Serum 25-hydroxyvitamin D is associated with major cardiovascular risk factors and cardiac structure and function in patients with coronary artery disease.

BACKGROUND AND AIMS: Vitamin D deficiency has been associated with increased risk for cardiovascular (CV) disease, but the possible effects of Vitamin D on cardiac structure and function are not well characterized. METHODS AND RESULTS: The correlation between 25-hydroxyvitamin D levels and metabolic and cardiac echocardiographic parameters was studied in ARTEMIS study population including 831diabetic and 659 non-diabetic patients with stable coronary artery disease (CAD). Low levels of Vitamin D were associated with high BMI (p < 0.001), high total and LDL cholesterol and triglyceride levels (p < 0.001 for all) in both diabetics and non-diabetics. Among non-diabetic patients, low Vitamin D was also associated independently with elevated systolic and diastolic blood pressure (p < 0.005). Low Vitamin D levels were independently associated with reduced left ventricular (LV) ejection fraction (p < 0.005) and increased left atrial diameter (p < 0.03) measured by cardiac ultrasound by 2-dimensional echo. In the non-diabetic group, low Vitamin D levels were associated with impaired LV filling (high E/E') (p < 0.03) and low E/A mitral flow pattern measured by Doppler echocardiography (p < 0.05). Among diabetics, low Vitamin D levels were also related to increased LV end-systolic diameter (p < 0.05) and right ventricular diameter (p < 0.005). The association between LV diastolic filling (E/E') and Vitamin D levels was significant (p < 0.01) after adjustment for the commonly recognized risk factors of diastolic dysfunction in linear regression analysis. CONCLUSIONS: Low Vitamin D is associated with several major cardiovascular risk factors and cardiac structural changes including impaired systolic and diastolic function, which together may explain the association of low Vitamin D to worse cardiovascular outcome.

Resistin is linked to inflammation, and leptin to metabolic syndrome, in women with inflammatory arthritis.

OBJECTIVE: To investigate how inflammation and metabolic syndrome (MetS) are associated with adipokine levels in patients with inflammatory arthritis. METHODS: Fifty-four female patients with arthritis were enrolled in the study. Twenty (37%) of these patients had MetS, which was diagnosed according to the definition of the International Diabetes Federation (IDF). Interleukin (IL)-6 and four adipokines (resistin, leptin, adiponectin, and adipsin) were determined by immunoassay. Healthy women with body mass index (BMI) between 22 and 25 kg/m(2) served as controls. RESULTS: The patients with arthritis had higher levels of resistin than the healthy controls. This difference was clear in patients without MetS (17.4 in patients vs. 10.8 ng/mL in controls, p < 0.001), and even higher resistin levels were found in the patients with MetS (20.7 ng/mL; p < 0.001 vs. healthy controls; and p = 0.095 vs. patients without MetS). In the patients with arthritis and MetS, resistin correlated positively with IL-6 (Pearson's r = 0.5, p = 0.03). Leptin levels were increased in arthritis patients with MetS as compared to healthy controls, but not in patients without MetS. The statistically significant difference between patients with MetS and controls remained when leptin was adjusted with BMI. Accordingly, adiponectin levels were lower in patients with MetS than in healthy controls (p < 0.05). Leptin, adiponectin, and adipsin did not correlate with the inflammatory cytokine IL-6 or with C-reactive protein (CRP). CONCLUSIONS: The results show that high resistin levels are associated with arthritis independently of MetS, whereas leptin is increased only in arthritis patients with MetS.

Serum ghrelin and the prediction of the development of impaired glucose regulation and Type 2 diabetes in middle-aged subjects.

