Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study.

AIMS: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. METHODS: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged ≥18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for >12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. RESULTS: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. CONCLUSIONS: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Growth in childhood predicts hip fracture risk in later life.

UNLABELLED: The incidence of hip fracture was estimated in 6,370 women born in Helsinki between 1934 and 1944. Women in the lowest quarter of adiposity gain had an 8.2-fold increase in hip fracture risk compared with those in the highest quarter (p < 0.001). These data point to a relationship between childhood growth and fracture risk during later life. INTRODUCTION: Previous findings show that discordance between childhood increase in height and weight is associated with an increased risk of osteoporotic fractures during later life. METHODS: We studied 6,370 women born in Helsinki between 1934 and 1944. Each woman's birth weight and length at birth was recorded, as well as her height and weight through childhood. We identified the occurrence of hip fracture through the National Finnish Hospital discharge register. RESULTS: There were 49 hip fractures in the 6,370 women over 187,238 person-years of follow-up. Hip fracture was associated with increasing Z-scores for height between 1 and 12 years, not matched by a corresponding increase in weight. Therefore, reduction in the Z-score for body mass index was associated with increased risk of hip fracture. Women in the lowest quarter of change in Z-scores for body mass index had an 8.2-fold increase in hip fracture risk (95% CI 1.9 to 35), compared with those in the highest quarter (p < 0.001). CONCLUSION: Thinness in childhood is a risk factor for hip fracture in later life. This could be a direct effect of low fat mass on bone mineralization, or represent the influence of altered timing of pubertal maturation.

Prenatal growth, postnatal growth and trait anxiety in late adulthood - the Helsinki Birth Cohort Study.

OBJECTIVE: Trait anxiety may predispose to anxiety disorders and cardiovascular events. We tested whether prenatal growth or postnatal growth from birth to 11 years of age and in adulthood predict trait anxiety in late adulthood. METHOD: Women (n = 951) and men (n = 753) reported trait anxiety using the Spielberger Trait Anxiety Scale at an average age of 63.4 years and growth was estimated from records. RESULTS: Higher trait anxiety was predicted by smaller body size at birth, in infancy and in adulthood. Moreover, faster growth particularly from seven to 11 years of age and slower growth between 11 and 63 years predicted higher trait anxiety. CONCLUSION: We found a pattern of pre- and postnatal growth that predisposed to higher trait anxiety in late adulthood. This pattern resembles that found to increase the risk of cardiovascular events and, thus, points to a shared common origin in a suboptimal prenatal and childhood developmental milieu.

Childhood growth and future risk of the metabolic syndrome in normal-weight men and women.

AIM: The aim of this study was to examine the effects of early growth on the risk of developing the metabolic syndrome in normal-weight individuals. METHODS: We examined 2003 subjects born in Helsinki, Finland, between 1934 and 1944, focusing on 588 individuals who were normal weight (body mass index [BMI] less than or equal to 25 kg/m(2)). These subjects had a median of seven measurements of height and weight from birth to 2 years, and eight measurements from 2 to 11 years of age. The metabolic syndrome was defined according to the 2005 criteria of the International Diabetes Federation. RESULTS: Individuals with the metabolic syndrome were heavier, had higher mean BMI and higher body fat percentages than those without the syndrome. No differences were seen in body size at birth and at 2 years but, by the age of 7 years, those men who later developed the metabolic syndrome were thinner (P=0.01). Changes in BMI during infancy were predictive of the syndrome, with an OR of 0.57 (95% CI: 0.36-0.90) per one S.D. increase in BMI from birth to 2 years. In women, these associations paralleled those in men, but did not reach statistical significance. CONCLUSION: Among normal-weight men, those who developed the metabolic syndrome in adulthood had smaller gains in BMI during infancy and were thinner at age 7 years. These results support findings that early growth may play an important role in the development of the metabolic syndrome.

Role of childhood growth on the risk of metabolic syndrome in obese men and women.

