Kjetil Retterstøl

Dairy products and metabolic effects in overweight men and women: results from a 6-mo intervention study

BACKGROUNDnSome epidemiologic studies have suggested inverse relations between intake of dairy products and components of the metabolic syndrome.nnnOBJECTIVEnThe objective was to investigate the effects of an increased intake of dairy products in persons with a habitually low intake on body composition and factors related to the metabolic syndrome.nnnDESIGNnMiddle-aged overweight subjects (n = 121) with traits of the metabolic syndrome were recruited in Finland, Norway, and Sweden and randomly assigned into milk or control groups. The milk group was instructed to consume 3-5 portions of dairy products daily. The control group maintained their habitual diet. Clinical investigations were conducted on admission and after 6 mo.nnnRESULTSnThere were no significant differences between changes in body weight or body composition, blood pressure, markers of inflammation, endothelial function, adiponectin, or oxidative stress in the milk and the control groups. There was a modest unfavorable increase in serum cholesterol concentrations in the milk group (P = 0.043). Among participants with a low calcium intake at baseline (<700 mg/d), there was a significant treatment effect for waist circumference (P = 0.003) and sagittal abdominal diameter (P = 0.034). When the sexes were analyzed separately, leptin increased (P = 0.045) and vascular cell adhesion molecule-1 decreased (P = 0.001) in women in the milk group.nnnCONCLUSIONSnThis study gives no clear support to the hypothesis that a moderately increased intake of dairy products beneficially affects aspects of the metabolic syndrome. The apparently positive effects on waist circumference and sagittal abdominal diameter in subjects with a low calcium intake suggest a possible threshold in relation to effects on body composition.

Pregnancy Outcomes in Familial Hypercholesterolemia A Registry-Based Study

Background— Women with familial hypercholesterolemia (FH) are prone to early cardiovascular disease and death. It is unknown whether FH adversely affects pregnant women and birth outcomes. We determined whether heterozygous FH women are at higher risk of premature birth (<37 gestational weeks), delivering children with low birth weight (<2500 g) and/or with congenital malformations compared to women in general. Methods and Results— We linked information from the Medical Genetics Laboratory with that of the Medical Birth Registry of Norway. We included 1869 FH women (≥14 years) from the Medical Genetics Laboratory and about 2 million (general population) from the Medical Birth Registry of Norway during the period 1967 to 2006. The registry match resulted in analysis of 2319 births of 1093 women with heterozygous FH. The mean (SD) prepregnancy total cholesterol concentration was 9.59 (2.06) mmol/L (370 [80 mg/dL]), whereas the concentration of total cholesterol was not available during pregnancy. The frequencies of prematurity, low birth weight, and congenital malformations for the 40-year period in the FH population were 6.8, 5.0, and 3.3, respectively. The corresponding values for the general population were 6.2, 5.2, and 3.2. The corresponding odds ratios were 1.11 (95 confidence interval 0.94–1.31; P=0.23), 0.96 (0.79–1.15; P=0.64), and 1.09 (0.87–1.37; P=0.45). Conclusions— Women with FH do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malformations than women in general, but, although this is unlikely, some undetected bias may obscure the real differences.

HypoCol (red yeast rice) lowers plasma cholesterol – a randomized placebo controlled study

Abstract Objective. The primary endpoint in our study was to investigate the effect of a red yeast rice (RYR) product on plasma lipids. Design. A randomized, double-blind, placebo controlled study was performed. Patients were randomized to either RYR (HypoCol, 4 capsules/day) (n=22) or placebo (n=20) for 16 weeks. Inclusion criteria were male or female, 18–75 years, LDL-cholesterol between 3.0 and 6.0 mmol/L, fasting triglyceride level less than 4.5 mmol/L. Results. Patients receiving RYR experienced a significant reduction in LDL-cholesterol (23.0%) and total cholesterol (15.5%) compared to placebo after 16 weeks of treatment (p<0.001). Conclusion. The tested red yeast rice product demonstrated a significant cholesterol lowering effect compared to placebo, and was well tolerated in this Caucasian population.

Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia.

