A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes.

AIMS/HYPOTHESIS: Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). METHODS: We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n = 911) or type 1 diabetes (n = 406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n = 4,002). RESULTS: Variants in the ZMIZ1 (rs12571751, p = 4.1 × 10(-5)) and TCF7L2 (rs7903146, p = 5.8 × 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p = 0.0012), HHEX (rs1111875, p = 0.0024 in Finns) and MTNR1B (rs10830963, p = 0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p = 9.5 × 10(-4) in Finns), TP53INP1 (rs896854, p = 0.005), CDKAL1 (rs7756992, p = 7.0 × 10(-4); rs7754840, p = 8.8 × 10(-4)) and PROX1 (rs340874, p = 0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p = 3.2 × 10(-6)) and HNF1A (rs2650000, p = 0.0012). CONCLUSIONS/INTERPRETATION: LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.

Foetal and childhood growth and asthma in adult life.

AIM: Recent research suggests that asthma may originate through defects in the airway epithelium, acquired in utero, and an altered response to infections after birth. Here, we examine whether asthma in adult life is associated with reduced body size at birth and poor living conditions in childhood. METHODS: We studied 658 people taking medication for asthma in a cohort of 13 345 men and women born in Helsinki, Finland, during 1934-1944. Their body and placental size at birth, and their living conditions and growth in childhood, had been recorded. RESULTS: The odds ratios for asthma were 0.93 (95% CI 0.89-0.97, p = 0.001) per cm increase in birth length and 0.92 (0.89-0.96, p < 0.001) per cm increase in the length of placental surface. After allowing for size at birth, growth during childhood was unrelated to asthma. People who were born into families of low socio-economic status were at increased risk of later asthma. CONCLUSION: Slow linear growth in utero, which could be a result of impaired placentation, increases the risk of later asthma. Slow linear growth may be associated with impaired development of the airways. Babies with impaired lung development born into families of low socio-economic status may be most vulnerable to the disease.

Prenatal and childhood growth and leisure time physical activity in adult life.

BACKGROUND: Physical activity plays an important role in prevention of chronic diseases. Animal studies have suggested that lifestyle and exercise habits may have a prenatal origin. Our aim was to assess the role of early growth on leisure time physical activity (LTPA) in later life among 57-70-years-old men and women. METHODS: We examined 2003 individuals born in Helsinki, Finland between 1934 and 1944. Of them, 1967 individuals with adequate information on their LTPA in adult life were included in this study. LTPA was assessed by a validated exercise questionnaire (KIHD Study 12 month physical activity history). Subjects' birth and serial growth measurements were obtained from birth, child welfare and school health records. RESULTS: Participants with higher engagement in LTPA showed a more favourable adult anthropometric and body composition profile than those who were less active. LTPA was positively associated with adult social class. Higher weight and length at birth, and weight at 2 years after adult BMI adjustment, predicted higher intensity of total LTPA (P = 0.04, P = 0.01 and P = 0.03), respectively. Higher height at 2, 7 and 11 years predicted higher intensity of conditioning LTPA (P = 0.01, P = 0.04 and P = 0.004). Higher weight and height at 2, 7 and 11 years predicted higher energy expenditure (EE) of total LTPA (P-values being from 0.01 to 0.03). Furthermore, higher height at 2 and 11 years predicted higher EE of conditioning LTPA (P = 0.02 and P = 0.03). CONCLUSION: People who as children were taller and weighed more engage more in leisure time physical activity in late adulthood.

Prenatal origins of hospitalization for personality disorders: the Helsinki birth cohort study.

Although a suboptimal prenatal environment has been linked with schizophrenia and depression, possible associations with personality disorders remain unclear. The aim of this study was to examine the associations of body size at birth and length of gestation with hospitalization for personality disorders in a cohort study of 6506 men and 5857 women born in Helsinki, Finland, between 1934 and 1944. International Classification of Diseases (-8, -9, -10) diagnoses of personality disorders were extracted from the national Finnish Hospital Discharge Register since 1969. 102 men and 80 women had been hospitalized due to any personality disorder. 41 men and 30 women had dramatic personality disorders. Among men, head circumference showed an inverse J-shaped, nonlinear association with hospitalization for personality disorders. Men with a small head circumference were at increased risk. Also in men, a smaller head-to-length ratio linearly predicted personality disorders. Among women, a smaller placental area predicted increased risk of hospitalization for dramatic personality disorders. Vulnerability to personality disorders may be programmed during fetal life.

