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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%; X2; 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. [ABSTRACT FROM AUTHOR]

The roles of ghrelin, a peptide hormone that has a role in regulating food intake and energy homeostasis, in the cardiovascular system have not yet been unambiguously established. We evaluated the association between plasma ghrelin concentrations and −501A>C single-nucleotide polymorphism (SNP) in the ghrelin gene 5′ flanking area and echocardiographic measurements in 1037 middle-aged subjects. Left ventricular mass index (LVMI) was calculated according to Devereux's method. The ambulatory blood pressure (BP) was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Results suggested that plasma ghrelin was not related to mean ambulatory BP values. However, the highest plasma ghrelin tertile was associated with increased intraventricular septum (P=0.043) and posterior ventricular wall (P=0.002) thicknesses as well as left ventricular mass (P=0.05). After adjustment for age, sex, body mass index and systolic BP, the association persisted between ghrelin tertiles and intraventricular septum (P=0.05) and posterior ventricular wall (P=0.001) thicknesses. The SNP −501A>C polymorphism was associated with LVMI after adjustments for age, sex and systolic BP. In conclusion, ghrelin and its promoter variant are associated with cardiac hypertrophy indexes independent of BP. Positive correlation between ghrelin levels and increased wall thickness parameters may reflect compensatory up-regulation of ghrelin concentrations or direct effects of ghrelin on myocardium. The effects of the SNP seem not to be mediated through its effects on ghrelin plasma levels. [ABSTRACT FROM AUTHOR]

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//m2 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. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyse the relationship between the ambulatory blood pressure (ABP) measurement and plasma adiponectin levels in a population-based cohort. Non-hypertensive, non-diabetics from the Oulu Project Elucidating Risk of Atherosclerosis cohort aged 40–60 years with ABP measurement available in 226 men and 236 women were analysed. ABP was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Plasma adiponectin concentrations were assayed using the enzyme-linked immunosorbent assay method. Without adjustment the highest plasma adiponectin tertile was associated with the lowest ABP and office BP measurements (P from 0.025 to P<0.001, respectively). Only the association of plasma adiponectin concentration with systolic ABP was independent of other conventional risk factors (age, body mass index (BMI), waist, gender, insulin sensitivity index, smoking and alcohol consumption) for hypertension (P=0.017). No association was observed between systolic dipping pattern and adiponectin level. The plasma high adiponectin concentration is independently associated with low daytime systolic ABP value. The mechanisms may include effects on endothelial function and the sympathetic nervous system. [ABSTRACT FROM AUTHOR]

A non-dipping pattern in ambulatory blood pressure monitoring (ABPM) increases the risk of cardiovascular disease. The association between renal function and the dipping pattern has not been studied in a random middle-aged population. This is a cross-sectional population-based study of 226 males and 234 females aged 40 to 62 years. Renal function was assessed with estimated glomerular filtration rate (eGFR). Non-dipping status was defined as a reduction of <10% between the daytime and the nighttime systolic BP. Non-dippers represented 18.7% of the study population. Their mean eGFR was 79.1 (s.d. 15.7) ml min–1 per 1.73 m2 as compared with a mean eGFR of 84.1 (s.d. 16.2) ml min–1 per 1.73 m2 in dippers (P=0.005); this difference remained significant after adjustments. Subjects in the lowest and in the middle eGFR tertiles had an independently increased risk of non-dipping in comparison with those in the highest eGFR tertile (odd ratios (OR), 2.34 (95% confidence interval (CI), 1.18 to 4.63) and OR, 2.01 (95% CI, 1.06 to 3.83), respectively). This study showed that even a minor deterioration in renal function is associated with increased risk of non-dipping pattern in ABPM in a random middle-aged population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcγRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG2 ICs and a functional point mutation 131His/Arg diminishes IgG2 binding to the receptor. Study design We examined FcγRIIa-131His/Arg polymorphism, IgG2 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 IgG2 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 FcγRIIa genotype and antibody titres to OxLDL. Conclusions Our data demonstrate that FcγRIIa 131His/Arg polymorphism is associated with subclinical atherosclerosis in non-smoking subjects. Furthermore, FcγRIIa genotype is associated with IgG2 titres to bacterial CWPS, but not to OxLDL. These data propose possible involvement of FcγRIIa receptor in atherogenesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.Sponsorship:None.European Journal of Clinical Nutrition (2007) 61, 1102–1105; doi:10.1038/sj.ejcn.1602621; published online 31 January 2007 [ABSTRACT FROM AUTHOR]

