[New and old glucose lowering drugs; a state-of-the-art review]. / Nieuwe en oude bloedglucoseverlagende middelen.

High glucose values are associated with vascular risk in observational studies, but glucose lowering does not automatically translate into better outcomes for patients In patients with type 2 diabetes and cardiovascular disease, cardiovascular benefits of GLP-1 receptor agonists and SGLT-2 inhibitors have been demonstrated. However, experience in clinical practice is limited and costs are high. In diabetic patients with heart failure and renal complications, SGLT-2 inhibitors may have additional beneficial effects. Metformin may have vascular benefits, but this has not been demonstrated for sulphonylurea derivatives, insulin and DPP-4 inhibitors In patients with a low cardiovascular risk, beneficial vascular effects of glucose lowering drugs have not convincingly been demonstrated. The outcomes of the recent studies will lead to a more personalized treatment strategy for type 2 diabetes. Treatment choices will depend upon patient's risk of complications, the goal of therapy, patient preferences and costs.

The Association of Olfactory Function with BMI, Appetite, and Prospective Weight Change in Dutch Community-Dwelling Older Adults.

OBJECTIVES: The olfactory decline that often accompanies aging is thought to contribute to undernutrition in older adults. It is believed to negatively affect eating pleasure, appetite, food intake and subsequently nutritional status. We have evaluated the associations of olfactory function with BMI, appetite and prospective weight change in a cohort of Dutch community-dwelling older adults. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Dutch community-dwelling older adults from the ongoing Longitudinal Aging Study Amsterdam (LASA). Measurements and setting: In 2012-2013, the 40-item University of Pennsylvania Smell Identification Test (UPSIT) was administered to 824 LASA participants to evaluate their olfactory function. Body weight, height, appetite, comorbidity, cognitive status and socio-demographic factors were also assessed. Follow-up weight was measured after three years. RESULTS: 673 participants (aged 55-65 years) were included in the regression analyses. Median UPSIT-score was 33. When adjusted for potential confounders, lower UPSIT-score (indicative of poorer olfactory function) was not associated with poor appetite (OR = 1.062, p = 0.137) or prospective weight change (B = -0.027, p = 0.548). It was, however, associated with lower BMI in smokers (B = 0.178, p = 0.032), but not in non-smokers (B = -0.015, p = 0.732). CONCLUSION: Lower olfactory function scores were associated with lower BMI in community-dwelling older adults who smoke, but not with appetite or prospective weight change. Therefore, smoking older adults with olfactory impairments may pose as a vulnerable group with respect to developing undernutrition.

Peripartum fetal distress in diabetic women: a retrospective case-cohort study.

BACKGROUND: Major concerns of pregnancies complicated by diabetes mellitus are an increased risk of adverse perinatal outcome. The objective of this study was to analyse the rate of fetal distress during labor in women with type 1, type 2 and gestational diabetes compared to control women. METHODS: A retrospective case-cohort study was conducted at the VU University Medical Center, Amsterdam; a tertiary care hospital. 117 women with type 1 diabetes, 59 women with type 2 diabetes, 303 women with gestational diabetes and 15,260 control women were included, who delivered between March 2004 and February 2014. Linear and logistic regression analyses were used to compare maternal and pregnancy characteristics. Risk of fetal distress and perinatal asphyxia was assessed by multiple regression analyses, adjusted for confounding factors as age, smoking, parity, previous cesarean section, hypertensive disorder, pre-eclampsia, prematurity, induction of labor and macrosomia. Main outcome measure was fetal distress, defined either as clinical indication for instrumental or cesarean delivery; or low umbilical artery pH (UA pH), or admission to neonatal unit (NU). RESULTS: The indication for instrumental or cesarean delivery in women with type 1 and type 2 diabetes mellitus was more frequently based on fetal distress as compared to controls (adjusted OR 2.76 CI 1.74-4.40 and adjusted OR 2.31 CI 1.19-4.51, respectively). In comparison with the control group, infants of women with type 1 diabetes had an increased risk of UA pH < 7.20 (adjusted OR 1.88 CI 1.23-2.87) or UA pH < 7.10 (adjusted OR 3.35 CI 1.79-6.27). Also, infants of women with type 1 diabetes were at increased risk for admission to NU as compared to infants of control women (OR 8.07 CI 4.75-13.70). CONCLUSIONS: Women with type 1 and type 2 diabetes are at increased risk of fetal distress during labor as compared to controls.

Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans.

AIM: To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. METHODS: As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n = 48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps. RESULTS: Body mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects. CONCLUSIONS: Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating.

Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS.

The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behaviour and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.

Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control.

AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log10HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.

Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS.