AIM: Although obesity is the key characteristic of the metabolic syndrome, not all obese individuals develop the syndrome. Our aim was to identify characteristics of early growth that protect these individuals from the metabolic syndrome. METHODS: We examined 2003 subjects born in Helsinki, Finland, between 1934 and 1944. We focused on the 499 who were obese (BMI> or =30 kg/m(2)), 400 of whom had the metabolic syndrome according to IDF 2005 criteria. The subjects had a median of seven measurements of height and weight from birth to two years of age, and eight measurements from two to 11 years of age. RESULTS: Among obese individuals, those with the metabolic syndrome had a higher mean body mass index (BMI) and larger waist circumference than those who did not. The two groups were similar in body size at birth but, by two years of age, those who later developed the metabolic syndrome were lighter and thinner, and remained so up to age 11 years. The period when BMI changes were predictive of the syndrome was from birth to seven years. OR was 0.72 (95% CI: 0.57-0.92) per 1 S.D. increase in BMI from birth to two years and 0.63 (95% CI: 0.49-0.81) per 1 S.D. increase in BMI from two to seven years. CONCLUSION: Among obese individuals, those who develop the metabolic syndrome were lighter and thinner from the age of two to 11 years compared with those who did not. These findings support the importance of early childhood growth in determining the metabolic consequences of obesity.

Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood.

BACKGROUND: Nutritional factors in early life may contribute to the neurodevelopmental deficit in schizophrenia. This study explores the influence of maternal body size, size at birth, and childhood growth on future risk for schizophrenia. SUBJECTS AND METHODS: This population-based cohort study comprised births at Helsinki University Central Hospital in Helsinki, Finland, from 1924 to 1933. Prospective data from birth and school health records of 7086 individuals were collected and linked to the Finnish Hospital Discharge Register. RESULTS: Schizophrenia or schizoaffective disorder had been diagnosed in 114 individuals. A lower late-pregnancy maternal body mass index (BMI) increased the risk (odds ratio [OR], 1.09 per kilogram/meter(2); 95% confidence interval [CI], 1.02-1.17) for schizophrenia among the offspring. The risk of schizophrenia increased with low birth weight (OR, 1.48 per kilogram; 95% CI, 1.03-2.13), shortness at birth (OR, 1.12 per centimeter; 95% CI, 1.03-1.22), and low placental weight (OR, 1.22 per 100 g; 95% CI, 1.04-1.43). Schizophrenia cases were thinner than comparison subjects from 7 to 15 years of age. In a joint model comprising late-pregnancy maternal BMI, body size at birth, and childhood BMI, childhood BMI was an independent predictor of schizophrenia, whereas other factors exhibited attenuated effects. CONCLUSION: Indicators of intrauterine and childhood undernutrition are associated with an increased lifetime risk of schizophrenia.

Fetal origins of adult disease: strength of effects and biological basis.

BACKGROUND: Low birthweight has been consistently shown to be associated with coronary heart disease (CHD) and its biological risk factors. The effects of low birthweight are increased by slow infant growth and rapid weight gain in childhood. To quantify the importance of developmental processes in the genesis of CHD it is necessary to establish the impact of fetal, infant and childhood growth on major pathological events in later life-death, hospital treatment and the need for medication. METHODS: Longitudinal study of 13 517 men and women who were born in Helsinki University Hospital during 1924-1944, whose body sizes at birth and during childhood were recorded, and in whom deaths, hospital admissions, and prescription of medication for chronic disease are documented. RESULTS: The combination of small size at birth and during infancy, followed by accelerated weight gain from age 3 to 11 years, predicts large differences in the cumulative incidence of CHD, type 2 diabetes and hypertension. CONCLUSIONS: Coronary heart disease and type 2 diabetes may originate through two widespread biological phenomena-developmental plasticity and compensatory growth.

Growth in childhood and blood pressure in Finnish children.