Background. Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima-media thickness (IMT) in a population-based cohort of 1024 middle-aged (40–60 years) men and women. Methods. Intima-media thickness and the number of atherosclerotic plaques were determined ultrasonographically. Fasting plasma ghrelin concentrations were analysed using RIA-kit (PhoenixPeptide). Results. There was a positive association between mean IMT and ghrelin concentration in the analysis of males before and after adjustments for the traditional risk factors of atherosclerosis [age, systolic blood pressure, LDL cholesterol, body mass index (BMI), and smoking (ancova, P = 0.004 and P = 0.007, respectively)]. However, no such association was found in females ( P = 0.985 and P = 0.915). There was no correlation between ghrelin and CRP concentrations or ghrelin and smoking. Conclusion. Ghrelin concentrations and carotid artery atherosclerosis are positively associated in males even after adjustment for the commonly recognized risk factors of atherosclerosis. Experimental and prospective studies are warranted to elucidate the role of ghrelin in atherosclerosis. [ABSTRACT FROM AUTHOR]

Resistin is a hormone secreted by adipocytes and it is also expressed in monocytes. Resistin has been found to increase insulin resistance, a key feature in Type 2 diabetes. The aim of this study was to investigate whether resistin polymorphisms are associated with Type 2 diabetes and its clinical characteristics.We studied the allele and genotype frequencies of the single-nucleotide polymorphisms (SNPs)−420 (C > G),+157 (T > C) and+299 (G> A) in the resistin gene in 258 Finnish Type 2 diabetics and 494 controls.These three markers were in significant linkage disequilibrium with each other. No significant (P < 0.05) differences in the allele or genotype frequencies were observed between the study groups. Subjects with Type 2 diabetes showed a significant association between cerebrovascular disease and the SNPs−420 (P = 0.004) and+299 (P = 0.007), the G-G and A-A genotypes, respectively, had the highest frequencies. SNPs−420 (P = 0.000) and+299 (P = 0.002) in men and SNP+157 in men (P = 0.005) and in women (P = 0.019) showed significant association with higher mean blood glucose. The rare allele homozygotes also had the highest mean blood glucose values. We also observed associations between at least one of the SNPs and fasting blood glucose, glycosylated haemoglobin A1 (GHbA1), low-density lipoprotein (LDL) cholesterol and systolic and diastolic blood pressure. After correction for multiple comparisons, the association between the promoter variant SNP−420 and cerebrovascular disease in both genders and the associations between mean blood glucose and SNP−420 and SNP+299 in men remained significant.The results suggest that resistin may play a role in atherogenesis probably through increasing insulin resistance.Diabet. Med. 22, 583–589 (2005) [ABSTRACT FROM AUTHOR]

Abstract Aims/hypothesis: Ghrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association. Methods: We analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middleaged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI. Results: IGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (β= -0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (β=-0.40, p<0.001). The association was particularly strong in males and in the higher BMT tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r2=6.5% (p<0.001), insulin resistance without type 2 diabetes: r2=21.0% (p< 0.001), type 2 diabetes: r2=25.4 (p<0.001). IGF-I levels explained larger proportion (r2=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r2=3.0%) and BMI (r2=1.5%). Conclusions/interpretation: There is a negative and independent association between ghrelin and IGF-I concentrations in middleaged subjects. The interaction between IGF-I and ghrelin is modified by obesity, JR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states. [ABSTRACT FROM AUTHOR]

