clinics in rural Ethiopia: why patients are lost to follow-up.

BACKGROUND: Providing medical care for non-communicable diseases (NCDs) in rural sub-Saharan Africa has proved to be difficult because of poor treatment adherence and frequent loss to follow-up (LTFU). The reasons for this are poorly understood. OBJECTIVE: To investigate LTFU among patients with two different but common NCDs who attended rural Ethiopian health centres. METHOD: The study was based in five health centres in southern Ethiopia with established NCD clinics run by nurses and health officers. Patients with epilepsy or hypertension who were lost to follow-up and non-LTFU comparison patients were identified and traced; a questionnaire was administered enquiring about the reasons for LTFU. RESULTS: Of the 147 LTFU patients successfully located, 62 had died, moved away or were attending other medical facilities. The remaining 85 patients were compared with 211 non-LFTU patients. The major factors associated with LTFU were distance from the clinic, associated costs and a preference for traditional treatments, together with a misunderstanding of the nature of NCD management. CONCLUSIONS: The delivery of affordable care closer to the patients' homes has the greatest potential to address the problem of LTFU. Also needed are increased levels of patient education and interaction with traditional healers to explain the nature of NCDs and the need for life-long management.

Childhood growth and cardiovascular reactivity to psychological stressors in late adulthood.

OBJECTIVE: Specific childhood growth patterns relate to risk of cardiovascular (CV) disease later in life, but the underlying mechanisms are unclear. We studied whether CV reactivity, a predictor of CV disease risk, is associated with childhood growth trajectories. METHODS: A total of 144 (77 women and 67 men) participants of the Helsinki Birth Cohort Study born 1934-1944, whose height and weight were recorded repeatedly during the first 11 years, underwent the Trier Social Stress Test at the average age of 63 years. Beat-to-beat blood pressure was monitored via noninvasive finger photoplethysmograph (Finometer), and CV reactivity scores were determined as the mean increment from baseline. RESULTS: In both women and men, systolic blood pressure (SBP) reactivity increased by 3.8 mmHg (95% CI 0.8-6.9) and diastolic BP (DBP) reactivity by 1.4 mmHg (95% CI 0.0-2.8) for every standard deviation increase in gain in body mass index (kg m(-2)) between 7 and 11 years. By contrast, effects of height gain were dissimilar between sexes. In women, higher DBP reactivity was associated with a slow gain in height between 0 and 2 years, whilst in men higher SBP reactivity was associated with a slow gain in height between 2 and 7 years, which was preceded by a more rapid gain in height between 0 and 2 years. Adjusting for adult body size, body size at birth or childhood socio-economic status did not change the results. CONCLUSIONS: We found that growth during childhood is associated with CV reactivity to stress later in adulthood. Early life programming of CV reactivity may partly underlie the link between early growth and CV disease.

Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.

OBJECTIVE: Maternal undernutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. We investigated whether these effects may persist in subsequent generations. DESIGN: Historical cohort study. SETTING: Interview during a clinic or home visit or by telephone. POPULATION: Men and women born in the Wilhelmina Gasthuis in Amsterdam between November 1943 and February 1947. METHODS: We interviewed cohort members (F1) born around the time of the 1944-45 Dutch famine, who were exposed or unexposed to famine in utero, about their offspring (F2). MAIN OUTCOME MEASURES: Birthweight, birth length, ponderal index and health in later life (as reported by F1) of the offspring (F2) of 855 participating cohort members, according to F1 famine exposure in utero. RESULTS: F1 famine exposure in utero did not affect F2 (n = 1496) birthweight, but, among the offspring of famine-exposed F1 women, F2 birth length was decreased (-0.6 cm, P adjusted for F2 gender and birth order = 0.01) and F2 ponderal index was increased (+1.2 kg/m(3), P adjusted for F2 gender and birth order = 0.001). The association remained unaltered after adjusting for possible confounders. The offspring of F1 women who were exposed to famine in utero also had poor health 1.8 (95% CI 1.1-2.7) times more frequently in later life (due to miscellaneous causes) than that of F1 unexposed women. CONCLUSIONS: We did not find transgenerational effects of prenatal exposure to famine on birthweight nor on cardiovascular and metabolic disease rates. F1 famine exposure in utero was, however, associated with increased F2 neonatal adiposity and poor health in later life. Our findings may imply that the increase in chronic disease after famine exposure in utero is not limited to the F1 generation but persists in the F2 generation.