The aims of this prospective cohort study were to monitor childhood blood pressure (BP) and cholesterol and link them to fetal and childhood growth. Of the 215 children recruited after delivery in a rural county of eastern Finland during 1981 and 1982, 180 (83.7%) stayed in the study until the age of seven. The measurements assessed were BP, serum cholesterol and anthropometry. Of the children originally in the highest BP quartile at the age of 6 months, 58% (systolic BP (SBP)) and 68% (diastolic BP (DBP)), respectively, remained in the same quartile until the age of 7 years; 53% (SBP) and 60% (DBP), respectively, remained in the same lowest quartile. Consequently, BP at 6 months correlated strongly with SBP (r=0.69, P < 0.001) and DBP (r=0.75, P < 0.001) at 7 years of age. Birth weight, ponderal index, placental weight and placental to birth weight ratio were not related to BP level during the follow-up. Weight at 1 year of age correlated positively with SBP (r=0.18-0.25, P=0.0008-0.0215) but not with DBP during the follow-up. Weight gain during the first year of life was directly related to subsequent SBP (r=0.11-0.22, P=0.005-0.16). There was an inverse relationship between serum cholesterol at 7 years of age and placental weight (r=-0.16, P=0.048) and placental to birth weight ratio (r=-0.16, P=0.045). The BP level is already determined at 1 year of age and a higher SBP is associated with a higher growth rate during the first year of life.

Resistance training improves the metabolic profile in individuals with type 2 diabetes.

Aerobic endurance exercise has traditionally been advocated in the treatment of type 2 diabetes, while the potential role of resistance training has often been overlooked. The aim of the present study was to determine the effect of circuit-type resistance training on blood pressure, lipids and long-term glycaemic control (HbAlc) in type 2 diabetic subjects. Thirty-eight type 2 diabetic subjects were enrolled in the study; 18 participated in a 5-month individualized progressive resistance training programme (moderate intensity, high volume) twice a week, while the remaining 20 served as controls. The exercise group showed improvements in total cholesterol (6.0 +/- .3 vs 5.3 +/- .3 mM; P < 0.01), low density lipoprotein (LDL)-cholesterol (3.90 +/- .22 vs 3.35 +/- .21 mM; P < 0.01) and triglycerides (1.91 +/- .25 vs 1.53 +/- .22 mM; P < 0.01). Also, the difference in the change in HbAlc between the groups (0.5%) achieved statistical significance (P < 0.01). Circuit-type resistance training seems to be feasible in moderately obese, sedentary type 2 diabetic subjects and the inclusion of circuit-type resistance training in exercise training programmes for type 2 diabetic subjects seems appropriate.

The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus.

A possible relationship between the pathogenesis of type 2 diabetes and coenzyme Q10 (CoQ10) deficiency has been proposed. The aim of this study was to assess the effect of CoQ10 on metabolic control in 23 type 2 diabetic patients in a randomized, placebo-controlled trial. Treatment with CoQ10 100 mg bid caused a more than 3-fold rise in serum CoQ10 concentration (p < 0.001). No correlation was observed between serum CoQ10 concentration and metabolic control. No significant changes in metabolic parameters were observed during CoQ10 supplementation. The treatment was well tolerated and did not interfere with glycemic control, therefore CoQ10 may be used as adjunctive therapy in patients with associated cardiovascular diseases.

Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study.

OBJECTIVE: To determine whether restricted growth in utero is associated with an increased risk of coronary heart disease are among men in Finland, where rates of the disease are among the highest in the world. DESIGN: Follow up study. SETTING: Helsinki, Finland. SUBJECTS: 3302 men born in Helsinki University Central Hospital during 1924-33 who went to school in the city of Helsinki and were resident in Finalnd in 1971. MAIN OUTCOME MEASURES: Standardised mortality ratios for coronary heart disease. RESULTS: Men who were thin at birth, with low placental weight, had high death rates from coronary heart disease. Men whose mothers had a high body mass index in pregnancy also had high death rates. In a multivariate analysis the hazard ratio for coronary heart disease was 1.37 (95% confidence interval 1.20 to 1.57) (P < 0.0001) for every standard deviation decrease in ponderal index at birth and 1.24 (1.10 to 1.39) (P = 0.0004) for every standard deviation increase in mother's body mass index. The effect of mother's body mass index was restricted to mothers of below average stature. CONCLUSION: These findings suggest a new explanation for the epidemics of coronary heart disease that accompany Westernisation. Chronically malnourished women are short and light and their babies tend to be thin. The immediate effect of improved nutrition is that women become fat, which seems to increase the risk of coronary heart disease in the next generation. With continued improvements in nutrition, women become taller and heavier; their babies are adequately nourished; and maternal fatness no longer increases the risk of coronary heart disease, which therefore declines.

