T.W.A. de Bruin

Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis.

Non‐insulin‐dependent diabetes mellitus is frequently associated with premature atherosclerosis. Abnormalities in lipid and lipoprotein metabolism contribute to the increased risk of coronary heart disease. One of the most common lipid abnormalities in non‐insulin‐dependent diabetes mellitus is hypertriglyceridaemia. In the present paper, the authors review the metabolism of triglyceride‐rich lipoproteins, with special emphasis on the post‐prandial state. Several studies have demonstrated that levels of atherogenic post‐prandial lipoproteins are increased in patients with non‐insulin‐dependent diabetes mellitus. An increased supply of glucose and free fatty acids contributes to overproduction of very low‐density lipoproteins, increasing the burden of triglyceride‐rich lipoproteins on the common lipolytic pathway at the level of lipoprotein lipase. Low lipoprotein lipase activity and increased amounts of lipolysis‐inhibiting free fatty acids further impair lipolysis of post‐prandial lipoproteins. The clearance of atherogenic remnants is also delayed in non‐insulin‐dependent diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant‐receptor interaction and increased competition with very low density lipoprotein remnants. Correction of the increased post‐prandial lipaemia in non‐insulin‐dependent diabetes mellitus is advisable, as it may contribute to attenuation of the risk on premature atherosclerosis. When dietary measures and hypoglycaemic agents have failed to achieve acceptable lipid levels, lipid‐lowering drugs should be advised. Fibric acids and hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.

Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM): preliminary results after one year

AIMS: Important risk factors for the progression from impaired glucose tolerance to type II diabetes mellitus are obesity, diet and physical inactivity. The aim of this study is to evaluate the effect of a lifestyle-intervention programme on glucose tolerance in Dutch subjects with impaired glucose tolerance (IGT).METHODS: A total of 102 subjects were studied, randomised into two groups. Subjects in the intervention group received regular dietary advice, and were stimulated to lose weight and to increase their physical activity. The control group received only brief information about the beneficial effects of a healthy diet and increased physical activity. Before and after the first year, glucose tolerance was measured and several other measurements were done.RESULTS: Body weight loss after 1 y was higher in the intervention group. The 2-h blood glucose concentration decreased 0.8±0.3 mmol/l in the intervention group and increased 0.2±0.3 mmol/l in the control group (P<0.05). Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity.CONCLUSION: A lifestyle-intervention programme according to general recommendations is effective and induces beneficial changes in lifestyle, which improve glucose tolerance in subjects with IGT. Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity.

Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance : population-based studies and meta-analyses

Aims  To evaluate the relation between common variants in the ATP‐sensitive K+ channel genes and glucose intolerance.

Direct association of a promoter polymorphism in the CD36/FAT fatty acid transporter gene with Type 2 diabetes mellitus and insulin resistance

Aims  The membrane‐bound fatty acid transporter CD36/FAT may play a role in disturbed fatty acid handling as observed in the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Genetic variation in the CD36 gene may contribute to the aetiology of diabetes.

A proposal to redefine familial combined hyperlipidaemia -- third workshop on FCHL held in Barcelona from 3 to 5 May 2001, during the scientific sessions of the European Society for Clinical Investigation.

Familial combined hyperlipidaemia (FCHL) was described in 1973 by three separate groups as a common familial disorder characterized by multiple lipoprotein phenotypes and an increased risk of premature coronary artery disease [1– 3]. No metabolic explanation was offered for the variable lipid phenotypes and opinion differed as to whether this was likely to be a monogenic or polygenic disorder. In 1986, the first FCHL workshop was held in Seattle and at that meeting an elevated plasma apolipoprotein B (apoB) was added to the list of characteristics. However, it was not made an essential feature, nor was any change to the fundamental approach to phenotypic classification suggested, notwithstanding that complexity of diagnosis severely limits clinical application and comparison of research results [4]. In 1998, investigators met in Helsinki for the second FCHL workshop and heard of the newest efforts to identify the genetic and metabolic bases for FCHL. All of the analyses were presented within the context of the original diagnostic approach. At the most recent meeting of the European Society for Clinical Investigation in Barcelona, the third workshop on FCHL was organized by Dr J. Ribalta (Reus, Spain) and Dr M. Castro Cabezas (Utrecht, the Netherlands) to reconsider this most common, but least well characterized, familial atherogenic dyslipoproteinaemia. Our objective became to search for the most important pathophysiological features. From the outset, as outlined by Professor M-R. Taskinen (Helsinki, Finland) , the two most well-documented features are increased very low-density lipoprotein (VLDL) secretion and impaired clearance of postprandial lipoproteins [5,6]. The increased VLDL2 secretion results in hypertriglyceridaemia and an elevated plasma apoB. Long residence time of VLDL1 particles favour the formation of small dense low-density lipoprotein (LDL). Based on this, we considered the hypothesis that the phenotype of FCHL might not be multiple but unitary – namely, hypertriglyceridaemic (hyperTg) hyperapoB. If so, FCHL phenotype could be defined more simply and consistently as follows. The phenotype of hyperTg hyperapoB would have to be present in more than one family member and at least one individual in the family must have premature symptomatic coronary artery disease. Other genetic disorders and secondary causes of dyslipidaemia, including type 1 and type 2 diabetes would, of course, have to be excluded [4,5]. It was emphasized that such a change only represents an evolution in diagnosis based on the advances in knowledge and technology that have occurred since the disorder was Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, McGill University, Montreal, Quebec, Canada (A. D. Sniderman); Departments of Internal Medicine and Endocrinology, University Medical Centre, Utrecht, the Netherlands (M. Castro Cabezas, D. W. Erkelens); Unitat de Recerca de Lípids i Arteriosclerosi, Facultat de Medicina, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Reus, Spain (J. Ribalta, L. Masana); Servicio de Endocrinología, Departamento de Medicina, Universidad de Valencia, Valencia, Spain (R. Carmena, J. T. Real); Departments of Medicine and Endocrinology, Academic Hospital, 6202 AZ Maastricht, the Netherlands (T. W. A. de Bruin); Department General Internal Medicine 541, UMC Nijmegen, the Netherlands (J. de Graaf); Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London WC1E 6JJ, UK (S. E. Humphries, P. J. Talmud); Department of Medicine, University of Helsinki, Helsinki, Finland (M. R. Taskinen).

Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia

Castro Cabezas M, De Bruin TWA, Westerveld HE, Meijer E, Erkelens DW (Departments of Internal Medicine and Endocrinology, University Hospital Utrecht and University Hospital Maastricht, The Netherlands). Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia. J Intern Med 1998; 244: 299–307.

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan.DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied.SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity.RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3).CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.

Postprandial apolipoprotein B100 and B48 metabolism in familial combined hyperlipidaemia before and after reduction of fasting plasma triglycerides.

Abstract Hepatic VLDL overproduction in familial combined hyperlipidaemia (FCH) may delay the clearance of atherogenic apolipoprotein (apo) B containing particles. We investigated if normalization of fasting plasma triglycerides (TG) by hypolipidaemic treatment results in improved metabolism of apo B48 and apo B100 in six male subjects with FCH and compared them to six normolipidaemic controls. The FCH patients were studied before (TG, 5·2±1·2 mmoll‐1; mean ± SEM) and after therapy (TG, 2·1±0·3 mmoll‐1) with either simvastatin (n= 4) or combined therapy with gemfibrozil (n= 2). The post‐prandial changes of apo B100 and apo B48 were studied after a single oral fat meal (24h; 50 gram fatm‐2). Changes in triglyceride rich particles (TRP; d < 1·006 gml‐1) and remnant fractions (REM; d: 1·006–1·019g ml‐1) of apo B were quantitated by scanning silverstained SDS‐PAGE (4–15%). Apo B48 in fasting TRP in untreated and treated FCH was 15% and 14% of total apo B, and 6% in controls (P < 0·05). In controls, postprandial B48 increased maximally at 4h by 81% in TRP and by 137% in REM compared to baseline. In treated FCH, the post‐prandial apo B48 pattern normalized in TRP compared to the untreated state. Postprandial apo B100 in controls decreased in TRP and REM by 33% and 18% (P < 0·05). In untreated and treated FCH, postprandial apo B100 remained unchanged vs. baseline in TRP and in REM suggesting hypersecretion of VLDL. The elimination of B100—assessed as area under the curve—in TRP (32·5±3·6 au.h; mean±SEM) and REM fractions (33·2±3·1 au.h), improved significantly after treatment (21·0±2·8 and 20·4±3·3 au.h, respectively). The apo B48 clearance in TRP fractions was improved after treatment (4·3±1·4 au.h vs. 2·9±1·2 au.h; P= 0·06), but not in REM fractions (2·8±1·0 au.h vs. 1·8±0·5 au.h; NS). In conclusion, in FCH subjects with apo B100 hypersecretion and increased fasting plasma apo B48 levels, reduction of fasting plasma TG improved, but did not normalize, TRP apo B48 and B100 metabolism. However, therapy normalized postprandial apo B100 remnant metabolism. Impaired postprandial apo B metabolism may be instrumental in the development of premature atherosclerosis in FCH subjects.

Subclasses of Low-Density Lipoprotein and Very Low-Density Lipoprotein in Familial Combined Hyperlipidemia: Relationship to Multiple Lipoprotein Phenotype

Objective—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. Methods and Results—Hyperlipidemic FCHL relatives (n=72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size <258 Å) and pattern A LDL (buoyant LDL, particle size ≥258 Å) 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. Conclusions—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.

Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus

Aims  Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose‐responsive gene in pancreatic B‐cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21‐1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM.