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 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.

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.

Birth size, adult body composition and muscle strength in later life.

OBJECTIVE: Low birth weight has been linked to lower lean body mass and abdominal obesity later in life, whereas high birth weight has been suggested to predict later obesity as indicated by high body mass index (BMI). We examined how birth weight was related to adult body size, body composition and grip strength. DESIGN/SUBJECTS: Cross-sectional study on 928 men and 1075 women born in 1934-1944, with measurements at birth recorded. MEASUREMENTS: Height, weight, waist and hip circumference and isometric grip strength were measured. Lean and fat body mass were estimated by bioelectrical impedance with an eight-polar tactile electrode system. RESULTS: A 1 kg increase in birth weight corresponded in men to a 4.1 kg (95% CI: 3.1, 5.1) and in women to a 2.9 kg (2.1, 3.6) increase in adult lean mass. This association remained significant after adjustment for age, adult body size, physical activity, smoking status, social class and maternal size. Grip strength was positively related to birth weight through its association with lean mass. The positive association of birth weight with adult BMI was explained by its association with lean mass. Low birth weight was related to higher body fat percentage only after adjustment for adult BMI. Abdominal obesity was not predicted by low birth weight. CONCLUSIONS: Low birth weight is associated with lower lean mass in adult life and thus contributes to the risk of relative sarcopenia and the related functional inability at the other end of the lifespan. At a given level of adult BMI, low birth weight predicts higher body fat percentage.

Patterns of growth among children who later develop type 2 diabetes or its risk factors.

AIMS/HYPOTHESIS: We studied fetal and childhood growth patterns that are associated with IGT and type 2 diabetes in adult life. METHODS: We examined clinically 2,003 subjects born in Helsinki between 1934 and 1944. They had on average 11 measurements of height and weight between birth and 2 years of age, and seven measurements between 2 and 11 years of age. Glucose tolerance in adult life was assessed by a 75-g oral glucose tolerance test. RESULTS: We identified 311 subjects with type 2 diabetes and 496 with IGT. Both IGT and type 2 diabetes were associated with low birthweight (p < 0.0001 adjusting for current BMI). The risk of these conditions was increased by low weight gain between birth and 2 years. A 1 SD increase in weight at 2 years was associated with an odds ratio for either type 2 diabetes or IGT of 0.76 (95% CI 0.69-0.84). This effect was greatest in people who had low birthweight. Low growth in the first 6 months after birth was a critical period for the development of insulin resistance in later life; other critical periods were associated with slow fetal growth and rapid increase in BMI between age 2 and 11 years. CONCLUSIONS/INTERPRETATION: Low weight gain during infancy increases the risk of IGT and type 2 diabetes. The effect is greater in people who had low birthweight. The first 6 months after birth may be the most critical period for growth, in relation to development of glucose intolerance.

Infant growth and income 50 years later.

Among 4630 boys, irrespective of the social class into which they were born, those who grew slowly during infancy had poor educational achievements and had lower incomes than those who grew more rapidly. One interpretation of this is that biological processes linked to slow infant growth may lead to lifelong impairment of cognitive function.

The association between nutritional conditions during World War II and childhood anthropometric variables in the Nordic countries.

BACKGROUND: The purpose of the study was to examine the height and weight in Nordic children during the years around World War II (WWII), and compare them with the nutritional situation during the same period. METHODS: Information on food consumption and energy intake were obtained from the literature. Anthropometric data were collected from the Nordic capitals and cover the period from 1930 to 1960 for ages 7-13 years. RESULTS: The greatest energy restriction took place in Norway (20%), followed by Finland (17%), while Sweden and Denmark had a restriction of 4-7% compared to pre-war levels. The most pronounced effect of WWII on height and weight is seen in Norwegian children, while some effect is observed for the youngest children in Finland. Little or no effect is seen in Sweden and Denmark. CONCLUSION: The Nordic children were affected by WWII in terms of a transient reduction in temporal trends in height and weight, and the magnitude of this decrease was associated with the severity of the energy restriction prevailing in the respective country during the war. These findings warrant further studies of the chronic diseases associated with height and weight for cohorts being in their growth periods during WWII.