Catch-up growth in childhood and death from coronary heart disease: longitudinal study.

OBJECTIVE: To examine whether catch-up growth during childhood modifies the increased risk of death from coronary heart disease that is associated with reduced intrauterine growth. DESIGN: Follow up study of men whose body size at birth was recorded and who had an average of 10 measurements taken of their height and weight through childhood. SETTING: Helsinki, Finland. SUBJECTS: 3641 men who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. MAIN OUTCOME MEASURES: Hazard ratios for death from coronary heart disease. RESULTS: Death from coronary heart disease was associated with low birth weight and, more strongly, with a low ponderal index at birth. Men who died from coronary heart disease had an above average body mass index at all ages from 7 to 15 years. In a simultaneous regression the hazard ratio for death from the disease increased by 14% (95% confidence interval 8% to 19%; P<0.0001) for each unit (kg/m3) decrease in ponderal index at birth and by 22% (10% to 36%; P=0.0001) for each unit (kg/m2) increase in body mass index at 11 years of age. Body mass index in childhood was strongly related to maternal body mass index, which in turn was related to coronary heart disease. The extent of crowding in the home during childhood, although related to body mass index in childhood, was not related to later coronary heart disease. CONCLUSION: The highest death rates from coronary heart disease occurred in boys who were thin at birth but whose weight caught up so that they had an average or above average body mass from the age of 7 years. Death from coronary heart disease may be a consequence of poor prenatal nutrition followed by improved postnatal nutrition.

Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study.

OBJECTIVE: To examine whether women who develop coronary heart disease have different patterns of fetal and childhood growth from men in the same cohort who develop the disease. DESIGN: Follow up study of women whose body size at birth was recorded and who had an average of 10 measurements of height and weight during childhood. SETTING: Helsinki, Finland. SUBJECTS: 3447 women who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. MAIN OUTCOME MEASURES: Hazard ratios for hospital admission for or death from coronary heart disease. Results Coronary heart disease among women was associated with low birth weight (P=0.08 after adjustment for gestation, P=0.007 after adjustment for placental weight) and was more strongly associated with short body length at birth (P=0.001 and P<0.0001, respectively). The hazard ratio for women developing coronary heart disease increased by 10.2% (95% confidence interval 4.3 to 15.7) for each cm decrease in length at birth. The effect of short length at birth was greatest in women whose height "caught up" after birth so that as girls they were tall. Such girls tended to have tall mothers. In contrast, men in the same cohort who developed the disease were thin at birth rather than short, showed "catch up" growth in weight rather than height, and their mothers tended to be overweight rather than tall. CONCLUSION: Coronary heart disease among both women and men reflects poor prenatal nutrition and consequent small body size at birth combined with improved postnatal nutrition and "catch up" growth in childhood. The disease is associated with reductions in those aspects of body proportions at birth that distinguish the two sexes-short body length in women and thinness in men.

Early growth and coronary heart disease in later life: longitudinal study.

