Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort.

OBJECTIVE: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. DESIGN: Cohort identified from detailed birth records, with 97% follow up. SETTING: Uppsala Academic Hospital, Sweden. PARTICIPANTS: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. MAIN OUTCOME MEASURES: Incidence of breast cancer before (at age <50 years) and after (> or = 50 years) the menopause. RESULTS: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed > or =4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. CONCLUSIONS: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer.

Muscle morphology, self-reported physical activity and insulin resistance syndrome.

In a population-based sample of 475 men the associations between muscle morphology, self-reported physical activity (PA) and insulin resistance (IR) syndrome were investigated. Also, we studied to what degree muscle morphology contributes to the association between PA and IR syndrome. Muscle morphology and the components of IR syndrome were compared in four groups categorized according to self-reported habitual PA data. We found a significantly higher percentage of type I fibres, fibre area and number of capillaries around the fibres and a lower proportion of type IIB fibres with higher level of PA. The relative distribution of type I fibres and capillarization were positively related to high density lipoprotein (HDL) cholesterol and negatively to serum triglycerides (TG) and plasminogen activator inhibitor-1 (PAI-1) activity. The percentage of type IIB fibres was were inversely related to HDL cholesterol and positively to serum TG, PAI-1 activity and resting heart rate. Insulin sensitivity was positively and independently related to PA level (P < 0.001). Regression analysis including all relevant variables regarding insulin sensitivity indicated that the significant explanatory variables left in the equation were body mass index (BMI), glucose intolerance, PAI-1 activity, serum free fatty acid concentration, proportion of type IIB fibres, HDL cholesterol level, drug treatment, PA level, and waist-to-hip ratio, which together explained 55% of the variation in the insulin sensitivity index. In conclusion, both fibre type distribution and muscle capillary density might contribute to the beneficial effect of PA on IR syndrome.

Insulin-mediated changes in leg blood flow are coupled to capillary density in skeletal muscle in healthy 70-year-old men.

The aim of this study was to investigate to what degree the capillarization in the skeletal muscle explains the leg blood flow (LBF) changes during hyperinsulinaemia. Fifteen normotensive men from a population-based cohort of 70-year-old men in Uppsala, Sweden, were investigated. Their metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test results), serum lipid profile, muscle fiber distribution (myosin adenosine triphosphatase staining), and capillary supply (amylase-periodic acid-Schiff method) was evaluated. Doppler ultrasound was used before and after the clamp test to detect insulin-induced changes in LBF. Physiologic hyperinsulinemia (serum insulin, 107 mU/L) caused a moderate increase in LBF (15% +/- 11%; P =.07). Change in LBF was closely related to capillary density (r =.66; P <.01) independent of obesity, smoking and level of physical activity. An association was observed between LBF and serum free fatty acid (FFA) concentrations (r = -.57; P <.05). In multiple regression analysis, capillary density and serum FFA level together explained 71% of the variation in insulin-mediated LBF changes. Capillary rarefaction and elevated serum FFA values were associated with a vasoconstrictive effect of insulin. In conclusion, capillarization in skeletal muscle and serum FFA concentration seem to be determinants of endothelial function.

Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men.

BACKGROUND: The increased risk associated with left ventricular hypertrophy (LVH) diagnosed echocardiographically (Echo-LVH) or electrocardiographically (ECG-LVH) is well known, but the clinically relevant question of how much additional prognostic information would be provided by echocardiographically assessing LVH if a subject's ECG-LVH and hypertension status are known has not been addressed. METHODS AND RESULTS: We investigated whether Echo-LVH and ECG-LVH predicted total and cardiovascular mortality and morbidity independently of each other and of other cardiovascular risk factors by using a population-based sample of 475 men investigated at age 70 with a median follow-up time of 5.2 years. Echocardiographic left ventricular mass index (LVMI) predicted total mortality (hazards ratio [HR] 1.44, 95% CI 1.09 to 1.92, for a 1-SD increase in LVMI) and cardiovascular mortality (HR 2.38, 95% CI 1.52 to 3.73) independently of ECG-LVH and other cardiovascular risk factors. ECG-LVH, defined as Cornell product >244 microV. s, predicted total mortality (HR 2.89, 95% CI 1.41 to 5.96) independently of LVMI and other cardiovascular risk factors. Thus, Echo-LVH and ECG-LVH provided complementary prognostic information, especially in hypertensive subjects. CONCLUSIONS: Echo-LVH and ECG-LVH predict mortality independently of each other and of other cardiovascular risk factors, implying that Echo-LVH and ECG-LVH in part carry different prognostic information. Therefore, to fully assess the increased risk associated with these conditions, both ECG and echocardiography should be performed.