OBJECTIVEnFamilial hypercholesterolemia (FH) is caused by defects in genes coding for proteins involved in low density lipoprotein (LDL) metabolism, and is associated with increased risk of premature coronary heart disease (CHD). The clinical phenotype of FH exhibits marked variability due to additional metabolic and environmental factors, and further biomarkers are required for appropriate risk assessment. The aim of the present study was to search for risk markers among FH patients.nnnMETHODS AND RESULTSnClinical and biochemical parameters of FH subjects with early CHD events (CHD-susceptible) and FH subjects with late or no CHD events (CHD-resistant) were compared. Our data show that CHD-susceptible FH patients had significantly higher Lipoprotein (Lp) (a) levels compared to CHD-resistant FH patients. When subdividing by gender, the main findings were that (i) CHD-susceptible women had significantly higher levels of both Lp(a), low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B as compared to CHD-resistant women, and (ii) CHD-resistant women had significantly lower Lp(a) levels and higher high density lipoprotein (HDL) cholesterol and apoA-I levels compared to CHD-resistant men.nnnCONCLUSIONSnThe data suggest that Lp(a) may be an important coronary risk marker in FH patients, in particular in combination with elevated LDL cholesterol levels among female subjects. Thus, measurement of Lp(a) levels may help identifying high-risk individuals who could benefit from an aggressive therapy, including statins to reduce LDL-cholesterol to guideline-recommended levels.

Effect of the fat composition of a single high-fat meal on inflammatory markers in healthy young women

The aim of the present study was to examine the effect of a single high-fat meal with different fat quality on circulating inflammatory markers and gene expression in peripheral blood mononuclear cells (PBMC) to elucidate the role of fat quality on postprandial inflammation. A postprandial study with fourteen healthy females consuming three test meals with different fat quality was performed. Test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6xa0h after intake were analysed. The test meal consisted of three cakes enriched with coconut fat (43xa0% energy as saturated fat and 1xa0% energy as α-linolenic acid (ALA)), linseed oil (14xa0% energy as ALA and 30xa0% energy as saturated fat) and cod liver oil (5xa0% energy as EPA and DHA and 5xa0% energy as ALA in addition to 31xa0% energy as saturated fat). In addition, ex vivo PBMC experiments were performed in eight healthy subjects investigating the effects of EPA and ALA on release and gene expression of inflammatory markers. The IL-8 mRNA level was significantly increased after intake of the cod liver oil cake at 6xa0h compared with fasting level, which was significantly different from the effect observed after the intake of linseed cake. In contrast, no effect was seen on circulating level of IL-8. In addition, ALA and EPA were shown to elicit different effects on the release and mRNA expression levels of inflammatory markers in PBMC cultured ex vivo, with EPA having the most prominent pro-inflammatory potential.

No effect of combined coenzyme Q10 and selenium supplementation on atorvastatin-induced myopathy.

Abstract Objective. The aim of the present study was to evaluate the possible effects of Q10 and selenium supplementation on statin-induced myopathy (SIM), both for subjective symptoms and muscle function. Design. Patients (N = 43) who had experienced previous or ongoing SIM on atorvastatin therapy were recruited. Following a 6-week washout period during which no statins were administered, the patients were re-challenged with 10 mg of atorvastatin. Patients (N = 41) who experienced SIM continued the atorvastatin treatment and were in addition randomized to receive 12 weeks supplement of 400 mg Q10 and 200 μg selenium per day or a matching double placebo. SIM was assessed using 3 validated symptom questionnaires, and a muscle function test was performed at the beginning and at the end of the study. Results. The patients receiving the active supplement experienced significant increases in their serum Q10 and selenium concentrations compared with the group receiving placebo. No statistically significant differences in symptom questionnaire scores or muscle function tests were revealed between the groups. Conclusions. Despite substantial increases in the serum Q10 and selenium levels following the oral supplementation, this study revealed no significant effects on SIM compared with the placebo. Trial registration: ClinicalTrials.gov identifier: NCT00113477.

Improved plasma lipids and body weight in overweight/obese patients with type III hyperlipoproteinemia after 4 weeks on a low glycemic diet.

BACKGROUND & AIMnThe optimal diet for type III hyperlipoproteinemia is unknown. We examined blood lipids and body weight following low or high glycemic index diets in comparison with a lipid-lowering diet.nnnMATERIALS AND METHODSnSixteen overweight/obese men completed a cross-over study where they followed a standard lipid-lowering diet, a high and a low glycemic index diet, each lasting 4 weeks. Measurements were obtained at the end of each diet intervention.nnnRESULTSnThe lipid-lowering diet reduced significantly LDL cholesterol, and apolipoprotein B by 24%, and 17%, whereas high glycemic index increased LDL cholesterol with 21%. The low glycemic index diet reduced (p<0.05) total and LDL cholesterol and apolipoprotein B compared with the lipid-lowering diet. A moderate weight loss (p<0.05) was achieved after the lipid-lowering diet compared with baseline: 1.4 (-3.6-0.2; median, 95% CI) kg and similar to that after high glycemic index diet. A low glycemic index diet resulted in 2.4 (-3.9-1.4) kg weight loss compared with the high glycemic index diet (p<0.05).nnnCONCLUSIONnA low glycemic index diet may be superior to that of a standard lipid-lowering diet in type III hyperlipoproteinemia.