BACKGROUND: Insulin resistance, i.e. impaired insulin-mediated glucose uptake (IMGU), is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). Insulin-induced capillary recruitment (IICR) is considered a significant determinant of IMGU. We investigated whether IICR is a determinant IMGU in obese and lean women with and without PCOS. METHODS: The study included 36 women with PCOS (20 lean, BMI 21.9 ± 2.3 kg/m(2) and 16 obese, BMI 35.9 ± 6.0 kg/m(2)) and 27 age-matched healthy controls (14 lean, BMI 22.2 ± 1.8 kg/m(2) and 13 obese, BMI 40.5 ± 7.0 kg/m(2)). IICR was evaluated by capillary microscopy during an isoglycemic-hyperinsulinemic clamp. IMGU was expressed as M/I value. RESULTS: The M/I value was significantly lower in obese PCOS women compared with obese controls [0.5 (0.2-1.1) versus 0.8 (0.3-1.4) (mg kg(-1) min(-1) pmol l(-1)) × 100, P < 0.01], whereas the small difference between lean PCOS and lean control women was non-significant [1.5 (0.5-2.6) versus 1.7 (1.0-3.7) (mg kg(-1) min(-1) pmol l(-1)) × 100, P = 0.17]. Hyperinsulinemia increased capillary recruitment in lean controls (53.5 ± 20.3 versus 64.9 ± 27.4 n/mm(2), P < 0.05), but not in either PCOS group nor in obese controls. IICR and androgens were a determinant of M/I value only in lean women with or without PCOS. CONCLUSIONS: PCOS per se is associated with impaired IICR. Obese women with PCOS, in part independent of obesity, demonstrated a profound insulin resistance, whereas the difference between lean PCOS women and healthy controls was small and statistically non-significant. IICR was a determinant of IMGU in lean, but not in obese, women regardless of the presence of PCOS.

Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on left ventricular mass (LVM) index and arterial stiffness in hypertensive type II diabetic individuals. Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mm Hg. After titration, patients were treated for 12 months. Mean blood pressures were 157/93, 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide (n = 24), candesartan (n = 24) and lisinopril (n = 22) groups, and 135/80, 135/82 and 131/80 mm Hg after titration. About 70% reached target blood pressures, with the median use of three antihypertensive drugs. Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months: that is, LVM index (-11 g/m(2); -8%); carotid distensibility coefficient (DC; +2.8 x 10(-3) kPa(-1); +27%), compliance coefficient (CC; +0.13 mm2/kPa; +21%) and elastic modulus (-0.19 kPa; -16%); femoral DC (+1.6 x 10(-3) kPa(-1); +50%) and CC (+0.08 mm2/kPa; +26%); brachial DC (+2.1 x 10(-3) kPa(-1); +39%) and CC (+0.03 mm2/kPa; +27%) and total systemic arterial compliance (+0.29 ml/mm Hg; +16%). No differences in outcome variables between treatment groups were observed. Aggressive antihypertensive treatment, although difficult to achieve, resulted in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals. Strategies based on renin-angiotensin system inhibitors were not clearly superior to conventional (i.e. diuretic-based) strategies.

[Microvascular dysfunction as an explanation for the metabolic syndrome]. / Microvasculaire disfunctie als verklaring van het metabool syndroom.

The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.

Aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril as initial choice in hypertensive type II diabetic individuals: effects on albumin excretion, endothelial function and inflammation in a double-blind, randomized clinical trial.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, -2.40 mg/24 h (P<0.001), -85 ng/ml (P=0.01) and -50 ng/ml (P=0.02)), but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and -1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.

Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers.

AIMS/HYPOTHESIS: Insulin possesses vasodilatory actions that may be important in regulating its access to insulin-sensitive tissues. Our study aims to directly measure changes in response to insulin in the human skeletal muscle microcirculation. Measurement was by an implanted laser Doppler probe. METHODS: We investigated changes in intramuscular and skin microvascular perfusion in 12 healthy individuals during a hyperinsulinaemic and a control clamp. We determined leg blood flow with plethysmography, finger skin functional capillary recruitment with capillaroscopy, endothelium-(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside, and leg intramuscular reactive hyperaemia and vasomotion with laser Doppler measurements. RESULTS: Compared to the control study, hyperinsulinaemia (416+/-82 pmol/l) caused: (i) an increase in leg blood flow (1.0+/-1.0 vs 0.1+/-0.6 ml.min(-1).100 ml, p<0.05); (ii) an increase in finger skin capillary recruitment (14.9+/-10.1 vs -5.6+/-11.0%, p<0.01); (iii) no change in baseline laser Doppler perfusion either in finger skin or leg muscle; (iv) a tendency to increase acetylcholine-mediated vasodilation (475+/-534 vs 114+/-337%, p=0.07) with no change in sodium-nitroprusside-mediated vasodilation ( p=0.2) in finger skin; (v) an increase in intramuscular reactive hyperaemia (423+/-507 vs 0+/-220%, p<0.01); and (vi) a decrease in time needed to reach peak intramuscular perfusion (-3.6+/-3.0 vs 1.1+/-3.1 s, p<0.01). In addition, hyperinsulinaemia induced an increase in intramuscular vasomotion by increasing the contribution of frequencies between 0.01 and 0.04 Hz ( p<0.05 for all), which probably represents increased endothelial and neurogenic activity. CONCLUSIONS/INTERPRETATION: Physiological hyperinsulinaemia not only stimulates total blood flow and skin microvascular perfusion, but also augments human skeletal muscle microvascular recruitment and vasomotion as detected directly by laser Doppler measurements.