OBJECTIVE: To determine how growth during infancy and childhood modifies the increased risk of coronary heart disease associated with small body size at birth. DESIGN: Longitudinal study. SETTING: Helsinki, Finland. SUBJECTS: 4630 men who were born in the Helsinki University Hospital during 1934-44 and who attended child welfare clinics in the city. Each man had on average 18.0 (SD 9.5) measurements of height and weight between birth and age 12 years. MAIN OUTCOME MEASURES: Hospital admission or death from coronary heart disease. RESULTS: Low birth weight and low ponderal index (birth weight/length(3)) were associated with increased risk of coronary heart disease. Low height, weight, and body mass index (weight/height(2)) at age 1 year also increased the risk. Hazard ratios fell progressively from 1.83 (95% confidence interval 1.28 to 2.60) in men whose body mass index at age 1 year was below 16 kg/m(2) to 1.00 in those whose body mass index was >19 (P for trend=0.0004). After age 1 year, rapid gain in weight and body mass index increased the risk of coronary heart disease. This effect was confined, however, to men with a ponderal index <26 at birth. In these men the hazard ratio associated with a one unit increase in standard deviation score for body mass index between ages 1 and 12 years was 1.27 (1.10 to 1.47; P=0.001). CONCLUSION: Irrespective of size at birth, low weight gain during infancy is associated with increased risk of coronary heart disease. After age 1 year, rapid weight gain is associated with further increase in risk, but only among boys who were thin at birth. In these boys the adverse effects of rapid weight gain on later coronary heart disease are already apparent at age 3 years. Improvements in fetal, infant, and child growth could lead to substantial reductions in the incidence of coronary heart disease.

Size at birth and resilience to effects of poor living conditions in adult life: longitudinal study.

OBJECTIVE: To determine whether men who grew slowly in utero or during infancy are more vulnerable to the later effects of poor living conditions on coronary heart disease. DESIGN: Follow up study of men for whom there were data on body size at birth and growth and social class during childhood, educational level, and social class and income in adult life. SETTING: Helsinki, Finland. PARTICIPANTS: 3676 men who were born during 1934-44, attended child welfare clinics in Helsinki, were still resident in Finland in 1971, and for whom data from the 1980 census were available. MAIN OUTCOME MEASURES: Hospital admission for or death from coronary heart disease. RESULTS: Men who had low social class or low household income in adult life had increased rates of coronary heart disease. The hazard ratio among men with the lowest annual income (<8400 pound sterling) was 1.71 (95% confidence interval 1.18 to 2.48) compared with 1.00 in men with incomes above 15, 700 pound sterling. These effects were stronger in men who were thin at birth (ponderal index <26 kg/m(3)): hazard ratio 2.58 (1.45 to 4.60) for men with lowest annual income. Among the men who were thin at birth the effects of low social class were greater in those who had accelerated weight gain between ages 1 and 12 years. Low social class in childhood further increased risk of disease, partly because it was associated with poor growth during infancy. Low educational attainment was associated with increased risk, and low income had no effect once this was taken into account. CONCLUSION: Men who grow slowly in utero remain biologically different to other men. They are more vulnerable to the effects of low socioeconomic status and low income on coronary heart disease.

Childhood socioeconomic status modifies the association between intellectual abilities at age 20 and mortality in later life.

BACKGROUND: People who score poorly in intellectual ability tests have shorter life expectancy. A study was undertaken to determine whether this association is different in people from different socioeconomic backgrounds. METHODS: The mortality of 2786 men born in Helsinki, Finland during 1934-1944 who, as military conscripts, underwent a standardised intellectual ability test comprising verbal, visuospatial and arithmetic reasoning subtests was studied. Mortality data came from the Finnish Death Register. RESULTS: Comparing men in the lowest and highest test score quartiles, HRs for all-cause mortality were 1.9 (95% CI 1.4 to 2.5) for verbal reasoning, 2.2 (95% CI 1.6 to 3.0) for visuospatial reasoning and 1.9 (95% CI 1.4 to 2.5) for arithmetic reasoning, corresponding to 2.6, 3.4 and 2.6 excess years of life lost, respectively. Associations were similar for cardiovascular and non-cardiovascular mortality. Intellectual ability scores were stronger predictors in men who grew up in middle-class families. Compared with middle-class men in the highest quartile of the visuospatial reasoning score, middle-class men in the lowest quartile lost 6.5 years of life while men from families of manual workers in the highest quartile lost 2.8 years and men in the lowest quartile lost 5.6 years. CONCLUSIONS: High intellectual ability in men aged 20 protects them from mortality in later life. This effect is stronger in men who grew up in middle-class families than in those who grew up in manual worker families. This finding suggests that early life conditions that are unfavourable to the development of cognitive abilities negate the life expectancy benefits of being born into a more affluent family.