Suggestive evidence of associations between liver X receptor β polymorphisms with type 2 diabetes mellitus and obesity in three cohort studies: HUNT2 (Norway), MONICA (France) and HELENA (Europe)

BackgroundThe liver X receptors (LXR) α and β regulate lipid and carbohydrate homeostasis and inflammation. Lxrβ-/-mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRβ and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies.MethodsTwenty LXRβ SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRβ gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed.ResultsWe identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRβ basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed.ConclusionsOur results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.

Atorvastatin metabolite measurements as a diagnostic tool for statin-induced myopathy.

AbstractBackground: Myopathic complaints are common in the general population and are more frequent with increasing age. When myopathic symptoms arise in a patient treated with a HMG-CoA reductase inhibitor (statin), it is always a question of whether the symptoms are due to statin-induced myopathy (SIM) or not (non-SIM). Diagnosis of SIM is not as straightforward as previously thought, because the most commonly used biomarker, serum creatine kinase, shows low specificity and selectivity, except in serious cases of rhabdomyolysis. There is a definite need for a novel biomarker for SIM.n Objective: Based on a previous study reporting an altered metabolic profile with increased systemic exposure to the suspected muscle-toxic metabolite atorvastatin lactone in patients with SIM compared with healthy controls, this study aimed to explore the use of atorvastatin metabolite measurements to diagnose muscular complaints during statin treatment as being either SIM or non-SIM.n Patients, Setting, and Study Design: Fifty-three patients with self-reported myopathic symptoms during atorvastatin treatment were recruited from our outpatient clinic. The symptoms were clinically evaluated as being SIM or non-SIM, on the basis of atorvastatin re-challenge testing. Atorvastatin and its metabolites were measured at steady state in all patients and compared with the clinical evaluation to see if this could predict the outcome and hence be suitable as a diagnostic tool for SIM.n Main Outcome Measure: This was an exploratory study to investigate the proportion of patients correctly diagnosed by different metabolite cut-off ratios.n Results: With a cut-off ratio set at 1.1 for the atorvastatin lactone to atorvastatin acid ratio, 15 of 28 SIM patients (sensitivity of 54%) and 20 of 24 non-SIM patients (specificity of 83%) were correctly diagnosed. This corresponds to a positive predictive value of 79% and a negative predictive value of 61% (p = 0.006).n Conclusion: The present study confirms an altered metabolic pattern of atorvastatin in patients with SIM and substantiates a central role of the lactone forms of statins in future investigations of statin myotoxicity. The atorvastatin lactone to acid ratio seems to be a valuable supportive diagnostic tool with high specificity and moderate sensitivity, adding to ordinary clinical evaluations when diagnosing SIM.n Trial registration number (clinicaltrials.gov): NCT00414531

Dysregulated RANK Ligand/RANK Axis in Hyperhomocysteinemic Subjects Effect of Treatment With B-Vitamins

Background and Purpose— Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events. Matrix degradation and inflammation play an important role in these disorders, and we have demonstrated increased levels of matrix-degrading enzymes and inflammatory cytokines in hyperhomocysteinemic individuals. Recent studies suggest that RANK ligand (RANKL) through interaction with its receptor RANK can modulate matrix degradation and inflammation. The present study aimed to examine the role of the RANKL/RANK axis in hyperhomocystinemia. Methods— RANKL/RANK was measured on protein or mRNA level before and after B-vitamin supplementation in hyperhomocysteinemic individuals. We also examined the in vitro effects of soluble RANKL in peripheral blood mononuclear cells from hyperhomocysteinemic individuals. Results— Our main findings were: (1) compared to peripheral blood mononuclear cells from controls, cells from hyperhomocysteinemic individuals had significantly higher gene expression of RANKL and RANK; (2) folic acid treatment for 6 weeks in an open, uncontrolled study significantly reduced gene expression of RANKL/RANK in peripheral blood mononuclear cells from these individuals; (3) compared to placebo, treatment with folic acid, vitamin B12, and vitamin B6 for 3 months in a randomized, double-blind trial significantly lowered serum levels of soluble RANKL in hyperhomocysteinemic individuals; and (4) in vitro, soluble RANKL markedly increased the release of matrix metalloproteinase-9 and inflammatory cytokines from peripheral blood mononuclear cells in hyperhomocysteinemic subjects. Conclusions— Our findings suggest a dysregulated RANKL/RANK axis in hyperhomocysteinemic subjects. Based on their role in atherogenesis, this enhanced expression of RANKL and RANK could contribute to the increased risk of cardiovascular disease in hyperhomocystinemia. Moreover, treatment with B-vitamins may have beneficial implications for plaque stability in these individuals.