Santaniemi M, Ukkola O, Kesäniemi YA (University of Oulu, Oulu, Finland). Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2 diabetes. J Intern Med 2004; 256: 48–55. The association between three tyrosine phosphatase 1B (PTP1B) gene polymorphisms and type 2 diabetes was examined by comparing the prevalence rates of these polymorphisms in type 2 diabetic patients and healthy control subjects. Furthermore, the association of the polymorphisms and PTP1B and leptin receptor (LepR) gene­gene interactions with complications of type 2 diabetes were examined in type 2 diabetic patients. We did not find any differences in the genotype distributions or allele frequencies of IVS6 + G82A and Pro387Leu polymorphisms between the type 2 diabetics and controls. There were differences in the genotype frequencies of the Pro303Pro (C981T) ­ polymorphism between the two studied groups (P = 0,018); there were eight T981T subjects in the control population but none amongst the type 2 diabetics. However, there were no differences in the allele frequencies. In addition, significant associations between the IVS6 + G82A polymorphism and body mass index (BMI), albuminuria, glycohaemoglobin A1 (GHBA1) and hypertension in type 2 diabetic patients (P = 0,026–0,031) were observed. Pro387Leu and Pro303Pro did not associate with risk factors or diabetic complications. We also found a gene­gene interaction effect between PTP1B and the LepR gene with the genotype combination IVS6 + A82A and Arg223Arg having the highest BMI compared with the other genotype combinations (P = 0.0043 for trend). The interaction between these two polymorphisms explained 3% of the variation in BMI in diabetic patients when the other covariates were taken into account. We conclude that the PTP1B IVS6 + G82A polymorphism was associated with BMI, albuminuria, GHBA1 and hypertension in type 2 diabetic patients. The 981T/T-genotype of the Pro303Pro- polymorphism might have some protective role against the development of type 2 diabetes. The interaction effects between the PTP1B IVS6 + A82A and LepR Arg223Arg genotypes influenced BMI, explaining 3% of its variation. A synergistic effect of PTP1B and LepR variants on the leptin signalling may be involved. [ABSTRACT FROM AUTHOR]

OBJECTIVE AND SUBJECTS:: To investigate the role of resistin gene variants on the adiposity and metabolic changes observed in response to a 100-day overfeeding protocol conducted with 12 pairs of monozygotic twins. MEASUREMENTS:: Body-fat measurements included hydrodensitometry and abdominal fat from computed tomography. Plasma glucose and insulin during fasting and in response to an oral glucose tolerance test (OGTT) were assayed. A 4.2?MJ test meal was consumed, after which calorimetric measurements were performed for 240?min. RESULTS:: Respiratory quotient (RQ) decreased (P=0.001) more in AA/AG than in GG subjects of the IVS2+181G>A polymorphism after the caloric surplus and the significance persisted when correction for multiple testing was performed. Total abdominal (P=0.027) and visceral (P=0.004) fat increased more in TC than in TT subjects of the IVS2+39C>T polymorphism. In response to overfeeding, glucose area under the curve during the OGTT showed a slight decrease (P=0.031) in the TC while it increased in TT subjects. OGTT insulin area tended to increase less (P=0.055) in TC than in TT subjects. After overfeeding, fasting insulin was lower in TC than in TT subjects (P=0.010). In addition, TC subjects experienced more decrease in RQ than TT subjects (P=0.034). CONCLUSION:: The IVS2+181G>A variant was associated with the changes in RQ in response to overfeeding. The IVS2+39C>T polymorphism was associated with overfeeding-induced changes in abdominal visceral fat, OGTT glucose area and RQ. The results suggest that sequence variation in the resistin gene is involved in the adaptation to chronic positive energy balance.European Journal of Clinical Nutrition (2004) 58, 654-659. doi:10.1038/sj.ejcn.1601861 [ABSTRACT FROM AUTHOR]