Changes in physical activity are associated with changes in metabolic cardiovascular risk factors.

AIMS/HYPOTHESIS: To investigate the effect of changes in physical activity on changes in metabolic cardiovascular risk factors and to investigate what factors affect the association between physical activity and cardiovascular mortality. METHODS: Of the 1860 men who were 50 years of age and who were without pre-existing cardiovascular disease participating in a population-based study, 898 were re-examined 20 years later. Altogether 231 died from cardiovascular diseases during the follow-up (mean = 22.6 years). The examinations which the men underwent at 50 and 70 years of age included assessment of physical activity (self-reported at four alternative levels), anthropometry, measurements of fasting concentrations of glucose, specific insulin, proinsulin, split proinsulin and lipids. RESULTS: During the 20 years, 31 % increased their amount of physical activity while 51 % continued the same amount of exercise. Increased physical activity was associated with significant changes in several important metabolic variables, including fasting glucose, proinsulin and HDL cholesterol, independent of body weight changes. The risk of cardiovascular disease for men performing moderate, regular and athletic physical activity was 25 % (p = 0.127), 34 % (p = 0.022) and 71 % (p = 0.009) lower, respectively, compared with sedentary men. The association was attenuated by adjustment for baseline measurements of insulin, proinsulin and split proinsulin. Additional adjustment for other cardiovascular risk factors did not further attenuate the association. CONCLUSION/INTERPRETATION: Increased leisure time physical activity between the ages of 50 and 70 years, in the absence of active intervention, is associated with improved glucose, insulin and lipid metabolism in men. The concentrations of insulin, proinsulin and split proinsulin could mediate much of the association between a sedentary lifestyle and increased risk of cardiovascular mortality.

Left ventricular concentric remodeling rather than left ventricular hypertrophy is related to the insulin resistance syndrome in elderly men.

BACKGROUND: Associations between left ventricular (LV) geometry and the insulin resistance syndrome have been found, mostly in small studies of middle-aged hypertensives. The purpose of this study was to elucidate these associations through the use of a large sample of elderly men. METHODS AND RESULTS: We investigated 475 men (157 hypertensives) 71 years of age who were attending a population-based health survey in Uppsala County with echocardiography, oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, and lipid and 24-hour ambulatory blood pressure monitoring. LV relative wall thickness was significantly related to clamp insulin sensitivity index (r=-0.14), fasting insulin, 32-33 split proinsulin, triglycerides, nonesterified fatty acids, OGTT glucose and insulin levels, waist-to-hip ratio, body mass index, 24-hour blood pressure, and heart rate (r=0.10 to 0.22). Only 24-hour systolic pressure (r=0. 15), OGTT 2-hour insulin (r=-0.10), and heart rate (r=-0.14) were significantly related to LV mass index. Comparing subjects with various LV geometry (normal, concentric remodeling and concentric and eccentric hypertrophy) showed that 24-hour heart rate, OGTT glucose and insulin levels, waist-to-hip ratio, and body mass index were significantly higher (P<0.001 to 0.05) and clamp insulin sensitivity index was significantly lower (P<0.01) in the concentric remodeling geometry group than in the normal LV geometry group. The 24-hour blood pressure was significantly higher in the concentric hypertrophy group than in the normal LV geometry group (P<0.001). CONCLUSIONS: Several components of the insulin resistance syndrome were related to thick LV walls and concentric remodeling but less to LV hypertrophy in this population-based sample of elderly men.

Alterations in skeletal muscle morphology in glucose-tolerant elderly hypertensive men: relationship to development of hypertension and heart rate.

OBJECTIVE: To compare the muscle morphology in hypertensive subjects with that in controls and to test the hypothesis of a relation between heart rate, development of hypertension and muscle morphology that is independent of glucose intolerance. PATIENTS AND METHODS: We studied 43 glucose-tolerant, untreated hypertensive subjects and 113 healthy controls in a longitudinal cohort of 70-year-old men. Metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test), muscle fibre distribution (myosin ATPase staining) and capillary supply (amylase-PAS method) were evaluated. Blood pressure and heart rate data were available from both ages 50 and 70 years. RESULTS: Hypertensive subjects had a significantly smaller mean number of capillaries per fibre than controls (1.53 versus 1.64; P = 0.04). In hypertensive subjects, the proportions of type I and type II fibres were correlated to mean arterial pressure (r = -0.56 and r= 0.52, respectively, P < 0.05 for both). The increase in mean arterial pressure over 20 years was closely correlated to capillary density in mm2 (r= -0.62; P< 0.0001). Capillary supply was inversely related to resting heart rate both at ages 50 and 70 years. CONCLUSIONS: Skeletal muscle of glucose tolerant hypertensive subjects showed a lower capillary supply than that of controls. This capillary rarefaction was correlated to increase in mean arterial pressure over two decades and to supine heart rate. This is compatible with the suggestion that higher sympathetic drive might generate structural alterations in muscle capillarization.

Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances.

AIMS/HYPOTHESIS: To distinguish the physiological disturbances related to birth weight from the cluster of disturbances called the insulin resistance syndrome. METHODS: Men participating in a population-based study in Uppsala, Sweden, with recordings of birth weight, were metabolically characterised at age 50 (n = 1268) and re-investigated at age 70 (n = 734). Blood pressure, BMI, glucose and insulin concentrations are associated with birth weight in this cohort. RESULTS: Birth weight was inversely associated (p < 0.03) with subscapular:triceps skinfold ratio (truncal fat), plasminogen activator inhibitor-1 (PAI-1) activity, specific insulin and proinsulin-like molecules when adjusted for BMI. Birth weight was not related (p > 0.10) with waist circumference, serum triglycerides or HDL cholesterol. The insulin resistance syndrome was defined as the combination of hypertension, insulin resistance and dyslipidaemia. The prevalence of this syndrome at age 50 and 70 was inversely related to birth weight with odds ratio 0.66 and 0.71, respectively, per kg increase in birth weight. When the syndrome was defined to include truncal obesity or raised plasminogen activator inhibitor-1 instead of dyslipidaemia, the corresponding odds ratios were 0.51 and 0.66, respectively. CONCLUSIONS/INTERPRETATION: Low birth weight predicts high blood pressure, insulin resistance, truncal obesity and high plasminogen activator inhibitor-1 activity but not the abdominal obesity or dyslipidaemia present in the insulin resistance syndrome. The cluster of disturbances associated with low birth weight is a subset of the disturbances that are clustered in the general population as the insulin resistance syndrome. This subset of physiological disturbances is possibly linked by a specific pathway.

Is the effect of low birth weight on cardiovascular mortality mediated through high blood pressure?

OBJECTIVE: To explore whether the inverse association between birth weight and mortality from circulatory diseases is mediated through blood pressure in men aged 50-75 years. DESIGN: Cohort study with retrospectively collected data on size at birth. SUBJECTS AND SETTING: The study included 1334 men born during 1920-1924, living in Uppsala, Sweden, who were examined at the ages of 50 and 60 years, and followed-up to the end of 1995. MAIN OUTCOME MEASURES: Mortality from circulatory diseases based on routine death registration. RESULTS: Birth weight showed a specific, inverse association with mortality from circulatory diseases: the rate ratio was 0.67 (95% confidence interval 0.50 to 0.89) per 1000 g increase in birth weight. This association was not appreciably affected by adjustment for sociodemographic characteristics or smoking, but was strengthened slightly by adjustment for body mass index at the ages of 50 and 60 years. Adjustment for systolic blood pressure at the age of 50 years only slightly reduced the strength of the inverse association between birth weight and mortality from ischaemic heart disease, and did not affect the inverse association between birth weight and mortality from stroke. Adjustments for systolic and diastolic blood pressure and hypertension treatment at the ages of 50 and 60 years did not reduce the strength of the association between birth weight and mortality from circulatory diseases at the age of 60-75 years. CONCLUSIONS: The inverse association between birth weight and mortality from circulatory diseases in men aged 50-75 years is independent of adult sociodemographic characteristics, smoking and adult obesity and does not seem to be mediated through an increased blood pressure in those with low birth weight.