Health behaviour among bilingual Swedish speaking patients in the Finnish healthcare setting.

OBJECTIVE: We assessed the prevalence and consequences of discordant language communication between bilingual Swedish speaking emergency patients and general practitioners (GPs) in Finnish healthcare. We compared the results with Finnish speaking emergency patients provided with language concordant healthcare. MATERIALS AND METHODS: A researcher-designed questionnaire was used to collect data about both Swedish and Finnish speaking emergency patients' health and socioeconomic status, reason for emergency visits and use of healthcare. Furthermore, the Swedish speakers' nonnative language proficiency and preferred communication language were examined. The study was performed in 16 healthcare centers and outpatient departments in bilingual regions in Finland. RESULTS: The Swedish speakers (n = 139) visited healthcare centers less than the Finnish speakers (n = 736) (P = 0.001) and communicated less frequently with the GP in their native language (P < 0.001). The Swedish speakers more often planned to revisit their assigned GP (P < 0.001) after the emergency visit. No differences in health conditions and socioeconomic status between the language groups were observed. CONCLUSION: Although Swedish and Finnish speaking emergency patients report a similar prevalence of chronic noncommunicable diseases, Swedish speakers make fewer annual visits to a physician. We suggest that discordant language communication might relate to decreased healthcare visits among bilingual Swedish speaking emergency patients.

Growth trajectories and intellectual abilities in young adulthood: The Helsinki Birth Cohort study.

Slow childhood growth is associated with poorer intellectual ability. The critical periods of growth remain uncertain. Among 2,786 Finnish male military conscripts (1952-1972) born in 1934-1944, the authors tested how specific growth periods from birth to age 20 years predicted verbal, visuospatial, and arithmetic abilities at age 20. Small head circumference at birth predicted poorer verbal, visuospatial, and arithmetic abilities. The latter 2 measures were also associated with lower weight and body mass index (weight (kg)/height (m)(2)) at birth (for a 1-standard-deviation (SD) decrease in test score per SD decrease in body size > or = 0.05, P's < 0.04). Slow linear growth and weight gain between birth and age 6 months, between ages 6 months and 2 years, or both predicted poorer performance on all 3 tests (for a 1-SD decrease in test score per SD decrease in growth > or = 0.05, P's < 0.03). Reduced linear growth between ages 2 and 7 years predicted worse verbal ability, and between age 11 years and conscription it predicted worse performance on all 3 tests. Prenatal brain growth and linear growth up to 2 years after birth form a first critical period for intellectual development. There is a second critical period, specific for verbal development, between ages 2 and 7 years and a third critical period for all 3 tested outcomes during adolescence.

Trajectories of growth among children who have coronary events as adults.

BACKGROUND: Low birth weight is a risk factor for coronary heart disease. It is uncertain how postnatal growth affects disease risk. METHODS: We studied 8760 people born in Helsinki from 1934 through 1944. Childhood growth had been recorded. A total of 357 men and 87 women had been admitted to the hospital with coronary heart disease or had died from the disease. Coronary risk factors were measured in a subset of 2003 people. RESULTS: The mean body size of children who had coronary events as adults was below average at birth. At two years of age the children were thin; subsequently, their body-mass index (BMI) increased relative to that of other children and had reached average values by 11 years of age. In simultaneous regressions, the hazard ratios associated with a 1 SD increase in BMI were 0.76 (95 percent confidence interval, 0.66 to 0.87; P<0.001) at 2 years and 1.14 (95 percent confidence interval, 1.00 to 1.31; P=0.05) at 11 years among the boys. The corresponding figures for the girls were 0.62 (95 percent confidence interval, 0.46 to 0.82; P=0.001) and 1.35 (95 percent confidence interval, 1.02 to 1.78; P=0.04). Low BMI at 2 years of age and increased BMI from 2 to 11 years of age were also associated with raised fasting insulin concentrations (P<0.001 for both). CONCLUSIONS: On average, adults who had a coronary event had been small at birth and thin at two years of age and thereafter put on weight rapidly. This pattern of growth during childhood was associated with insulin resistance in later life. The risk of coronary events was more strongly related to the tempo of childhood gain in BMI than to the BMI attained at any particular age.

Infant growth and hostility in adult life.