BACKGROUND: Ghrelin is a peptide hormone which has been shown to associate with obesity, hypertension and Type 2 diabetes (T2DM) in cross-sectional studies. AIM: To study whether total ghrelin levels have predictive value for the incidence of impaired glucose regulation (IGR) or T2DM. SUBJECTS AND METHODS: The subjects of this prospective follow-up study (no.=201) belonged to a population-based cohort collected in Northern Finland. Oral glucose tolerance tests (OGTT) and measurements of fasting serum total ghrelin, lipids, blood pressure and body mass index were performed at the beginning and at the end of the study. The mean follow-up time was 5.1 yr. The subjects had normal glucose tolerance (NGT) at the beginning of the study. RESULTS: T2DM developed in 6 (3%), impaired fasting glucose (IFG) in 6 (3%) and impaired glucose tolerance (IGT) in 35 (17.4%) subjects. The baseline ghrelin concentrations did not differ between the two studied groups: median fasting serum total ghrelin concentration was 733 pg/ml (25th-75th percentiles: 571-961 pg/ml) among those who maintained NGT, and 661 pg/ml (25th-75th percentiles: 527- 878 pg/ml) among those who developed IGR (IFG and/or IGT) or T2DM (p=0.421). The baseline ghrelin concentrations did not explain the changes in the 0-h or 2-h blood glucose concentrations in regression models. CONCLUSIONS: Our findings suggest that fasting serum total ghrelin levels measured at one time point might not have predictive value for the development of abnormalities in glucose tolerance.

Circulating cell-free DNA level predicts all-cause mortality independent of other predictors in the Health 2000 survey.

Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46-76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008-1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008-1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001-1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

Early atherosclerosis and IgG2 to bacteria are associated with FcgammaRIIa genotype in non-smokers.

BACKGROUND: Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcgammaRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG(2) ICs and a functional point mutation 131His/Arg diminishes IgG(2) binding to the receptor. STUDY DESIGN: We examined FcgammaRIIa-131His/Arg polymorphism, IgG(2) antibody titres to oxidized low-density lipoprotein (OxLDL) and Streptococcus pneumoniae cell wall polysaccharide (CWPS) and subclinical atherosclerosis in a large cohort of Finnish subjects (n = 1041). RESULTS: Non-smoking subjects with homozygous 131His/His genotype had more premature atherosclerosis (P = 0.004) and higher IgG(2) to bacterial CWPS (P = 0.002) compared with other genotypes. Smoking subjects had significantly higher intima-media thickness (IMT) than that of non-smokers (P < 0.001) and genotype-dependent associations were indistinct. There was no association between FcgammaRIIa genotype and antibody titres to OxLDL. CONCLUSIONS: Our data demonstrate that FcgammaRIIa 131His/Arg polymorphism is associated with subclinical atherosclerosis in non-smoking subjects. Furthermore, FcgammaRIIa genotype is associated with IgG(2) titres to bacterial CWPS, but not to OxLDL. These data propose possible involvement of FcgammaRIIa receptor in atherogenesis.

ApoE phenotype is associated with inflammatory markers in middle-aged subjects.

OBJECTIVES: Apolipoprotein (apo) E phenotype has been associated with inflammation markers. The determinants of these associations and the relationship between novel inflammation marker, resistin, and apoE phenotype are studied here. METHODS AND RESULTS: Middle-aged subjects of the population- based cohort (n = 526) of the OPERA- study were studied. Intima-media thickness (IMT) was measured with carotid ultrasound. The results suggest that, apoE phenotype was a significant independent predictive factor for resistin (p < 0.01) and hsCRP (p < 0.01) levels. The association of ApoE phenotype with hsCRP was seen among the subjects with the normal renal function (p = 0.005). ApoE4 was associated (p < 0.01) with the lowest hsCRP in the lowest IMT quartile while it's relation with the highest resistin levels was evident in the highest IMT quartile. CONCLUSIONS: ApoE phenotype is an independent determinant of plasma resistin and hsCRP levels. The extent of atherosclerosis and renal function seem to modify the effects of apoE phenotype on inflammatory parameters.

The effect of a short-term hypocaloric diet on liver gene expression and metabolic risk factors in obese women.