Abstract Ukkola O, Kesäniemi YA (University of Oulu, Oulu, Finland). Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. J Intern Med 2003; 254: 391–394. Objectives. The association between the Leu72Met polymorphism of the preproghrelin gene and diabetic complications was examined in patients with type 2 diabetes mellitus. Subjects and methods. A total of 258 patients with type 2 diabetes mellitus and 522 control subjects were screened. Genotypes were determined by polymerase chain reaction technique. The diagnosis of coronary heart disease was based on clinical and ECG criteria. Laboratory analyses were carried out in the hospital laboratory. Results. No differences in the genotype distributions and allele frequencies of the preproghrelin Leu72Met polymorphism were found between type 2 diabetes mellitus patients and controls. The polymorphism was not associated with macro- or micro-angiopathy or hypertension. However, Leu72Met polymorphism was associated with serum creatinine (P = 0.006) and lipoprotein(a) [Lp(a)] levels (P = 0.006) with Leu72Leu subjects showing the highest values. This association was observed only amongst diabetic group. Conclusions. The Leu72Met polymorphism of the preproghrelin gene was not related to cardiovascular disease in type 2 diabetes mellitus patients. Leu72Met polymorphism was, however, associated with serum creatinine and Lp(a) levels in diabetic patients. The mechanism might be associated with a possible change in ghrelin product and its somatotropic effect. [ABSTRACT FROM AUTHOR]

Objectives: The role of adipsin and adipsin Hinc II polymorphisms on the metabolic and body composition changes in response to overfeeding was studied. Subjects: A total of 12 pairs of male monozygotic twins ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. Results: The preoverfeeding plasma adipsin concentration correlated positively with the change in CT-measured abdominal total and subcutaneous (P<0.05) fat. The changes in abdominal total fat and abdominal subcutaneous fat correlated negatively with changes in plasma adipsin concentrations (P<0.005). Overfeeding induced greater increases in body weight, fat mass, abdominal total and subcutaneous fat (P<0.05) in 6.1 kb noncarriers (n = 10) than in 6.1 kb carriers (n = 14) of the adipsin Hinc II polymorphism. The 6.1 kb noncarriers had a greater increase in plasma leptin levels (P<0.01). Also the total (P<0.01) and very-low-density lipoprotein (VLDL)-triglycerides (P<0.05), apolipoprotein B (P<0.05) and VLDL-cholesterol (P<0.05) levels increased more in the 6.1 kb noncarriers than in the 6.1 kb carriers. Conclusions: Adipsin plasma level could be a predictor of the changes in abdominal subcutaneous fat during times of increased energy intake. However, a greater increase in the abdominal subcutaneous fat was related to a lower increase in the plasma adipsin level. The adipsin Hinc II 6.1 kb allele noncarriers gained more abdominal subcutaneous fat and had a greater increase in plasma levels of leptin- and triglyceride-rich lipoproteins when exposed to a long-term positive energy balance. These findings provide new information on the role of adipsin on individual differences in response to chronically elevated food intake. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Experimental studies have suggested that ghrelin, a novel gastrointestinal peptide hormone, could play a role in glucose homeostasis. In addition, ghrelin has been associated with beneficial haemodynamic effects in experimental settings. Since the Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone and is associated with low ghrelin concentrations, we assessed the hypothesis that Arg51Gln mutation is a risk factor for Type 2 diabetes, impaired glucose tolerance, and hypertension. Methods. Blood pressure recordings and oral glucose tolerance test were carried out in the hypertensive (n=519) and control cohorts (n=526) of our well-defined OPERA study. The genotypes and plasma IGF-I and IGFBP-1 concentrations of 1031 subjects were analysed. Results. The ghrelin 51Gln allele was a risk factor for Type 2 diabetes, and the effect remained significant after adjustment for age, BMI, and study group (OR=2.53, CI: 1.11–5.75, p=0.027). In addition, the 51Gln allele was a risk factor for hypertension (OR=2.63, CI: 1.37–5.08, p=0.003). 51Gln carriers had lower concentrations of IGF-I and higher concentrations of IGFBP-1 compared to non-carriers. Conclusion/interpretation. The ghrelin 51Gln allele could increase the risk for Type 2 diabetes and hypertension. The low IGF-I concentrations in 51Gln carriers suggest that the mechanism might be associated with low GH concentrations. [ABSTRACT FROM AUTHOR]