Insulin-mediated vasodilation and glucose uptake are independently related to fasting serum nonesterified fatty acids in elderly men.

OBJECTIVES: To investigate candidate predictors for insulin sensitivity in healthy elderly males, with special reference to the influence of insulin-mediated skeletal muscle blood flow and serum nonesterified fatty acids (NEFA). SUBJECTS: From the participants in a health survey of 70-year-old males, focusing on cardiovascular risk factors, a subgroup of 46 men was sampled. Only men who declared themselves healthy and without medication were included. INTERVENTIONS: Insulin sensitivity was measured with the euglycaemic hyperinsulinaemic clamp. Leg blood flow was measured before and during the clamp, using the Doppler ultrasound technique. RESULTS: Hyperinsulinaemia [steady-state plasma insulin 105(15) mU L-1] increased leg blood flow by 10% (P < 0.004). When tested in bivariate analysis incremental leg blood flow was only significantly related to the serum NEFA concentration (r = - 0.38, P < 0.01) amongst a number of measured variables. Insulin-mediated glucose disposal was related to body mass index (BMI) (r = -0.49, P = 0. 0006), waist/hip ratio (r = - 0.31, P = 0.036), NEFA (r = - 0.50, P = 0.0004) and heart rate (r = - 0.34, P = 0.02). In multivariate analysis only BMI and NEFA remained significantly related to whole-body glucose uptake. CONCLUSIONS: The study demonstrates that in elderly men BMI and fasting serum NEFA but not insulin-induced vasodilation are related to insulin sensitivity. High fasting levels of NEFA relate to both impaired insulin-mediated vasodilation and impaired glucose disposal, respectively. These two insulin actions were not interrelated, however, a finding which may indicate dissociated mechanisms.

Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth.

Although several studies have shown that reduced size at birth predicts glucose intolerance and insulin resistance in adult life, the relation has been inconsistent and usually stronger for ponderal index than for birthweight. We examined glucose tolerance and insulin sensitivity (by the euglycaemic clamp method) in relation to size at birth in 709 men aged 69-73 years in Uppsala, Sweden. After adjusting for adult body mass index, prevalence of glucose intolerance (defined as diabetes or impaired glucose tolerance) was inversely related to birthweight. In men born at term, there was a positive monotonic relation of insulin sensitivity with birthweight, strongest in those who were overweight at age 70. This relation was reversed in men born before term (p = 0.005 for interaction between pre-term birth and birthweight effect). Glucose intolerance and insulin resistance showed inverted U-shaped relations with ponderal index, in contrast with the monotonic inverse relation seen in this cohort at earlier ages. This change in form of the relations was partly accounted for by selective loss to follow-up between ages 60 and 70 years. These results confirm that the association between reduced fetal growth and glucose intolerance is mediated through insulin resistance and depends upon an interaction with obesity in adult life. This relation is obscured when pre-term births are included. Failure to stratify by gestational age in previous studies could account for inconsistencies in the relations of insulin resistance and glucose intolerance to size at birth and for the detection of stronger associations with ponderal index than with birthweight.

Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29.

OBJECTIVE: To establish whether fetal growth rate (as distinct from size at birth) is associated with mortality from ischaemic heart disease. DESIGN: Cohort study based on uniquely detailed obstetric records with 97% follow up over the entire life course and linkage to census data in adult life. SUBJECTS: All 14 611 babies delivered at the Uppsala Academic Hospital, Sweden, during 1915-29 followed up to end of 1995. MAIN OUTCOME MEASURES: Mortality from ischaemic heart disease and other causes. RESULTS: Cardiovascular disease showed an inverse association with birth weight for both men and women, although this was significant only for men. In men a 1000 g increase in birth weight was associated with a proportional reduction in the rate of ischaemic heart disease of 0.77 (95% confidence interval 0.67 to 0.90). Adjustment for socioeconomic circumstances at birth and in adult life led to slight attenuation of this effect. Relative to the lowest fourth of birth weight for gestational age, mortality from ischaemic heart disease in men in the second, third, and fourth fourths was 0.81 (0.66 to 0.98), 0.63 (0.50 to 0.78), and 0.67 (0.54 to 0.82), respectively. The inclusion of birth weight per se and birth weight for gestational age in the same model strengthened the association with birth weight for gestational age but removed the association with birth weight. CONCLUSION: This study provides by far the most persuasive evidence of a real association between size at birth and mortality from ischaemic heart disease in men, which cannot be explained by methodological artefact or socioeconomic confounding. It strongly suggests that it is variation in fetal growth rate rather than size at birth that is aetiologically important.

Insulin resistance and diabetes in the context of treatment of hypertension.

Diabetes is emerging as a new epidemic world-wide because of the ageing of the population but changes in lifestyle are also contributing. All means to prevent this development should be undertaken. In this context, treatment of hypertension is of importance due to the large number of people treated with antihypertensive drugs, many of which interfere with glucose metabolism. In three prospective cohort studies, treatment with beta-blockers and diuretics has been associated with an increased risk of development of diabetes. Prospective, randomized studies with antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus, treatment with beta-blockers or high-dose diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium-channel blockers and angiotensin converting enzyme (ACE) inhibitors are neutral. However, there are exceptions within the different classes. Captopril differs from the other ACE inhibitors and results in improvement of insulin sensitivity. The most pronounced improvements have been obtained with alpha1-blockers. In a recent study, the data indicate that also moxonidine, an imidazoline1 receptor agonist, is effective in lowering blood pressure and improving insulin sensitivity in insulin-resistant patients. In populations at high risk for diabetes, it may be justified to select drugs that improve insulin sensitivity when treating hypertension in insulin-resistant individuals.

Size at birth and hypertension in longitudinally followed 50-70-year-old men.

We investigated the relationship between weight at birth and the prevalence of hypertension (defined as treatment and/or systolic blood pressure > 160 mmHg) at ages 50, 60 and 70 years in a cohort of Swedish men followed longitudinally, in which we had previously found a strong inverse association of birthweight with blood pressure at age 50. In men of above median adult height (> 176 cm), a 1000 g decrease in birthweight was associated with an odds ratio for hypertension of 2.53 (95% CI 1.10, 5.85) at age 50, 1.63 (95% CI 0.97, 2.72) at 60 and 1.72 (95% CI 1.10, 2.69) at 70. As the overall prevalence of hypertension increased steeply with age, the absolute difference in the risk of hypertension between those of low and high birthweight increased with age. In men of below median height, birthweight was not significantly associated with blood pressure at any age. Small size at birth is associated with hypertension at 50, 60 and 70 years in men of a high growth potential. The strength of the relationship between birthweight and hypertension does not increase from 50 to 70 years, although the risk of hypertension attributable to low birthweight does increase with age.

Insulin resistance as an intermediary endpoint.

In three prospective cohort studies, treatment with beta-blockers and diuretics has been associated with an increased risk of diabetes developing. Prospective, randomized studies with antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus, treatment with beta-blockers or diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors are neutral. However, there are exceptions within the different classes. Captopril seems to differ from the other ACE inhibitors in that the result is an improvement of insulin sensitivity. In the Captopril Primary Preventive Project the effects on cardiovascular disease and diabetes of captopril-based and conventional treatment are compared. This study will hopefully give the answer to the question whether insulin resistance is a valid intermediary endpoint.

Considerations in the treatment of insulin resistance and related disorders with a new sympatholytic agent.

BACKGROUND: Prospective studies have documented the importance of blood glucose control in diabetic patients for risks for cardiovascular diseases. At age 70 years, more than 30% of people are hypertensive and among these about one-third have diabetes or impaired glucose tolerance. It is urgent to treat hypertension in these patients with drugs that do not further impair glucose control. DRUG STUDIES: Prospective, randomized studies with antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus, treatment with beta-blockers or diuretics is associated with impaired insulin sensitivity, whereas most modern calcium channel blockers and angiotensin converting enzyme inhibitors are neutral. The most pronounced improvements have been obtained with alpha1-blockers. A new class of drugs, imidazoline I1-imidazoline receptor agonists, may be of interest in this context. Moxonidine, a drug in this class, inhibits sympathetic outflow and causes vasodilation. This effect together with other characteristics may lead to improved insulin resistance and glucose control. CONCLUSIONS: In populations at high risk for diabetes, it may be justified to select drugs that improve insulin sensitivity when treating insulin-resistant individuals for hypertension.