BACKGROUND AND AIMS: Most gene expression studies examining the effect of obesity and weight loss have been performed using adipose tissue. However, the liver also plays a central role in maintaining energy balance. We wanted to study the effects of a hypocaloric diet on overall hepatic gene expression and metabolic risk factors. METHODS AND RESULTS: The study subjects were middle-aged, obese women. The diet intervention subjects (n=12) were on a hypocaloric, low-fat diet for 8 weeks with a daily energy intake of 5.0 MJ (1200 kcal), while the control subjects (n=19) maintained their weight. Liver biopsies were taken at the end of the diet period during a gallbladder operation. Hepatic gene expression was analyzed using microarrays by comparing the gene expression profiles from four subjects per group. A global decrease in gene expression was observed with 142 down-regulated genes and only one up-regulated gene in the diet intervention group. The diet resulted in a mean weight loss of 5% of body weight. Triglyceride and fasting insulin concentrations decreased significantly after the diet. CONCLUSIONS: The global decrease in hepatic gene expression was unexpected but the results are interesting, since they included several genes not previously linked to weight reduction. However, since the comparison was made only after the weight reduction, other factors in addition to weight loss may also have been involved in the differences in gene expression between the groups. The decrease in triglyceride and fasting plasma insulin concentrations is in accordance with results from previous weight-loss studies.

Leptin and lipid metabolism in chronic kidney failure.

OBJECTIVE: In the general population, leptin has been associated with atherosclerosis and has been shown to interfere with lipoprotein profiles. Patients with chronic renal failure are at increased risk of cardiovascular disease and display alterations in both lipoprotein and leptin levels. The aim of this study was to investigate the relationship between leptin and the lipoprotein profile in non-dialyzed patients with chronic kidney disease (CKD). MATERIAL AND METHODS: Leptin and lipid and lipoprotein concentrations were studied in 73 CKD patients and in 68 healthy controls in a cross-sectional case-control design. RESULTS: The mean leptin levels were increased in the CKD patients (24.0 (SD 37.1) ng/mL) compared to those in controls (9.0 (SD 8.5) ng/mL) (p = 0.008). Also, the ratio between leptin levels and body mass index (leptin/BMI) was increased in CKD patients (mean 0.80 (SD 1.03)) compared to that in controls (0.31 (SD 0.24)) (p = 0.001). In linear regression analysis, leptin independently predicted total cholesterol and triglycerides in CKD patients (p = 0.010 and p = 0.001, respectively) and ratio between total and HDL cholesterol (Chol/HDL) in controls (p = 0.024). Furthermore, in CKD patients, the leptin/BMI predicted the variation in total cholesterol and triglycerides (p = 0.010 and p = 0.002, respectively). CONCLUSIONS: Leptin concentrations and leptin/BMI were elevated in CKD patients compared to those in controls. Leptin levels in both study groups, and leptin/BMI in the CKD group, were associated with atherogenic lipid profiles, which may contribute to the elevated cardiovascular risk that has been linked to hyperleptinaemia.

Gastric bypass and glucose metabolism.

Roux-en-Y gastric bypass leads to a marked improvement of glucose control. The mechanisms are only partly known. Gastrointestinal hormones may play a role. Of these, glucagon-like peptide 1 and peptide YY have been most consistently associated with the beneficial effects of gastric bypass on glucose metabolism and weight. In this paper, a short review of the topic is presented and a suggestion of the improvement of glucose metabolism is made based on the current published work.

Cord compression may rapidly influence the expression of placental angiogenic genes in pre-eclampsia.

Gene expression studies have demonstrated the altered expression level of placental angiogenesis related genes in severe pre-eclampsia (PE). In cord compression, the transportation of oxygen from the placenta to the fetus is blocked, and it is speculated that during blockade the originally hypoxic placenta may become hyperoxic. We compared the placental gene expression profiles of one pre-eclamptic patient with cord compression (the index patient) to the profiles of patients with PE and those of normal pregnancy controls (including one woman with cord compression). The gene expression of the cord compression PE patient resembled that observed in the normal pregnancies. We hypothesize that umbilical blockade may in a short period of time lead to placental hyperoxia, which in turn has an effect on angiogenic gene expression profile.

