Mikko Syvänne

Postprandial metabolism of apolipoprotein B-48- and B-100-containing particles in type 2 diabetes mellitus: relations to angiographically verified severity of coronary artery disease

The aim of the present cross-sectional angiographic study was to examine if there is a relationship between the severity of CAD and postprandial lipemia in patients with type 2 diabetes mellitus. Special emphasis was directed to determining the contribution of apolipoprotein B-48 (apoB-48)-containing and B-100 (apoB-100)-containing triglyceride-rich particles to the magnitude of postprandial lipemia and degree of CAD. The role of apolipoprotein E (apoE) phenotype as a modulator of postprandial lipemia was also evaluated. The severity of CAD was determined by a quantitative coronary angiography and the subjects were classified into two groups based on the presence (severe CAD) or absence (mild CAD) of at least 50% stenosis in a major coronary vessel. The study population consisted of 43 subjects (31 men and 12 women) with fair glycemic control and comparable fasting lipids and body mass index. Postprandial responses of TG, apoB-48 and apoB-100 in lipoprotein subfractions (chylomicrons, VLDL1, VLDL2 and IDL) were determined after a fat load. Type 2 diabetic patients exhibited the classical dyslipidemia of the insulin resistance syndrome and delayed clearance of both hepatic and intestinal particles. Fasting or postprandial lipid or lipoprotein measurements, including apoB-48 and apoB-100 concentrations, did not differ between the groups. The presence or absence of apoE-4 allele did not significantly influence postprandial lipemia. The severity of the most significant coronary stenosis in angiography correlated with plasma and with chylomicron area under curve (AUC) for TG (n=27) and chylomicron AUC for apoB-48 (n=20). The strongest correlate of maximal stenosis was area under incremental curve (AUIC) for apoB-100 in IDL fraction (r=0.548, P=0. 012, n=20). In conclusion, postprandial apoB-48 and apoB-100 metabolism in triglyceride rich lipoproteins is distorted in type 2 diabetic patients, even in those with only mild CAD. The data suggest that postprandial change in small remnant particle numbers may contribute to the severity of CAD in type 2 diabetes.

Gemfibrozil reduces postprandial lipemia in non-insulin-dependent diabetes mellitus.

The effect of gemfibrozil on postprandial lipoprotein metabolism was investigated in a 12-week, randomized, double-blind, placebo-controlled trial in 20 non-insulin-dependent diabetic patients with moderate hypertriglyceridemia. The patients were given a meal containing 78 g of fat and 345,000 units of vitamin A to label chylomicrons and their remnants. Plasma obtained at various times during the fat-load test was separated into six fractions by gradient-density ultracentrifugation. Gemfibrozil reduced the postprandial triglyceride response, measured as the area under the time-dependent concentration curve, on average by 32% in whole plasma, by 38% in the Svedberg flotation unit (Sf) 1,100-3,200 chylomicron fraction, by 36% in Sf 400-1,100 chylomicrons, and by 38% in the Sf 60-400 lipoproteins. Retinyl palmitate, a measure of intestinally derived particles, was reduced in plasma by 34%, in Sf 1,100-3,200 by 46%, in Sf 400-1,100 by 44%, and in Sf 60-400 by 37%. All these reductions were significant in comparison with the placebo group. Particles with Sf < 60 were not significantly affected. In contrast to earlier observations in healthy subjects, no significant negative correlations existed between postprandial lipemia and high density lipoprotein cholesterol or the postheparin lipoprotein lipase activity. The reduction of the potentially atherogenic chylomicron remnants may decrease the risk of atherosclerosis in non-insulin-dependent diabetes mellitus, a hypothesis that awaits testing in prospective studies.

Postprandial lipid metabolism in diabetes

Postprandial lipemia is an inherent feature of diabetic dyslipidemia and highly prevalent in diabetic patients even with normal fasting triglyceride concentrations. Postprandial lipemia is characterized by long residence time of chylomicron and VLDL remnants in the circulation. Insulin resistance causes increased flux of free fatty acids, and thus enhanced VLDL apolipoprotein B (apo B) synthesis in the liver. Together with chylomicron and VLDL remnant competition for the common removal mechanisms the increased substrate input results in exaggerated and prolonged postprandial lipemia. Studies using both apo B-48 and retinyl esters as a marker for intestinally derived particles have shown that increased postprandial lipemia does not predict the presence or absence of coronary artery disease between non-insulin-dependent diabetes mellitus (NIDDM) subjects. Recent data have shown that postprandial triglyceride-rich remnants are atherogenic, and postprandial hypertriglyceridemia contributes to the metabolic disturbances transforming LDL and HDL subclasses into more atherogenic direction in diabetic subjects.

Phenotype expression in familial combined hyperlipidemia

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

New Insights into Lipid Metabolism in Non-insulin-dependent Diabetes Mellitus

Perturbations of lipid metabolism are common in diabetes. Therefore, an understanding of the underlying mechanism of lipid metabolism and in particular the role of insulin is a critical issue. The review aims to provide evidence that hypertriglyceridaemia is central to many features of diabetic dyslipidaemia.