OBJECTIVE: Hostility may confer a risk of cardiovascular disease and all-cause mortality, but why is uncertain. A common origin in suboptimal fetal and early postnatal life may lie beneath. This study tested whether prenatal and postnatal growth predicts hostility in adult life. METHODS: Women (n = 939) and men (n = 740) born in Helsinki, Finland, from 1934 through 1944 filled out the Cook-Medley Hostility Scale at an average age of 63.4 years. Growth was estimated from birth, child welfare clinic, and school records. Adult body size was measured in a clinic. RESULTS: Men and women who had higher levels of hostility in adulthood were born lighter and thinner, showed slower weight gain from birth to 6 months of age, were lighter throughout childhood (standardized regression coefficients (beta) <-0.05; 95% confidence intervals (95% CI), -0.14 to -0.00; p values <.05), but were heavier in adulthood (beta values > 0.06; 95% CIs, 0.02-0.14; p values <.01). They were also shorter from 6 months until the age of 1 year (beta values <-0.09; 95% CIs, -0.14 to -0.03; p values <.003), and tended to be shorter in adulthood (beta = -0.05; 95% CI, -0.09 to 0.00; p = .06). The latter effects were largely attributable to slower growth in stature from birth to 6 months (beta = -0.08; 95% CI, -0.14 to -0.02; p = .005). The associations were not explained by major confounders. CONCLUSIONS: Our study suggests that slow prenatal and infant growth is linked with hostility in adult life.

Body size at birth and socio-economic status in childhood: implications for Cloninger's psychobiological model of temperament at age 60.

Small birth size predicts various psychiatric outcomes, including depression. While biologically based temperamental traits may constitute a vulnerability factor for depression, the extent to which birth size predicts these traits in adulthood is not known. We studied, in 1369 women and men identified from a cohort born in 1934-44 in Helsinki, Finland, whether birth size predicts the temperamental traits measured with Cloninger's Tridimensional Personality Questionnaire at an average age of 63 years. Moreover, we examined whether socio-economic status (SES) in childhood modified the associations. Data on birth size were obtained from birth records, and SES in childhood was obtained from school records. Weight and length at birth showed curvilinear, reverse J-shaped effects on harm avoidance (HA), such that the highest HA scores were most characteristic of those born small. Furthermore, high HA was confined to those belonging to a low SES group in childhood regardless of birth size, and to those belonging to the high SES group in childhood if their birth size was small. The associations were independent of several confounders. Since small birth size as well as high HA in adulthood may associate with subsequent depression, our findings might shed light on understanding the early neurodevelopmental processes that predispose to depression through vulnerability characteristics.

Reproductive traits following a parent-child separation trauma during childhood: a natural experiment during World War II.

Given the ethical limitations of exposing children to experimentally manipulated adverse experiences, evidence of the effects of childhood traumas on subsequent life history are based mostly on women's retrospective reports and animal studies. Only a few prospective studies have assessed the life-long consequences of childhood trauma. We asked whether a traumatic separation from both parents during childhood is associated with reproductive and marital traits later in life, measured by age of onset of menarche, timing of menopause, period of fertile years, age at first childbirth, birth spacing, number of children, and history of divorce. We studied members of the 1934-1944 Helsinki Birth Cohort, including 396 former war evacuees from varying socioeconomic backgrounds, who were sent unaccompanied by their parents to temporary foster families in Sweden and Denmark, and 503 participants who had no separation experiences. Data on separation experiences, number of children, and divorces experienced came from national registers, and the remaining data from a survey among the participants aged 61.6 years (SD = 2.9). Former evacuees had earlier menarche, earlier first childbirth (men), more children by late adulthood (women), and shorter interbirth intervals (men), than the non-separated. A traumatic experience in childhood is associated with significant alterations in reproductive and marital traits, which characterize both women and men. The implications are relevant to the 9.2 million child refugees living throughout the world today.

Birth weight and risk of type 2 diabetes: a systematic review.

CONTEXT: Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. OBJECTIVE: To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. DATA SOURCES AND STUDY SELECTION: Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. DATA EXTRACTION: Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. DATA SYNTHESIS: Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. CONCLUSION: In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Pain assessment in native and non-native language: difficulties in reporting the affective dimensions of pain.