The association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences.

Low birth weight is associated with an increased risk of atherothrombosis, which may be related in part to the association between low birth weight and high plasma fibrinogen. The association between birth weight and fibrinogen may be explained by intrauterine, socio-economic or genetic factors. We examined birth weight and fibrinogen in 52 dizygotic and 56 adolescent monozygotic (genetically identical) twin pairs. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a fibrinogen level that was higher compared with their co-twins with the highest birth weight [dizygotic twins: 2.62 +/- 0.46 g L(-1) vs. 2.50 +/- 0.41 g L(-1) (P = 0.04); monozygotic twins: 2.42 +/- 0.45 g L(-1) vs. 2.49 +/- 0.39 g L(-1) (P = 0.2)]. These findings suggest that the association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences and therefore that this association has genetic causes. Improvement of intrauterine nutrition may not lower fibrinogen levels in later life.

Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin.

BACKGROUND: To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk. MATERIALS AND METHODS: Forty-six healthy White individuals aged 30-70 years were studied. Coronary heart disease risk was assessed with the use of the CHD risk score according to the Framingham Heart Study, which is based on the risk factors age, blood pressure, cigarette smoking, total cholesterol, HDL cholesterol and diabetes. Endothelium-dependent and -independent vasodilation in skin were evaluated with laser Doppler after iontophoresis of acetylcholine and sodium nitroprusside. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion. RESULTS: Coronary heart disease risk score (i.e. the 10-year probability of CHD) varied from 1-37%. Microvascular function decreased with increasing quartiles of CHD risk (for acetylcholine-mediated vasodilation: 687, 585, 420 and 326%, P = 0.002; for nitroprusside-mediated vasodilation: 776, 582, 513 and 366%, P = 0.02; for capillary recruitment: 49.9, 44.6, 27.2 and 26.7%, P = 0.001). These trends were similar in men and women (P for interaction > 0.2) and independent of body mass index. CONCLUSIONS: Increased CHD risk is associated with an impaired endothelium-dependent vasodilatation and capillary recruitment in skin, suggesting that microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function.

Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: analysis in twins.

Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low birth weight was associated with high levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (-0.17 mmol/liter per kg, P = 0.07; -0.18 mmol/liter per kg, P = 0.04; and -0.07 g/liter per kg, P = 0.02, respectively) and with low levels of high-density lipoprotein (HDL) cholesterol (+0.04 mmol/liter per kg, P = 0.1), after adjustment for age, sex, and body mass index. Intrapair differences in birth weight were significantly associated with differences in total cholesterol, LDL cholesterol, and apolipoprotein B in dizygotic twins after adjustment for differences in current body mass index (-0.49 mmol/liter per kg, P = 0.02; -0.51 mmol/liter per kg, P = 0.01; and -0.10 g/liter per kg, P = 0.04, respectively), demonstrating that the larger the difference in birth weight, the higher these risk factors in the twin with the lower birth weight, compared with the cotwin with the higher birth weight. In monozygotic twins, however, the associations between intrapair differences in birth weight and differences in total cholesterol, LDL cholesterol, and apolipoprotein B were in the opposite direction (+0.32 mmol/liter per kg, P = 0.03; +0.23 mmol/liter per kg, P = 0.08; and +0.06 g/liter per kg, P = 0.04, respectively). The association between intrapair differences in birth weight and differences in HDL cholesterol was not significant in dizygotic twins (+0.04 mmol/liter per kg, P = 0.6) and of borderline significance in monozygotic twins (+0.11 mmol/liter per kg, P = 0.05). These data suggest that genetic factors account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association between birth weight and HDL cholesterol.

Intra-uterine and genetic influences on the relationship between size at birth and height in later life: analysis in twins.

