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ABSTRACT: BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.
Nutrition, metabolism, and cardiovascular diseases: NMCD 01/2013; · 3.52 Impact Factor
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ABSTRACT: Background:Dysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood.Aim:The aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects.Methods:Whole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity.Results:Functional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR < 1E-30]. Higher adipocyte complement expression in FCHL was confirmed in the appropriate confirmation group. Higher complement gene expression was associated with lower adipocyte insulin receptor substrate-1 expression as marker of adipocyte insulin resistance, independent of age, sex, or disease status, and this association was corroborated in the two confirmation groups. Additionally, complement gene expression was associated with triglycerides in the discovery set and with triglycerides and/or waist circumference in the confirmation groups. Complement pathway up-regulation did not appear to be driven by hypertriglyceridemia because a 40% pharmacological reduction in triglycerides did not affect complement expression.Conclusions:These findings point to an up-regulation of a complement-related transcriptome in sc adipocytes under metabolically stressed conditions, even in the absence of overt obesity. Such up-regulation may subsequently influence downstream processes, including macrophage infiltration into adipose tissue and adipocyte insulin resistance.
The Journal of clinical endocrinology and metabolism 10/2012; · 6.50 Impact Factor
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ABSTRACT: The existence of metformin-induced lactic acidosis has been questioned, in particular in the absence of specific risk factors such as impaired renal function. This report describes the presence of lactic acidosis in a patient with normal kidney function and normal doses of metformin. Subsequent positive rechallenge with metformin confirms causality.
Diabetes research and clinical practice 08/2011; 96(3):e57-8. · 2.16 Impact Factor
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ABSTRACT: Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B and triglycerides levels, reduced HDL cholesterol and the presence of small-dense LDL particles. The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia.
Plasma PCSK9 was measured in a cohort of subjects with normal glucose metabolism (NGM; n=288), impaired glucose metabolism (IGM; n=121) and type 2 diabetes mellitus (T2DM; n=139) to study whether its relation with plasma apolipoprotein B, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol and HDL cholesterol differed by levels of glucose metabolism status.
Plasma PCSK9 levels were not different between the three groups (82, 82 and 80 ng/mL in NGM, IGM and T2DM, respectively). PCSK9 was positively associated with total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B and triglycerides levels in all subgroups. The regression slopes for the associations with non-HDL cholesterol were steeper among individuals with T2DM than with NGM (β = 0.016 versus β=0.009, p-interaction=0.05). Similar results were obtained for the relation with apolipoprotein B (β = 0.004 versus β = 0.002, p-interaction=0.09).
Although glucose metabolism status per se is not associated with plasma PCSK9 levels, the presence of T2DM may modify the relation between plasma PCSK9 and non-HDL cholesterol and apolipoprotein B. These observations should be regarded as hypothesis generating for further studies aimed at elucidating the role of PCSK9 in the pathogenesis and treatment of diabetic dyslipidemia.
Atherosclerosis 03/2011; 217(1):263-7. · 3.79 Impact Factor
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ABSTRACT: The current study was conducted to investigate whether patients with familial combined hyperlipidaemia (FCHL ) are predisposed to the development of type 2 diabetes mellitus (T2DM).
A cohort of 56 FCHL patients and 54 spouses was followed over time with a five-year interval. Diagnosis of T2DM was based on fasting glucose levels or use of antidiabetic medication. Baseline body mass index, waist circumference, blood pressure, use of antihypertensive and lipid-lowering medication, plasma cholesterol, triglycerides, apolipoprotein B, glucose, insulin and alanine aminontransferase (ALAT) levels were determined as potential predictors of new onset T2DM.
Baseline prevalence of T2DM was 2% in spouses and 9% in FCHL patients, and 4 and 20%, respectively, after five-year follow-up. The incidence of T2DM was significantly higher in FCHL patients (2 vs 14%; OR 9.1; 95% CI 1.0 to 81.4; p=0.04; age and sex adjusted). Of all baseline variables, only plasma insulin levels (not glucose) significantly predicted the development of T2DM (p=0.04).
The present study is the first to present incidence numbers of T2DM in FCHL and demonstrates that FCHL patients, as compared with healthy controls, are predisposed to the development of T2DM. This is - at least in part - accounted for by an increased insulin resistance.
The Netherlands Journal of Medicine 04/2010; 68(4):163-7. · 2.07 Impact Factor
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ABSTRACT: Metformin-associated lactate acidosis is a rare, but life-threatening complication of a widely prescribed medication. We describe here a case of metformin-associated lactate acidosis that rapidly deteriorated probably as a consequence of concomitant glucose infusion that was initiated to correct sulphonylurea-induced hypoglycemia.
Diabetes research and clinical practice 06/2009; 85(1):e1-3. · 2.16 Impact Factor
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ABSTRACT: Low-density lipoprotein cholesterol (LDL-C) levels are often fairly normal in Type 2 diabetes mellitus (DM). We anticipated that a parabolic relation between plasma triglycerides and LDL-C, as previously demonstrated in familial combined hyperlipidaemia (FCHL), might account for this phenomenon.
Our hypothesis was tested in 1343 subjects derived from the general population who were studied on two occasions 6 years apart (the Hoorn study). Three groups were constructed depending on plasma triglycerides: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one above 1.5 mmol/l) and group C (both measurements above 1.5 mmol/l). Diabetes status was ascertained by an oral glucose tolerance test.
In a mixed linear model, a significant, positive relation between triglycerides and LDL-C was observed for males in group A (beta(a) = 0.5, P < 0.001) and group B (beta(b) = 0.2, P < 0.001), whereas a significant negative relation was found for males in group C (beta(c) = -0.2, P = 0.003). The regression slopes did not differ between diabetic and non-diabetic subjects. Similar results were obtained for women, with the exception that the relation was not significantly negative in group C (beta(c) = -0.1, P = 0.4).
Plasma triglycerides and LDL-C are related in a parabolic fashion, not only in FCHL, but also in the general population and Type 2 DM. These findings aid our interpretation of typical dyslipidaemia and the effects of treatment that are frequently observed in hypertriglyceridaemic states.
Diabetic Medicine 09/2008; 25(9):1121-4. · 2.90 Impact Factor
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ABSTRACT: The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses.
Hyperlipidemic FCHL relatives (n=72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size <258 A) and pattern A LDL (buoyant LDL, particle size > or =258 A) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, n=7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A.
The present observations underscore the importance of the VLDL triglyceride metabolic pathway in FCHL as an important determinant of the phenotypic heterogeneity of the disorder.
Arteriosclerosis Thrombosis and Vascular Biology 04/2004; 24(4):744-9. · 6.37 Impact Factor