Adiponectin concentration and insulin indicators following overfeeding in identical twins.

UNLABELLED: Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes. OBJECTIVE: To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations. SUBJECTS AND DESIGN: Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding. INTERVENTION: Subjects were overfed by 84,000 kcal over a 100-day period. OUTCOME MEASURES: The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin. RESULTS: Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait. CONCLUSIONS: These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.

Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study.

OBJECTIVE: Abdominal obesity, insulin resistance and compensatory hyperinsulinaemia play a central role in the pathogenesis of the polycystic ovary syndrome (PCOS). Abdominal adipose tissue is a source of adipokines, such as adiponectin and resistin, both of which may be involved in the development of insulin resistance and chronic inflammation in PCOS. Ghrelin, an important regulatory peptide of food intake, may also play a role in metabolic disturbances related to PCOS. The aim of this study was to examine the effects of 4 months of treatment with the insulin sensitizer rosiglitazone on plasma adiponectin, resistin and ghrelin levels in overweight women with PCOS. DESIGN: A randomised placebo-controlled study. METHODS: Thirty overweight/obese women with PCOS (body mass index>25 kg/m(2), mean age 29.1+/- 1.2 (S.E.M.) years) were randomly allocated to either rosiglitazone (Avandia, 4 mg twice a day) or placebo treatment. Plasma levels of adiponectin, resistin and ghrelin and their correlation to serum levels of insulin, C-peptide and steroid hormones, and insulin sensitivity (euglycaemic hyperinsulinaemic clamp) were assessed. RESULTS: Adiponectin and ghrelin levels correlated significantly with most metabolic markers of insulin resistance and with serum levels of DHEA and 17-hydroxyprogesterone. Plasma levels of adiponectin increased from 9.26+/-0.90 (S.E.M.) to 22.22+/-3.66 microg/ml (P<0.001) and those of resistin decreased from 12.57+/-1.63 to 9.21+/-0.53 ng/ml (P=0.009) at 4 months of treatment, but plasma ghrelin levels did not change. CONCLUSIONS: Rosiglitazone had beneficial effects on serum levels of adiponectin and resistin, suggesting that these adipocytokines may contribute to the improvement in insulin sensitivity observed during the treatment.

Leu7Pro polymorphism of PreproNPY associated with an increased risk for type II diabetes in middle-aged subjects.

OBJECTIVES: Neuropeptide Y (NPY) plays a central in energy homeostasis and potentially in the development of obesity-related comorbidities, like type II diabetes. As the PreproNPY Leu7Pro polymorphism probably changes the intracellular processing of the synthesized preproNPY peptide, we assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance and hypertension. DESIGN: Blood pressure recordings and oral glucose tolerance test were performed in the hypertensive (n=515) and control cohorts (n=525) of our well-defined Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study. The prevalence of type II diabetes was 9% (n=93). The genotypes, insulin and glucose metabolism indexes and plasma ghrelin of the subjects were determined. RESULTS: Pro7 allele frequencies were 5.9, 5.3 and 11.3% in the total cohort, in subjects without and with type II diabetes, respectively. The PreproNPY Pro7 carrier status was a significant risk factor for type II diabetes, and the effect remained significant after adjustment for age, sex, waist circumference and study group (odds ratio=3.02, confidence interval: 1.67-5.44 and P<0.001). Pro7 carriers were more insulin resistant and showed lower ghrelin levels compared to non-carriers. CONCLUSIONS: The PreproNPY Pro7 allele is associated with an increased risk for type II diabetes. The risk seems to be associated with a higher insulin resistance among Pro7 carriers whereas low ghrelin concentrations in Pro7 carriers are possibly a consequence of high insulin levels.

High plasma leptin levels are associated with impaired diastolic function in patients with coronary artery disease.