Epidemiological studies have consistently shown a positive association between size at birth (i.e. birth weight or birth length) and height in children, adolescents and adults. To examine whether this association is explained by genetic or nongenetic (intra-uterine) factors, we investigated birth weight, birth length and height in 60 dizygotic and 68 monozygotic adolescent twin pairs still living with their parents. Birth weight of the twins was obtained from their mothers. Height was measured in a standardised way. The mean age was 17+/-1.7 years for the dizygotic twins and 16+/-1.8 years for the monozygotic twins. Both dizygotic and monozygotic twins with the lowest birth weight from each pair had a height that was lower compared to their co-twins with the highest birth weight (dizygotic twins: 172.2+/-7.9 vs. 173.8+/-9.4 cm [p = 0.05]; monozygotic twins: 171.1+/-9.4 vs. 171.8+/-9.5 cm [p = 0.01]). Similarly, both dizygotic and monozygotic twins with the shortest birth length from each pair had a height that was lower compared to their co-twins with the longest birth length (dizygotic twins: 172.3+/-7.9 vs. 174.9plus minus9.7 cm [p < 0.05]; monozygotic twins: 168.9+/-10.6 vs. 169.9+/-10.2 cm [p < 0.01]). In addition, intra-pair differences in birth weight and birth length were significantly associated with differences in height in both dizygotic twins (regression coefficient: 4.3 cm/kg [95% confidence interval: 1.0 to 7.5] and 0.96 cm/cm [0.17 to 1.74], respectively) and monozygotic twins (2.8 cm/kg [1.4 to 4.1] and 0.73 cm/cm [0.40 to 1.06], respectively). These associations were stronger in dizygotic than in monozygotic twins, but this difference was not statistically significant (for birth weight p = 0.4; and for birth length p = 0.6). However, genetic model fitting indicated that models incorporating a genetic source of the covariance gave a better description of the observed association of birth weight and length with height in later life than models not incorporating this genetic source. The results were similar for data on adult height after 12 years of follow-up in a subgroup of these twin pairs. These data suggest that the association between size at birth and height in later life is influenced by non-genetic intra-uterine and by genetic factors.

Comparing blood pressure of twins and their singleton siblings: being a twin does not affect adult blood pressure.

The hypothesis was tested that monozygotic (MZ) and dizygotic (DZ) twins, with their lower average birth weight, have higher adult blood pressure than their singleton brothers or sisters. From the Netherlands Twin Registry, 261 twin families were recruited from a young adult and an older adult cohort with mean ages of 26.2 and 50.4 respectively. These families yielded 204 MZ twins with 71 singleton siblings and 271 DZ twins with 103 of their singleton siblings. Anti-hypertensive medication use of these 649 participants was assessed twice with a two-year interval. Resting blood pressure was measured thrice during a standardized laboratory protocol. In spite of a significant difference in birth weight (1036 gram), no differences were found in anti-hypertensive medication use at both time points between twins and singletons nor between their resting laboratory diastolic or systolic blood pressure. These results applied to each gender and to both age cohorts. Limiting the analyses to matched twin-sibling pairs of the same families and taking current weight and height into account did not change the results; no evidence was found for a twin-singleton difference. It was concluded that estimates of genetic and environmental contributions to blood pressure deriving from twin studies do not appear to be biased and may be generalized to singletons. Our results suggest that the lower birth weight in twins does not reflect the intrauterine disadvantage described by the Barker hypothesis.

Evidence for genetic factors explaining the birth weight-blood pressure relation. Analysis in twins.

Epidemiological studies have consistently shown an inverse association between birth weight and systolic blood pressure in later life after adjustment for current size. To examine whether this association is explained by intrauterine or genetic factors, we investigated birth weight and blood pressure data in 53 dizygotic and 61 monozygotic adolescent twin pairs. Birth weight was obtained from the mothers. Blood pressure measurements were performed 6 times at rest and during mental stress. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a systolic blood pressure measured at rest and during the reaction time experiment that was higher compared with their cotwins with the highest birth weight (dizygotic twins: blood pressure at rest, 119. 4+/-9.7 mm Hg versus 117.3+/-8.5 mm Hg, P=0.07, and during a reaction time task, 126.2+/-10.8 versus 123.6+/-9.5, P=0.09; monozygotic twins: blood pressure at rest, 117.4+/-6.4 versus 118. 4+/-9.0, P=0.4, and during a reaction time task, 122.9+/-8.4 versus 124.2+/-10.8, P=0.2). The differences in blood pressure between the cotwins with the lowest and the cotwins with the highest birth weight were different in dizygotic compared with monozygotic twin pairs (for blood pressure at rest, P=0.05; for blood pressure during reaction time, P=0.03). After adjustment for differences in current weight, intrapair differences in birth weight were negatively and significantly associated with differences in systolic blood pressure at rest and during the reaction time task in dizygotic twins (regression coefficient, -5.7 mm Hg/kg [95% confidence interval, -10.4 to -1.0] and -6.3 [-12.7 to 0], respectively) but not in monozygotic twins (-0.1 [-5.4 to 5.2] and +3.5 [-1.8 to 8.8], respectively). Interaction analysis indicated that the associations were different between dizygotic twins and monozygotic twins (P=0.1 and P<0.05, respectively). These data suggest that genetic factors may play an important role in the association between birth weight and blood pressure.