Association of adult height and leg length with fasting plasma cortisol concentrations: evidence for an effect of normal variation in adrenocortical activity on growth.

We have evaluated the relationship between activity of the hypothalamic-pituitary-adrenal (HPA) axis and adult height in adults recruited from the UK Hertfordshire Cohort Study. In a sample of 1,354 individuals, we found that height fell by 0.67 cm (95% CI 0.34-1.0) per SD (114 nmol/l) increase in fasting plasma cortisol concentrations. The association was continuous across the range of cortisol concentrations and was independent of the levels of corticosteroid binding globulin. It was of similar magnitude in men and women. In a subsample of the study available data on standing and sitting height was used to estimate trunk and leg length. Fasting plasma cortisol concentrations were found to have a much greater impact on leg length than trunk length. These findings suggest that physiological variations in adrenocortical glucocorticoid secretion in humans affect adult height. They also raise the possibility that the HPA axis may be involved in mediating resource allocation decisions and trade-offs during development perhaps by limiting physical growth to enable other competing processes.

Grip strength and the metabolic syndrome: findings from the Hertfordshire Cohort Study.

INTRODUCTION: Sarcopenia, the loss of muscle mass and strength with age, is significantly associated with type 2 diabetes in older people. AIM: To determine whether there is a relationship between grip strength and features of the metabolic syndrome. DESIGN: Cross-sectional study. METHODS: Data were collected on grip strength, fasting glucose, triglycerides and HDL cholesterol, blood pressure, waist circumference and 2 h glucose after an oral glucose tolerance test, in a population-based sample of 2677 men and women aged 59-73 years. RESULTS: In men and women combined, a standard deviation (SD) decrease in grip strength was significantly associated with higher: fasting triglycerides (0.05 SD unit increase, 95%CI 0.02-0.09, p = 0.006); blood pressure (OR 1.13, 95%CI 1.04-1.24, p = 0.004); waist circumference (0.08 SD unit increase, 95%CI 0.06-0.10, p < 0.001); 2 h glucose (0.07 SD unit increase, 95%CI 0.03-0.11, p = 0.001) and HOMA resistance (0.05 SD unit increase, 95%CI 0.01-0.09, p = 0.008), after adjustment for gender, weight, age, walking speed, social class, smoking habit and alcohol intake. Lower grip strength was also significantly associated with increased odds of having the metabolic syndrome according to both the ATPIII (OR 1.18, 95%CI 1.07-1.30, p < 0.001) and IDF definitions (OR 1.11, 95%CI 1.01-1.22, p = 0.03). DISCUSSION: Our findings suggest that impaired grip strength is associated with the individual features, as well as with the overall summary definitions, of the metabolic syndrome. The potential for grip strength to be used in the clinical setting needs to be explored.

Cardiovascular reactivity to psychological stressors in late adulthood is predicted by gestational age at birth.

The relationships of body size and gestational age at birth with adult blood pressure (BP) are relatively modest compared to their stronger associations with cardiovascular disease. BP reactivity is a strong predictor of cardiovascular morbidity, and it is possible that reactivity, rather than resting level, is determined in utero. We investigated whether body size and gestational age at birth predict BP reactivity during experimentally induced psychosocial stress in late adulthood. A total of 73 men and 80 women born after 36 weeks' gestation in Helsinki, Finland, during 1934-1944 underwent the Trier Social Stress Test (TSST); a standardized psychosocial stress test consisting of a public speech and an arithmetic task. Changes in BP were monitored continuously by a non-invasive finger photoplethysmography (Finometer, FMS, Amsterdam, The Netherlands). The results showed that the most robust early determinant of BP reactivity was gestational age; however, with opposite relationships between the sexes (P for interaction <0.001). A 1-week increase in gestational age was associated with a 3.1 mm Hg (95% confidence interval (CI), 0.2 to 6.0) and 1.2 mm Hg (95% CI, -0.1 to 2.6) decreases in systolic and diastolic BP reactivity in women, but with 5.2 mm Hg (95% CI, 1.9 to 8.4) and 2.3 mm Hg (95% CI, 0.9 to 3.8) increases in men. In conclusion, normal variation in gestational age at birth predicts cardiovascular stress reactivity in later adulthood. Given that hypothalamic-pituitary-adrenal axis contributes to the regulation of autonomic nervous system function and the timing of parturition, and shows well-established sex differences, we speculate a role for early programming of this axis in explaining the findings.

Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits.

BACKGROUND: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated. METHOD: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits. RESULTS: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant. CONCLUSIONS: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.

Investigating the role of the growth hormone-insulin-like growth factor (GH-IGF) axis as a determinant of male bone mineral density (BMD).

INTRODUCTION: The GH-IGF axis has profound effects on bone metabolism and may be important in the etiology of idiopathic osteoporosis. Serum IGF-I is often low in men with osteoporosis, which may be attributable to GH hypo-secretion or hepatic GH insensitivity. We studied the GH-IGF axis in depth to look for evidence to support these hypotheses. MATERIALS AND METHODS: 28 healthy 60- to 70-year-old men with low, intermediate, or normal BMD were studied. GH secretion was measured by overnight urine collection. GH reserve was assessed by exercise and glucagon stimulation tests. Hepatic IGF-I production was investigated using a GH-IGF-I generation test. Data were analyzed using Pearson's correlation coefficient, linear regression, and analysis of variance. RESULTS: Serum IGF-I was reduced in subjects with low BMD (P = 0.009). There was no difference in GH secretion or reserve between the groups. Overall, GH reserve and IGF-I were positively related but this was attenuated in the low BMD group. However, no statistically significant difference in IGF-I generation capacity between BMD groups was found. CONCLUSIONS: Men with reduced BMD have low IGF-I but normal GH secretion and reserve. Our data suggested, but could not confirm, hepatic resistance to GH as a mechanism for this association.

Birth weight and the future development of diabetes. A review of the evidence.

Recent studies in Europe, North America, and the developing world have shown that low birth weight and other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of glucose intolerance and NIDDM in adult life. Reduced fetal growth is also associated with a higher prevalence of the metabolic syndrome (in particular, hypertension and vascular disease) and with insulin resistance in adult life. Because birth size is determined largely by nongenetic factors, these findings have led to the "fetal origins" hypothesis, which proposes that fetal adaptations to an adverse intrauterine environment that reduces fetal growth program lifelong physiological changes. These changes in turn predispose to diabetes and the metabolic syndrome. The mechanisms are unknown, but evidence from animal studies and preliminary human evidence suggests that adverse events in early life may influence the neuroendocrine development of the fetus. This results in long-term alterations in the setpoint of several major hormonal axes, including an increase in adrenal glucocorticoid secretion. These hormonal alterations may contribute to the predisposition to diabetes and the metabolic syndrome in people who were small at birth.

David Barker, Buruli ulcer and the epidemiology of a neglected tropical disease.

In 1969, David Barker, his wife and four children moved to Uganda to work at Makerere Medical School in the capital Kampala. During the 1960s, Makerere had become a research and teaching centre with an international reputation based on the work of Trowell, Burkitt, Hutt and many others who had pioneered studies explaining the disease patterns in the West Nile area on the basis of the local climate, nutrition and lifestyle. David Barker was funded by the Medical Research Council to carry out research on a poorly understood disease, Buruli ulcer, joining Scottish surgeon Wilson Carswell, who was later to achieve fame as the role model for Dr Garrigan in Giles Foden's novel The Last King of Scotland.

Obesity and gender influence cortisol secretion and metabolism in man.

In obesity, urinary cortisol excretion is enhanced but plasma cortisol levels are not elevated, suggesting that metabolic clearance of cortisol is increased. Cortisol is metabolised in liver and fat by A-ring reductases but also regenerated from inactive cortisone in liver, fat, and skeletal muscle by 11 beta-reductase. These enzymes are regulated by estrogen. This study addressed whether there are differences in cortisol metabolism in obesity, and whether these differences are estrogen dependent. 31 men and 37 post-menopausal women (9 on estrogen replacement therapy) aged 47-53 y supplied 24 h urine for gas chromatography/mass spectrometry. Total cortisol metabolite excretion was higher in men than women, but weakly related to indices of obesity. By contrast, metabolism of cortisol favoured 5 alpha-rather than 5 beta-reduction in obese men and obese women, and favoured cortisol rather than cortisone in obese men. In women compared with men ratios of 5 alpha-/5 beta-reduced and cortisol/cortisone metabolites were also higher but these variables were not affected by estrogen replacement therapy. We conclude that in obesity, inactivation of cortisol by 5 alpha-reductase is enhanced but this is offset by impaired metabolism of cortisol by 5 beta-reductase in women and enhanced conversion of cortisone to cortisol by 11 beta-reductase in men. These observations suggest that cortisol clearance is altered in obesity, and this may account for activation of the hypothalamic-pituitary-adrenal axis. Moreover, these data predict that obese subjects will have higher concentrations of cortisol in key target tissues including liver and visceral fat. This may contribute to the adverse metabolic consequences of obesity.

Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance?

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GRalpha and GRbeta) and 11beta-hydroxysteroid dehydrogenase type I (11betaHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GRalpha, GRbeta, and 11betaHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GRalpha and 11betaHSD1 under basal conditions. The apparent K(m) and maximum velocity for the conversion of cortisone to cortisol were 440 +/- 14 nmol/L and 75 +/- 7 pmol/mg protein.h and 437 +/- 16 nmol/L and 33 +/- 6 pmol/mg protein.h (mean +/- SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50-1000 nmol/L) resulted in a dose-dependent decline in GRalpha expression and a dose-dependent increase in GRbeta expression. 11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50-1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GRalpha, GRbeta, and 11betaHSD1 expression is mediated exclusively by the GRalpha ligand-binding variant. In contrast, 11betaHSD1 was down-regulated by insulin (20-100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11betaHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11betaHSD1 activity. Although neither testosterone nor androstenedione (5-200 nmol/L) affected 11betaHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11betaHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GRalpha, GRbeta, and 11betaHSD1 expression by the ligand-binding GRalpha isoform. Additionally, insulin and insulin-like growth factor I regulation of 11betaHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action.

Thyroid peroxidase autoantibody fingerprints in hypothyroid and euthyroid individuals. I. Cross-sectional study in elderly women.

Human monoclonal immunoglobulin G-class autoantibodies to thyroid peroxidase (TPO), expressed as recombinant F(ab), are powerful tools for analyzing the individual components of polyclonal serum TPO autoantibodies. Four TPO-specific F(ab) interact with epitopes in two closely related domains (A and B) in the immunodominant region on TPO. In the present study, these TPO F(ab) were used to compete for serum autoantibody binding to [125I]TPO to determine the "epitopic fingerprints" in two groups of carefully controlled individuals. All individuals (14 hypothyroid and 32 euthyroid) were elderly women (60-71 yr old) with similar genetic and environmental backgrounds as well as comparable levels of serum TPO autoantibodies. Using the pool of four F(ab), serum TPO autoantibody binding was inhibited to the same extent (approximately 90%) in hypothyroid and euthyroid individuals, demonstrating that the majority of TPO autoantibodies in both groups recognize the TPO immunodominant domain. When tested individually, the F(ab) produced a spectrum of inhibition patterns, ranging from sera preferentially inhibited by domain A F(ab) to sera preferential inhibited by domain B F(ab). The ratio of inhibition by domain A F(ab) to inhibition by domain B F(ab) was similar in hypothyroid (0.11-1.39) and euthyroid (0.21-1.79) women. In conclusion, no difference in TPO autoantibody epitopes was observed in this cross-sectional study of hypothyroid and euthyroid individuals. Longitudinal studies are required to address the question of whether TPO autoantibody epitopic fingerprints are stable over time.

Elevated plasma cortisol in glucose-intolerant men: differences in responses to glucose and habituation to venepuncture.

Recent evidence suggests that variations in cortisol activity within the physiological range contribute to associations between multiple cardiovascular risk factors. Plasma cortisol measurements during a glucose tolerance test differ in men with hypertension, insulin resistance, and glucose intolerance, but it is unclear whether this reflects altered responses of cortisol to glucose, altered circadian rhythm, or altered habituation to multiple sampling. We performed a single-blind randomized cross-over study comparing 75 g oral glucose with placebo in 39 fasted men (22 glucose intolerant and 17 controls) aged 68-77 yr. In all subjects, plasma cortisol fell during the glucose tolerance test. Subjects with glucose intolerance had significantly higher plasma cortisol following placebo (P = 0.001), suggesting an altered circadian rhythm. Treatment with an oral glucose load blunted the circadian fall in plasma cortisol (P = 0.002), but this response was no different in controls or glucose intolerant subjects. In addition, 0900 h plasma cortisol was higher in the first study phase in controls (P = 0.01) but not in glucose-intolerant subjects (P = 0.18), who showed a lack of habituation to repeated plasma measurements. These data support the hypothesis that alterations in central regulation of the hypothalamic-pituitary-adrenal axis may be important in glucose intolerance.