Hyperinsulinemia, insulin resistance, and the treatment of hypertension.

Treatment with beta-blockers and diuretics has been associated with an increased risk of developing diabetes mellitus in three prospective cohort studies. Prospective, randomized studies with antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus, treatment with beta-blockers or diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors are neutral. However, there are exceptions within the different classes. Captopril seems to differ from the other ACE inhibitors and results in improvement of insulin sensitivity. The most pronounced improvements have been obtained with alpha 1-blockers. In populations at high risk for diabetes mellitus, it may be justified to select drugs that improve insulin sensitivity when treating hypertension in insulin resistant individuals.

Antihypertensive treatment in insulin resistant patients.

Epidemiological evidence suggests that treatment with beta-blockers and diuretics increase the risk to develop diabetes. Prospective, randomized studies of antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus treatment with beta-blockers or diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium-channel blockers and angiotensin converting enzyme inhibitors are neutral. However, captopril treatment seems to be different and result in improvement of insulin sensitivity. The most pronounced improvements have been obtained with alpha1-blockers. In populations at high risk for diabetes, it may be justified to select drugs that improve insulin sensitivity when treating hypertension in insulin resistant individuals.

Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men.

OBJECTIVES: To clarify the type of fetal growth impairment associated with increased blood pressure in adult life, and to establish whether this association is influenced by obesity and is mediated through impairment of insulin action. DESIGN: Cross sectional survey with retrospective ascertainment of size at birth from obstetric archives. SUBJECTS: 1333 men resident in Uppsala, Sweden, who took part in a 1970 study of coronary risk factors at age 50 and for whom birth weight was traced. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure at age 50. RESULTS: In the full study population for a 1000g increase in birth weight there was a small change in systolic blood pressure of -2.2mmHg (95% confidence interval -4.2 to - 0.3mmHg) and in diastolic blood pressure of -1.0mmHg (-2.2 to 0.1mmHg). Much stronger effects were observed among men who were born at term and were in the top third of body mass index at age 50, for whom a 1000g increase in birth weight was associated with a change of -9.1mmHg (-16.4 to-1.9mmHg) systolic and -4.2mmHg (-8.3 to -0.1mmHg) diastolic blood pressure. Men who were light at birth (<3250g) but were above median adult height had particularly high blood pressure. Adjustment for insulin concentrations reduced the associations of birth weight with systolic and diastolic blood pressure. CONCLUSIONS: A failure to realise growth potential in utero (as indicated by being light at birth but tall as an adult) is associated with raised adult blood pressure. Impaired fetal growth may lead to substantial increases in adult blood pressure among only those who become obese. Metabolic disturbances, possibly related to insulin resistance, may provide a pathway through which fetal growth affects blood pressure.

Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years.

OBJECTIVE: To establish whether the relation between size at birth and non-insulin dependent diabetes is mediated through impaired beta cell function or insulin resistance. DESIGN: Cohort study. SETTING: Uppsala, Sweden. SUBJECTS: 1333 men whose birth records were traced from a cohort of 2322 men born during 1920-4 and resident in Uppsala in 1970. MAIN OUTCOME MEASURES: Intravenous glucose tolerance test at age 50 years and non-insulin dependent diabetes at age 60 years. RESULTS: There was a weak inverse correlation (r=-0.07, P=0.03) between ponderal index at birth and 60 minute insulin concentrations in the intravenous glucose tolerance test at age 50 years. This association was stronger (r=-0.19, P=0.001) in the highest third of the distribution of body mass index than in the other two thirds (P=0.01 for the interaction between ponderal index and the body mass index). Prevalence of diabetes at age 60 years was 8% in men whose birth weight was less than 3250 g compared with 5% in men with birth weight 3250 g or more (P=0.08; 95% confidence interval for difference -0.3% to 6.8%). There was a stronger association between diabetes and ponderal index: prevalence of diabetes was 12% in the lowest fifth of ponderal index compared with 4% in the other four fifths (P=0.001; 3.0% to 12.6%). CONCLUSION: These results confirm that reduced fetal growth is associated with increased risk of diabetes and suggest a specific association with thinness at birth. This relation seems to be mediated through insulin resistance rather than through impaired beta cell function and to depend on an interaction with obesity in adult life.