Background and aims The language in assessing intensity or quality of pain has been studied but the results have been inconsistent. The physicians' language skills might affect the estimation of the severity of pain possibly leading to insufficient use of analgesics. Several interfering cultural factors have complicated studies aimed at exploring the language used to detect the quality of pain. We aimed to compare native and non-native language related qualitative aspects of pain chosen by Swedish speaking patients with diabetes. Methods In the study participated 10 Finnish and 51 Swedish speaking patients with diabetes. The Pain Detect-questionnaire was used for clarifying the patients' pain and the mechanism of their pain (neuropathic or not) and for assessing the intensity and quality of pain. In addition, the patients completed the short-form McGill Pain Questionnaire (sfMPQ) in Finnish (test I). After 30 min the subjects completed the sfMPQ a second time in their native language (test II). The Swedish speakers estimated their second language, Finnish, proficiency on a 5-graded scale. Results There were significantly more discrepancies between sfMPQ test I and test II among the Swedish speaking respondents who reported poor (hardly none) Finnish language proficiency compared with those with good Finnish proficiency. Discrepancies occurred especially between the affective qualities of pain. Conclusions Poor second language proficiency exposes Swedish speakers to pain communication difficulties related to the affective aspects of pain. Consequently, discordant language communication could cause underestimation of the severity of pain and pain undertreatment. Implications To ensure adequate pain treatment measuring the affective dimension of pain in the patient's native language is crucial.

Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables.

BACKGROUND: Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. METHODS: We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of ß-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. FINDINGS: We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. INTERPRETATION: We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. FUNDING: Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhälsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.

Infant growth and stroke in adult life: the Helsinki birth cohort study.

BACKGROUND AND PURPOSE: People who had low birth weight are at increased risk of stroke. Little is known about the effects of early postnatal growth on stroke risk. METHODS: We followed-up 12 439 people born in Helsinki during 1934 to 1944. Their body size was measured at birth and, on average, 9 times between birth and age 2 years; 507 of them were hospitalized with stroke or died from the disease. RESULTS: Hazard ratios for stroke declined progressively with increasing gain in weight between birth and age 2 years. The hazard ratio was 0.85 (95% CI, 0.78 to 0.93; P=0.0004) per standard deviation increase in the difference between the weight attained at age 2 years and that predicted from birth weight. A 1-standard deviation increase in body mass index at 2 years of age was associated with a hazard ratio for stroke of 0.84 (95% CI, 0.77 to 0.92; P=0.0002). This association was little changed by adjustment for measures of socio-economic status. Change in body size after the age of 2 years had little effect on the risk of later stroke. People whose mothers had a small external conjugate diameter of the pelvis had an increased risk of stroke. The hazard ratio associated with a diameter of < or =18 cm was 1.62 (95% CI, 1.30 to 2.02; P<0.0001). CONCLUSIONS: Thinness during infancy is associated with an increased risk of stroke in later life. This association may be the result of maternal influences which originated in the mother's infancy when her pelvic shape was established.

Depressive symptoms in adults separated from their parents as children: a natural experiment during World War II.

Despite the significance of childhood trauma for later life, there is little evidence on the long-term consequences of parent-child separation. World War II created a unique natural experiment that allowed the authors to test whether 1) evacuation to temporary foster care unaccompanied by either parent and 2) separation from the father because of his military service predicted depressive symptoms later on. Members of the Helsinki 1934-1944 Birth Cohort (n = 1,658) filled out the Beck Depression Inventory (BDI) at the ages of 61.6 (standard deviation: 2.9) and 63.4 (standard deviation: 2.9) years. The mean of the two BDI scores was used as the dependent variable. The data on separation experiences were extracted from the Finnish National Archives and from a survey among the participants. Former evacuees (n = 410) reported 20% (95% confidence interval: 8.7, 33.1) more severe depressive symptoms, and the odds ratio was 1.7 (95% confidence interval: 1.1, 2.6) for having at least mild (BDI score: > or =10) symptoms over time compared with those who were not separated. Those separated from their father because of the father's military assignment (n = 744) did not differ from those who were not separated.

Impact of hypoglycaemia on patient-reported outcomes from a global, 24-country study of 27,585 people with type 1 and insulin-treated type 2 diabetes.