BACKGROUND AND AIMS: Obese subjects have elevated leptin levels, which have been associated with increased risk of cardiovascular events. Because leptin has direct cellular effects on various tissues, we tested the hypothesis that leptin levels are associated with cardiac structure or function in patients with coronary artery disease (CAD). METHODS AND RESULTS: The study population consisted of 1 601 CAD patients, of whom 42% had type 2 diabetes mellitus. Plasma leptin was measured in fasted state and an echocardiography performed. Leptin levels were not related to LV dimensions or LV ejection fraction (NS for all), but higher leptin levels were associated with elevated E/E' (9.43 vs. 11.94 in the lowest and the highest leptin quartile, respectively; p=0.018 for trend). Correspondingly, a decreasing trend was observed in E/A (1.15 vs. 1.06; p=0.037). These associations were independent of obesity and other relevant confounding variables. CONCLUSION: We conclude that elevated plasma leptin levels are associated with impaired left ventricular diastolic function in patients with CAD independently of obesity and other confounding variables. Leptin may be one of the mechanistic links explaining the development of congestive heart failure in obese subjects.

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus.

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electrocardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4-5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1-3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0-2.2) or the D/D genotype patients (OR 1.7; CI 1.1-2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138 +/- 19 mmHg) than in those with the genotype I/D (149 +/- 22 mmHg) or D/D (150 +/- 21 mmHg; P < 0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.

Dietary sodium intake and prediction of cardiovascular events.

BACKGROUND/OBJECTIVES: The association of dietary sodium and cardiovascular disease (CVD), as well as the reduction of sodium intake in the prevention of CVD, has been under debate. To study whether sodium consumption has a role as a risk factor for fatal and non-fatal CVD. SUBJECTS/METHODS: A well-defined population-based cohort of 1045 subjects collected between 1991 and 1993 (mean age 51.4 years) was used with approximately 19 years' follow-up. At the baseline, 716 subjects filled in a 1-week food follow-up diary, which was used to calculate the daily sodium intake (mg/1000 kcal). RESULTS: The baseline sodium intake correlated significantly with age (rs=0.117, P=0.002), BMI (rs=0.216, P=0.000), waist circumference (rs=0.268, P=0.000), smoking (rs=0.144, P=0.000), alcohol consumption (rs=0.111, P=0.003), systolic blood pressure (rs=0.106, P=0.005) and low-density lipoprotein (LDL) cholesterol (rs=0.081, P=0.033). Those who had cardiovascular events in the follow-up consumed more sodium at the baseline (mean 2010.4 mg/1000 kcal/day, s.d. 435.2, n=101) compared with the subjects without events (mean 1849.9 mg/1000 kcal/day, s.d. 361.2, n=589; t-test; P=0.001). The incidence of cardiovascular events was greater in the highest quartile (22.1%) than in the lower quartiles (first 11.0%, second 9.9% and third 15.6%; X(2); P=0.005). Cox regression analysis showed that sodium intake as a continuous variable predicts CVD events (P=0.031) independently when age, sex, smoking, alcohol consumption, systolic blood pressure, LDL cholesterol and waist circumference were added as covariates. This predictive role is seen especially in the group of subjects on hypertensive medication (P=0.001). CONCLUSIONS: Dietary sodium intake is a significant independent predictor of cardiovascular events in the study population.

Mutations in the preproghrelin/ghrelin gene associated with obesity in humans.

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/- 3.4 kg/m(2)) and in 96 non-obese female controls (mean BMI 23.0 +/- 1.4 (kg/m2) of the Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg51Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p < 0.05). The self-reported weight at 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respectively, among obese Gln allele carriers versus obese non-carriers. In addition, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detected in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozygotes) subjects. This mutation outside the coding region of the mature ghrelin product tended to be associated with lower age of self-reported onset of obesity (15.6 +/- 7.9 vs. 20.5 +/- 10.5 years; p = 0.09). In addition to these two mutations in coding regions, a G274A base change in a non-coding region between exons one and two was found only in two obese individuals. The Arg51Gln amino acid substitution may alter the cleavage site of endoproteases and the length of the mature ghrelin product. The functional significance of the Leu72Met mutation and a G274A base change remains to be determined. In conclusion, the data provide evidence that a low frequency sequence variation in the ghrelin gene could play a role in the etiology of obesity.