Enrichment with apolipoprotein E characterizes postprandial TG-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus and coronary artery disease: a preliminary report

An oral fat-load test was carried out in patients with non-insulin-dependent diabetes mellitus (NIDDM) and angiographically verified coronary artery disease (CAD; group 1, n = 6); in patients with CAD but no diabetes (group 2, n = 6); in patients with NIDDM but no CAD (group 3, n = 4); and in healthy control subjects (group 4, n = 4). Concentrations of apolipoprotein (apo) E, apo C-II, triglyceride (TG), retinyl palmitate, and cholesterol were measured in fasting plasma and in plasma obtained after 2, 4, 6, 9, and 24 h after a meal containing 78 g of fat and 345,000 IU of vitamin A. The same measurements were carried out in the lipoprotein fractions with Svedberg flotation rates Sf 400-1100, 60-400, 20-60 and 12-20, obtained by density gradient ultracentrifugation. The postprandial apo E concentrations were highest in group 1 (NIDDM and CAD) in plasma and in the TG-rich lipoprotein fractions, with significant differences in comparison with the healthy subjects. As shown by apo E to TG ratios, the postprandial lipoproteins were enriched with apo E in the patients with NIDDM and CAD. The largest excesses of apo E in group 1 patients were observed in the atherogenic Sf 12-60 lipoproteins. Across the entire study population, there was a significant inverse correlation between the postprandial apo E responses and the postheparin lipoprotein lipase activity. The results suggest that enrichment of the remnant lipoproteins with apo E may have a role in the increased risk of CAD among patients with NIDDM.

Plasma cholesteryl ester transfer protein activity in non-insulin-dependent diabetic patients with and without coronary artery disease

The present study was designed to evaluate the potential role of plasma cholesteryl ester transfer protein (CETP) activity in the regulation of high-density lipoprotein (HDL) subclasses in non-insulin-dependent diabetes mellitus (NIDDM). We studied 45 men with NIDDM and angiographically defined coronary artery disease ([CAD] DM+CAD+, aged 54.4 +/- 6.1 years, mean +/- SD); 47 nondiabetic men with similarly proven CAD (DM-CAD+, aged 54.9 +/- 6.6 years; 43 men with NIDDM but no CAD (DM+CAD-, aged 55.2 +/- 7.3 years); and 29 nondiabetic men without CAD (DM-CAD-, aged 53.2 +/- 5.3 years). The groups were matched for age and body mass index (BMI). Plasma CETP activity was determined by measuring the ability of the plasma sample to transfer esterified cholesterol from exogenous 14C-cholesteryl ester-labeled low-density lipoprotein (LDL) to exogenous HDL. Plasma lipoproteins were separated by ultracentrifugation. The concentration of HDL cholesterol was reduced in the DM+CAD+ group as compared with the DM-CAD- group (P < .01). This change was due to a decrease of both HDL2 cholesterol (P < .05) and HDL3 cholesterol (P < .001). There was a clear-cut decrease in HDL3 cholesterol in the DM-CAD+ (P < .01) and DM+CAD- (P < .05) groups as compared with the DM-CAD- group. Plasma CETP activity was lower in the DM+CAD- group (1.06 +/- 0.24 arbitrary units [AU]) than in the DM-CAD- group (1.19 +/- 0.26 AU, P < .05). In the DM+CAD+ group, the mean of CETP activities was 1.09 AU.(ABSTRACT TRUNCATED AT 250 WORDS)

Attitudes and actions: A survey to assess statin use among Finnish patients with increased risk for cardiovascular events.

BACKGROUNDnStatins are the first-line treatment for lowering serum cholesterol and preventing coronary artery disease (CAD). Patients who fail to comply with the prescribed statin treatment face a markedly increased risk for cardiovascular events.nnnOBJECTIVEnThe aim of the article was to study the subjective factors, which modulate persistence with and adherence to statin therapy among Finnish patients at high risk for cardiovascular events.nnnMETHODSnA total of 1022 Finnish adults diagnosed with CAD, diabetes, hypertension, or severe hereditary dyslipidemia completed an electronic questionnaire survey during a visit in 1 of the 84 community pharmacies participating in the study.nnnRESULTSnThirty-four percent of the survey respondents were diagnosed with CAD or severe hereditary dyslipidemia and 82% were current or former statin users. Prevalence of nonpersistence with statin therapy was 15% among CAD patients and 17% among respondents without the diagnosis. Most of the nonpersistent statin users had discontinued the medication without consultation of a physician. None of the studied sociodemographic background factors were associated with persistence with statin therapy. Instead, experienced adverse effects, fear of adverse effects, perceived lack of need, and difficulties in use of a statin emerged as powerful predictors of nonpersistence. Awareness of treatment goals was low, and strikingly, public discussion about adverse effects of statins had induced nearly every third discontinuation of statin treatment.nnnCONCLUSIONnSeveral subjective, potentially modifiable reasons for nonpersistence were identified from the patient perspective. Improved utilization of patient-centered approaches in pharmacologic management of cardiovascular risks is necessary to improve adherence, and ultimately, treatment outcomes.