OBJECTIVE AND SUBJECTS:: Interactions between markers in the B2- and B3-adrenergic receptor (ADR) genes and total body fat and computerized tomography-measured abdominal fat phenotypes were studied in the HERITAGE Family Study cohort of Black (n=205; 81 males and 124 females) and White (n=415; 198 males and 217 females) subjects before and after an endurance training program. RESULTS:: In Black subjects, B2- and B3-ADR gene variants showed evidence of interactions on changes in total body fat mass and abdominal fat area (P<0.005 and =0.010, respectively). Black subjects who were carriers of both B2-ADR Arg16 and B3-ADR Arg64 alleles had a greater decrease in total fat mass as well as abdominal total and subcutaneous, but not visceral fat areas in response to endurance training than subjects with other genotype combinations (P from 0.011 to 0.047). After correction for multiple tests, the findings remained essentially unchanged for total body fat mass and abdominal fat area, but became nonsignificant for subcutaneous fat area. The changes in abdominal fat correlated positively with the changes in fat mass (P<0.0001). The interactions between B2 and B3-ADR gene markers accounted for a maximum of 3% of the variances in the response of total fat mass and abdominal fat area to endurance training in Black subjects but it was not significant in White subjects. CONCLUSION:: Interactions between sequence variants in the B2-B3-ADR gene contributed to the changes in fat mass and abdominal adiposity in response to endurance training in Black subjects.International Journal of Obesity (2003) 27, 389-393. doi:10.1038/sj.ijo.0802248 [ABSTRACT FROM AUTHOR]

Impaired insulin action is important in the pathophysiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signalling. This is best evidenced by studies on knockout mice showing that lack of PTP1B is associated with increased insulin sensitivity as well as resistance to obesity and in vitro studies whilst studies in animals and humans have given contradictory results. However, several studies support the notion that insulin signalling can be enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effective PTP1B inhibitor. The objective of this paper is to review the current evidence of PTP1B in the pathophysiology of obesity, type 2 diabetes and cancer as well as in the treatment of these disorders. [ABSTRACT FROM AUTHOR]

Objectives: The role of the lipoprotein lipase (LPL) gene Hind III, S447X, Bam HI and Pvu II polymorphisms on body composition and lipid and lipoprotein changes in response to long-term overfeeding was studied.Subjects: Twelve pairs of male monozygotic twins ate a 4.2 MJ day-1 energy surplus, 6 days a week, during a period of 100 days.Results: Overfeeding induced a decrease in high-density lipoprotein 2 cholesterol (HDL2-C) and HDL2-C to HDL3-C ratio in the H2H2 (n = 12) subjects of the LPL Hind III polymorphism. In contrast, the H1H1/H1H2 (n = 12) subjects experienced increases both in the HDL2-C and HDL2-C to HDL3-C ratio (P = 0.009 and 0.007, respectively, for differences in percentage changes between H2H2 and H1H1/H1H2). In addition, the H2H2 genotype was associated with higher levels of very-low-density lipoprotein triglyceride (VLDL-TG) (P < 0.03) and VLDL-C (P < 0.05) before and after overfeeding and higher HDL-TG levels (P < 0.003) after overfeeding. Postheparin lipoprotein lipase (PH-LPL) activity tended to increase in H1H1/H1H2 and decrease in H2H2 subjects. The H2H2 subjects had lower total HDL-C than those with the genotype H1H1/H1H2 4 months and 5 years after overfeeding (P = 0.04 and 0.10, respectively). The plasma lipid differences were similar amongst subjects with the S447S (n = 4) genotype of the S447X and H2H2 genotype of the Hind III polymorphisms. Body composition changes in response to overfeeding were not different between the Hind III genotypes. LPL Pvu II and Hind III polymorphisms were associated weakly with body weight gain (P = 0.015-0.039) but strongly with adipose tissue LPL activity (P < 0.01) after the caloric surplus.Conclusions: We conclude that the H2H2 subjects of the LPL gene Hind III polymorphism experience a decrease in the concentration of antiaterogenic lipoproteins when they are exposed to long-term positive energy balance. This may have been partly caused by a diminished catabolism of TG-rich particles in H2H2 subjects. LPL Pvu II and Bam HI polymorphisms were associated with body weight gain and adipose tissue LPL activity. Genetic variation at the LPL locus could thus be one of the factors responsible for the inter-individual differences observed in plasma lipid and lipoprotein responses to chronic positive energy balance. It must be kept in mind that the sample size for this study was small. Nonetheless, it provides useful information on the genes and pathways that should be further explored. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. The aim of this study was to investigate the role of insulin-like growth factor 1 (IGF1), IGF2, IGF binding protein 1 (IGFBP1) and IGFBP3 gene variants on the metabolic changes observed in response to a 100-day overfeeding protocol conducted with 12 pairs of monozygotic twins. Methods: Genotyping was done by PCR-RFLP and DNA sequencer methods. Body fat measurements included hydrodensitometry and abdominal fat from computed tomography. Plasma glucose and insulin during fasting and in response to an OGTT were assayed. Plasma lipids were measured enzymatically. Results: In response to caloric surplus, fasting plasma insulin (p < 0.05) and OGTT insulin (p = 0.004) but not glucose area, increased more among the subjects with IGF2 Apa I GG (n = 12) than those with AA + AG (n = 12). The changes were independent of changes in total fatness. The subjects with IGFBP1 Bgl II AA (n = 8) showed greater increases in abdominal visceral fat (p < 0.01), OGTT insulin area (p = 0.05) and total cholesterol (p < 0.03) with overfeeding than the subjects with AG + GG (n = 16). IGFBP3 Nde I and the IGF1 (CT)n markers were not associated with responsiveness to overfeeding. Conclusion/interpretation: Insulin sensitivity decreased in the subjects with IGF2 Apa I GG and the subjects with IGFBP1 Bgl II AA showed an accumulation of abdominal visceral fat and the early symptoms of the metabolic syndrome after long-term caloric surplus. Genetic variation at the IGF2 and IGFBP1 loci could be among the factors responsible for the inter-individual differences observed in the response to long-term alterations in energy balance and should be further investigated in larger cohorts. [Diabetologia (2001) 44: 2231–2236] [ABSTRACT FROM AUTHOR]