Role of candidate genes in the responses to long-term overfeeding: review of findings.

An overfeeding experiment conducted with 12 pairs of young male identical twins revealed that genetic factors were likely to play an important role in the response to caloric affluence. Significant intrapair resemblance was observed for the overfeeding-induced changes in body weight, fat mass, abdominal fat, fasting insulin, fasting cholesterol and triglycerides. In an attempt to define the molecular basis of these genotype-energy balance interaction effects, a panel of candidate genes has been investigated. Among the most significant findings, an adipsin polymorphism was associated with increases in body weight, total fat mass and subcutaneous fat in response to overfeeding. In addition, the beta2 adrenergic receptor gene Gln27Glu polymorphism showed a strong association with the gains in body weight and subcutaneous fat. Only a few markers were related to abdominal fat changes and, among them, the adipsin Hinc II polymorphism was associated with both computed tomography (CT)-measured abdominal visceral and total fat. The changes in insulin parameters brought about by long-term overfeeding were influenced most consistently by leptin receptor (LEPR) Gln223Arg and insulin-like growth factor-II Apa I polymorphisms. The LEPR Gln223Arg variant was also associated with the changes in plasma total triglycerides and high-density lipoprotein cholesterol concentrations. Further research with larger sample sizes should make it possible to identify the specific contributions of DNA sequence variations at multiple candidate gene loci in the complex response to chronic positive energy balance.

Glucocorticoid receptor Bcl I variant is associated with an increased atherogenic profile in response to long-term overfeeding.

The effect of the glucocorticoid receptor (GRL) gene Bcl I polymorphism on body composition and metabolic changes in response to overfeeding was studied. Twenty-four men (mean age 21+/-2 years) who constituted 12 pairs of identical twins ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. The GRL Bcl I marker was identified by Southern Blot technique. Total body fat was assessed by hydrodensitometry and abdominal fat areas were measured by computed tomography. Fasting plasma glucose and insulin during an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezoidal method. Triglyceride and cholesterol concentrations in plasma and lipoprotein fractions were determined enzymatically. The results showed that overfeeding induced a greater increase in body weight (p=0.002) in the 2.3/2.3 kb (n=12) than in the 4.5/2.3 kb (n=12) subjects. In addition, plasma levels of total (p=0.007) and low-density lipoprotein (LDL) cholesterol (p=0.003), as well as systolic blood pressure (p=0.036) increased more in the 2.3/2.3 kb than in the 4.5/2.3 kb subjects. The 2.3/2.3 kb genotype was also associated with a greater increase in abdominal visceral fat (p=0.040) compared to the 4.5/2.3 kb genotype. In conclusion, 2.3/2.3 kb subjects of the GRL Bcl I polymorphism experience greater increases in body weight, blood pressure and cholesterol levels as well as visceral fat than 4.5/2.3 kb subjects in response to overfeeding. These data suggest that overfeeding induces an atherogenic profile in subjects who are homozygotes for the 2.3 kb allele.

Apolipoprotein E phenotype is related to macro- and microangiopathy in patients with non-insulin-dependent diabetes mellitus.

The role of apoliprotein E (apo E) in modulating the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 143 male and 128 female patients with NIDDM. The data show that the apolipoprotein phenotype E2 somehow protects from macrovascular complications in NIDDM both in men and women. E2 also tends to protect from microvascular complications. In contrast, apo E phenotypes E4/4 and E4/3 tend to increase the risk for macroangiopathy in NIDDM patients. The lower prevalence of macroangiopathy in the subjects with E2 was associated with lower plasma total and LDL cholesterol concentrations and low plasma lipoprotein(a) levels. Overall, this study demonstrates the role of the apo E phenotype to modulate the risk for diabetic complications in patients with NIDDM. The confirmation of the association of apo E polymorphism with diabetic complications warrants, however, long-term follow-up studies.