AIMS: Data on the impact of hypoglycaemia on patients' daily lives and diabetes self-management, particularly in developing countries, are lacking. The aim of this study was to assess fear of, and responses to, hypoglycaemia experienced by patients globally. MATERIALS AND METHODS: This non-interventional, multicentre, 4-week prospective study using self-assessment questionnaires and patient diaries consisted of 27,585 patients, ≥18years, with type 1 diabetes (n=8022) or type 2 diabetes (n=19,563) treated with insulin for >12months, at 2004 sites in 24 countries worldwide. RESULTS: Increased blood glucose monitoring (69.7%) and seeking medical assistance (62.0%) were the most common responses in the 4weeks following hypoglycaemic events for patients with type 1 diabetes and type 2 diabetes, respectively. Approximately 44% of patients with type 1 diabetes or type 2 diabetes increased calorie intake in response to a hypoglycaemic episode. Following hypoglycaemia, 3.9% (type 1 diabetes) and 6.2% (type 2 diabetes) of patients took leave from work or study. Regional differences in fear of, and responses to, hypoglycaemia were evident - in particular, a lower level of hypoglycaemic fear and utilisation of healthcare resources in Northern Europe and Canada. CONCLUSIONS: Hypoglycaemia has a major impact on patients and their behaviour. These global data for the first time reveal regional variations in response to hypoglycaemia and highlight the importance of patient education and management strategies.

Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood.

BACKGROUND: The relationships of early growth with coronary heart disease and type 2 diabetes have received considerable attention. It is not known whether fetal or childhood growth is linked with autoimmune disorders. OBJECTIVE: Our objective was to assess whether the risk of adult-onset spontaneous hypothyroidism is predicted by body size at birth and during childhood. DESIGN AND SETTING: We conducted a birth cohort study in Helsinki, Finland. PARTICIPANTS: A total of 293 women who were born between 1934 and 1944 and had their heights and weights recorded at birth and during childhood participated in the study. MEASUREMENTS: We measured spontaneous hypothyroidism, defined as: 1) a disease history confirmed from medical records, or 2) previously undiagnosed hypothyroidism (TSH > 10 mU/liter). RESULTS: Twenty women (6.8%) had spontaneous hypothyroidism; 18 had been diagnosed previously, between 43 and 65 yr of age, and two had undiagnosed subclinical hypothyroidism. In addition, 59 women were thyroid peroxidase antibody positive. Compared with the 214 thyroid peroxidase antibody-negative women with no thyroid disorder, those with spontaneous hypothyroidism had on average 252 g [95% confidence interval (CI), 61 to 443 g; P = 0.01] lower birth weight and 1.2 cm (95% CI, 0.5 to 2.0 cm; P = 0.002) shorter length at birth. The odds of developing hypothyroidism increased 4.4-fold per kilogram decrease in birth weight (95% CI, 1.4 to 14.1). Hypothyroid subjects had been shorter in early childhood and had lower body mass index during later childhood. CONCLUSIONS: Small body size at birth and during childhood increases the risk of spontaneous hypothyroidism in adult women.

Associations of body size at birth with late-life cortisol concentrations and glucose tolerance are modified by haplotypes of the glucocorticoid receptor gene.

CONTEXT: Small body size at birth is associated with cardiovascular disease and type 2 diabetes in adult life. This link may be in part mediated by early-life programming of the hypothalamic-pituitary-adrenal axis (HPAA) function. OBJECTIVE: Our objective was to assess whether haplotypes of the glucocorticoid receptor (GR) gene modify this link. DESIGN AND PARTICIPANTS: We conducted a birth cohort study that included 437 men and women born in Helsinki, Finland, during 1924-1933, whose birth measurements were recorded. MAIN OUTCOME MEASURES: We studied how the oral glucose tolerance test and fasting plasma total and free cortisol concentrations and, in a subset of 162 women, a more detailed HPAA evaluation, are predicted by body size at birth and haplotypes of the GR locus. We also measured the haplotype-specific relative mRNA expression level for the haplotype of interest. RESULTS: One of the haplotypes was associated with lower birth weight and length and higher fasting plasma and mean 24-h salivary cortisol. Moreover, this haplotype modified the association of length at birth with adult phenotypes; in carriers, short length at birth was associated with increased fasting plasma cortisol, cortisol/corticosteroid-binding globulin ratio, impaired glucose tolerance or diabetes [1 cm decrease corresponded to 1.36-fold odds ratio; 95% confidence interval (CI), 1.09-1.70; P = 0.007], and higher 120-min glucose (5.8%; 95% CI, 2.5-9.1%; P = 0.0007), but no association was seen in noncarriers (P for interaction was 0.06, 0.01, 0.02, and 0.01, respectively). The mRNA expression level of this haplotype was 93.7% (95% CI, 90.5-96.8%; P = 2.2 x 10(-4)) of the expression level of the other haplotypes. CONCLUSIONS: A common GR haplotype may contribute to and modify the association of short length at birth with adult glucose tolerance and HPAA function by a mechanism that affects regulation of GR expression.

Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.

Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.