Growth of girls who later develop coronary heart disease.

OBJECTIVE: To determine the path of growth of girls who later develop coronary heart disease. DESIGN: Follow up study of girls whose body size at birth, during infancy, and childhood up to age 12 years was recorded. SETTING: Helsinki, Finland. PARTICIPANTS: 4130 girls who were born between 1934 and 1944, attended child welfare clinics in Helsinki, and were still resident in Finland in 1971. MAIN OUTCOME MEASURE: Hospital admission or death from coronary heart disease. RESULTS: In comparison with boys in the same cohort who later developed coronary heart disease the 87 girls were short at birth, rather than thin, had compensatory growth in height during infancy, became thin, and thereafter had a rapid increase in weight and body mass index. In a combined analysis the hazard ratios for coronary heart disease were 1.17 (95% confidence interval (CI) 1.03 to 1.32, p = 0.02) for each 1 cm decrease in length at birth, 1.52 (95% CI 1.23 to 1.89, p < 0.001) for each standard deviation score increase in body mass index after age 3 years, and 1.63 (95% CI 1.09 to 2.42, p = 0.02) for each decrease in level of education. CONCLUSIONS: Though broadly similar, the paths of growth associated with the later development of coronary heart disease differ in girls and boys. This may be because girls are less vulnerable to undernutrition in utero and are better able to sustain postnatal growth in an adverse environment.

The effects of the Pro12Ala polymorphism of the PPARgamma-2 gene on lipid metabolism interact with body size at birth.

Body size at birth is an indicator of the intrauterine environment. The effects of the Pro12Pro genotype and the 12Ala allele of the PPARgamma-2 gene on glucose and insulin metabolism in adult life depend on body size at birth. A low birth weight is associated with insulin resistance and type 2 diabetes. The peroxisome proliferator-activated receptor-gamma (PPARgammas) are also regulators of adipocyte differentiation, and the PPARgamma-2 gene could also contribute to the development of dyslipidemia. Therefore, the effects of the Pro12Ala polymorphisms of the PPARgamma-2 gene on lipid metabolism were measured in 476 elderly persons whose birth weight was known. The Ala12 allele was associated with increased serum total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol concentrations but only among those who had birth weights below 3000 g. These interactions between the effects of the PPARgamma-2 gene on adult traits and the effects of birth weight may be interpreted as examples of gene-environmental interactions, which underlie plasticity during development.

Obesity from cradle to grave.

BACKGROUND: Obesity is known to track from early life into adult life. OBJECTIVE: To examine the relation of obesity in adult life to growth and living conditions during childhood. DESIGN: Birth cohort study. PARTICIPANTS: A total of 4515 people (2135 men and 2380 women) who were born at Helsinki University Central Hospital between 1934 and 1944, who attended child welfare clinics and were still resident in Finland in the year 2000. MEASUREMENTS: Incidence of obesity based upon lifetime maximum body mass index (BMI) ascertained from a postal questionnaire and defined as a BMI>or=30 kg/m(2). The main explanatory measurements were size at birth, childhood growth, and socioeconomic status in childhood and in adult life. RESULTS: The cumulative incidence of obesity was 33.8% in men and 32.4% in women. The incidence rose with increasing body size at birth. From birth the mean weight and BMI of people who later became obese exceeded the average and remained above average at a statistically significant level at all ages from 6 months to 12 y. Childhood BMI was a stronger predictor of adult obesity than body size at birth. A higher maternal BMI in pregnancy was associated with a more rapid childhood growth and an increased risk of becoming obese in adult life. Higher socioeconomic status and better educational attainment were associated with a lower prevalence of obesity. There was no association between the duration of breastfeeding and later obesity. CONCLUSIONS: These results emphasize the importance of early life factors in the pathogenesis of adult obesity.