OBJECTIVE: The effects of alpha-2A (A2A)-, beta-2 (B2)- and beta-3 (B3)-adrenergic receptor (ADR) gene polymorphisms on adiposity, fat distribution and plasma insulin and leptin changes in response to long-term overfeeding were explored. METHODS: Twenty four men (mean (± s.d.) age 21 ± 2 y) who constituted 12 pairs of identical twins ate a 4.2 MJ/day energy surplus, 6 days a week, for a period of 100 days. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds. Abdominal fat areas were measured by computerized tomography (CT). Plasma glucose and insulin during fasting and in response to an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezoidal method. Plasma leptin was measured with an enzyme-linked immunosorbent assay. The ADR polymorphisms were identified by PCR or Southern blot technique. RESULTS: The ADRB2 GIn27GIn genotype (n = 10) was associated with a larger gain (percentage change) in weight (P < 0.001) and total subcutaneous (P < 0.005) fat than the Glu27Glu/GIn27Glu genotype (n = 14). In addition, overfeeding induced greater increases in the insulin areas under the curve during the OGTT and the fasting plasma level of leptin (P < 0.01 and < 0.03, respectively) among GIn27GIn than in the Glu27Glu/GIn27Glu subjects. The body composition and metabolic changes among the ADRB2 Banl 3.7/3.4 kb subjects (n = 10) were similar to those of GIn27GIn subjects. ADRA2A Dral (n = 4) 6.3/6.3 kb subjects experienced a decrease (-8%) while 6.7/6.3 kb subjects (n = 20) registered an increase (+10%; P = 0.017) of OGTT glucose area after the 100-day caloric surplus. The four carriers of the ADRB3 variant (Trp64Arg) experienced the same magnitude of changes as the 20 homozygotes for the Trp allele. In general, comparisons based on the 24 subjects considered as unrelated men and the mean values for each of the 12 pairs yielded similar results.... [ABSTRACT FROM AUTHOR]

Evaluates the effects of the uncoupling protein (UCP) 1, UCP2 and UCP3 gene variants on body composition and metabolic changes in response to chronic overfeeding and the recovery after the period of overfeeding. Changes in body weight; Resting metabolic rate measurements before and after overfeeding; Measurement of thyroid stimulating hormone concentrations after a thyrotropin releasing hormone injection.

OBJECTIVE:: To investigate whether interactions between glucocorticoid receptor (GRL), lipoprotein lipase (LPL) and adrenergic receptor (ADR) gene markers contribute to individual differences in indicators of adiposity and abdominal obesity, including visceral fat level. DESIGN AND SUBJECTS:: Cross-sectional study; 742 individuals from the phase 2 of the Québec Family Study cohort. MEASUREMENTS:: Total body fat assessed by hydrodensitometry and the sum of six skinfolds. Abdominal fat areas measured by computed tomography and adjusted for age, sex and total fat mass in all analyses. GRL Bcl I, α2A-ADR Dra I and β2-ADR Ban I markers were typed by Southern blot, and other markers by polymerase chain reaction technique. RESULTS:: It is confirmed that the 4.5 kb allele of the GRL BclI polymorphism is associated with a higher amount of abdominal visceral fat (AVF) depot (P for trend<0.001) independent of the level of total body fat. Furthermore, the α2-ADR Dra I variant is associated with lower cross-sectional areas of abdominal total (P=0.003) and subcutaneous (P=0.012) adipose tissue. Gene–gene interactions between GRL and α2-ADR genes affecting overall adiposity (P=0.016) as well as between GRL and β2-ADR genes (P=0.049) having influence on total abdominal fat levels were observed. When the three genes were considered together in the same analysis, significant interactions having influence on overall adiposity (P=0.017), abdominal total (P=0.032) and visceral fat (P=0.002) were observed. About 1–2% of the total variation in total fatness and abdominal fat was explained by these gene–gene interactions. CONCLUSION:: There is an association between the GRL BclI polymorphism and increased AVF levels independent of the level of total body fat. The α2-ADR DraI variant is associated with a lower cross-sectional area of abdominal total fat. Numerous interactions between GRL and ADR markers on overall adiposity and... [ABSTRACT FROM AUTHOR]

Abstract. Ukkola O, Erkkilä PH, Savolainen MJ, Kesäniemi YA (University of Oulu, Oulu, Finland). Lack of association between polymorphisms of catalase, copper–zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Intern Med 2001; 249: 451–459. Objectives. The association between the polymorphisms of three different antioxidative enzyme – catalase, copper–zinc superoxide dismutase (Cu/ Zn-SOD) and extracellular superoxide dismutase (EC-SOD) – genes and macroangiopathy was examined in patients with type 2 diabetes mellitus. The prevalence of the missense Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene and its association with macroangiopathy were also determined. Design. Cross-sectional study. Setting. District around Oulu University Hospital, North Finland. Subjects and methods. A total of 239 patients with type 2 diabetes mellitus and 245 control subjects were screened. Genotypes were determined by polymerase chain reaction (PCR) technique. The diagnosis of coronary heart disease (CHD) was based on clinical and ECG criteria. The prevalences of cerebrovascular (CVD) and peripheral vascular diseases (PVD) were assessed on the basis of clinical criteria. Laboratory analyses were carried out in the hospital laboratory. Results. No differences in the genotype distributions and allele frequencies of the antioxidative enzymes were found between type 2 diabetes mellitus patients and controls. The eNOS genotypes and allele frequencies were also similar in the diabetic patients and controls being close to that reported earlier in the British population. None of the polymorphisms were associated with macro- or microangiopathy or hypertension. However, male diabetic patients with eNOS Asp298Asp genotype had higher plasma very-low density lipoprotein (VLDL) cholesterol and VLDL-triglyceride concentrations than those with the genotypes Glu298Glu or Glu298Asp (P < 0.01 for trend). Conclusions. The polymorphism of catalase, Cu/Zn SOD and EC-SOD genes were not related to cardiovascular disease in type 2 diabetes mellitus patients. The eNOS Glu298Asp variant was associated with plasma VLDL-containing lipoproteins but not with macroangiopathy in diabetic male patients. The findings do not support the notion that the polymorphisms of the key antioxidative enzymes could be amongst the factors that explain the high prevalence of macroangiopathy in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Objectives: The role of the leptin receptor (LEPR) gene Gln223Arg polymorphism on the metabolic and body composition changes in response to overfeeding was studied.Subjects: Twelve pairs of male monozygotic twins ate a 4.2 MJ day-1 energy surplus, 6 days week-1, during a period of 100 days.Results: Overfeeding induced a significantly greater increase in glucose (P = 0.001 for percentage change) and insulin (P = 0.038) areas under the curve during oral glucose tolerance tests (OGTTs) in the GlnGln (n = 10) than in the GlnArg/ArgArg (n = 14) subjects. In addition, the GlnGln genotype was associated with a greater increase in plasma levels of leptin (P = 0.037) and total triglycerides (P = 0.003), as well as a greater decrease in high-density lipoprotein cholesterol (P = 0.010), than for the combined GlnArg/ArgArg genotypes. Body composition changes were not different between the genotypes.Conclusions: We conclude that the GlnGln subjects of the LEPR gene polymorphism are more susceptible to metabolic abnormalities when they are exposed to long-term positive energy balance. These findings provide new information on the genetic basis of individual differences in response to chronically elevated food intake. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of polymorphisms in codon 16 (Arg16Gly) and codon 27 (Gln27Glu) of the beta2-adrenergic receptor gene (ADRB2) on anthropometric, endocrine, metabolic and haemodynamic variables.Design: A cross-sectional study.Subjects: A subgroup of 284 Swedish men from a population sample of 1040 at the age of 51 years.Main Outcome Measures: Genotype examination of ADRB2 polymorphisms in codon 16 and codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Anthropometric measurements included body mass index, waist-to-hip ratio and abdominal sagittal diameter. Endocrine measurements included blood levels of testosterone, insulin-like growth factor I, and leptin plus salivary cortisol. Overnight fasting values of serum insulin, blood glucose, triglycerides, total, low and high density lipoprotein cholesterol, as well as blood pressure and resting heart rate, were also determined.Results: Polymorphisms were frequent in both codon 16 and codon 27. The Arg16Gly genotype showed significant relationships to elevated central distribution of body fat and to systolic blood pressure, whilst the Glu27Glu genotype was associated with elevated leptin and triglyceride levels but not to other measurements, including obesity variables.Conclusions: We conclude that only a few cardiovascular risk factors are associated with DNA sequence variation in the ADRB2 in Swedish men. [ABSTRACT FROM AUTHOR]