Early adiposity rebound in childhood and risk of Type 2 diabetes in adult life.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with a small body size at birth and a high BMI in adult life. The aim of our study was to assess the associations between Type 2 diabetes and birth size, infant growth and age at adiposity rebound. METHODS: We carried out a longitudinal study of 8760 subjects born in Helsinki during 1934 to 1944. On average, they had 18 measurements of height and weight between birth and 12 years of age. In western countries BMI usually decreases after the age of 2 years and rises again at around 6 years--the so-called adiposity rebound. We defined age at adiposity rebound by the age of lowest BMI between one and 12 years. We identified people with Type 2 diabetes using a national register. RESULTS: A total of 290 individuals developed Type 2 diabetes in adult life. The cumulative incidence of Type 2 diabetes decreased progressively from 8.6% in persons whose adiposity rebound occurred before the age of 5 years to 1.8% in those in whom it occurred after 7 years ( p<0.001). Early adiposity rebound was preceded by low weight gain between birth and 1 year ( p<0.001). CONCLUSION/INTERPRETATION: Large differences in the incidence of Type 2 diabetes are associated with growth rates in utero, weight gain in infancy and age at adiposity rebound.

Size at birth, fat-free mass and resting metabolic rate in adult life.

Resting metabolic rate is an important predictor of obesity and is closely related to fat-free mass. There is evidence that fat-free mass may be partly determined during critical periods of growth before and after birth. The objective of this study was to examine the relationship between size at birth, childhood growth and fat-free mass and resting metabolic rate in adult life. 318 men and women with detailed records of body size at birth and growth during school years participated in the study. Fat-free mass correlated positively with birth weight among both sexes (r = 0.264, p < 0.001). Those having a higher birth weight had a higher fat-free mass at any adult BMI. Fat-free mass among men increased by 2.2 kg (95 % Cl 0.5 to 3.9; p = 0.01) for every kg increase in birth weight and by 1.5 kg (95 % Cl 1.3 to 1.7, p < 0.0001) for every kg/m(2) BMI in adult life. In women, fat-free mass increased by 2.7 kg (95 % Cl 1.6 - 3.9; p < 0.001) for every kg increase in birth weight and by 0.8 kg (95 % CI 0.7 to 1.0, p < 0.001) for every kg/m(2) of BMI in adult life. Height, weight and body mass index at each age from 7 to 15 years were also strongly, positively associated with fat-free mass. A negative correlation between birth weight and resting metabolic rate expressed per unit of fat-free mass (r = - 0.158; p < 0.001) was found. Fat-free mass may be determined during critical periods of muscle growth in utero and during childhood. The muscle tissue of people who had a lower birth weight is more metabolically active than those with a higher birth weight. This may protect them from the increased risk of obesity associated with low fat-free mass.

Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals.

AIMS/HYPOTHESIS: A study of 7086 men and women born in Helsinki, Finland, has shown that the development of Type II (non-insulin-dependent) diabetes mellitus is associated with low birth weight followed by accelerated gain in height and weight during childhood and with high maternal BMI but the processes which underlie these associations are largely not known. METHODS: We carried out standard oral glucose tolerance tests, and measured plasma insulin and proinsulin, serum lipid concentrations and blood pressure in 474 patients from the Helsinki cohort. RESULTS: We used four indices of insulin resistance: fasting and 2-h plasma insulin, and fasting proinsulin and 32-33 split proinsulin concentrations. These were associated with small body size at birth and during childhood, rapid growth in height and low maternal BMI. CONCLUSION/INTERPRETATION: Insulin resistance and Type II diabetes share common associations with retarded fetal growth and accelerated growth during childhood. They are dissimilar, however, in that insulin resistance is associated with thinness in childhood and low maternal BMI, while Type II diabetes is associated with high BMI in childhood and high maternal BMI.

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.

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.