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 electro-cardiographic 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. [ABSTRACT FROM AUTHOR]

Editorial. Discusses the role of ghrelin peptide on glucose and insulin metabolism. Interaction between ghrelin and insulin; Effects of ghrelin on adiposity; Insulin secretion.

Abstract. Rosmond R, Ukkola O, Chagnon M, Bouchard C & Björntorp P (Department of Heart and Lung Diseases, Göteborg University, Sweden; Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA; Department of Internal Medicine, University of Oulu, Oulu, Finland). Polymorphisms of the β2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men. J Intern Med 2000; 248: 239–244. Objective. To investigate the effect of polymorphisms in codon 16 (Arg16Gly) and codon 27 (Gln27Glu) of the β2-adrenergic receptor gene (ADRB2) on anthropometric, endocrine, metabolic and haemodynamic variables. Design. A cross-sectional study. Subjects. A subgroup of 284 Swedish men from a population sample of 1040 at the age of 51 years. Main outcome measures. Genotype examination of ADRB2 polymorphisms in codon 16 and codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Anthropometric measurements included body mass index, waist-to-hip ratio and abdominal sagittal diameter. Endocrine measurements included blood levels of testosterone, insulin-like growth factor I, and leptin plus salivary cortisol. Overnight fasting values of serum insulin, blood glucose, triglycerides, total, low and high density lipoprotein cholesterol, as well as blood pressure and resting heart rate, were also determined. Results. Polymorphisms were frequent in both codon 16 and codon 27. The Arg16Gly genotype showed significant relationships to elevated central distribution of body fat and to systolic blood pressure, whilst the Glu27Glu genotype was associated with elevated leptin and triglyceride levels but not to other measurements, including obesity variables. Conclusions. We conclude that only a few cardiovascular risk factors are associated with DNA sequence variation in the ADRB2 in Swedish men. [ABSTRACT FROM AUTHOR]