Diabetes and atherosclerosis: epidemiology and intervention trials

Thursday 13 October 1994: Workshop Abstracts W20 Diabetes and atherosclerosis

CETP missense mutation (442D:G). In these patients, cholesteryl ester accumulates in the HDL2 fraction and the HDL particles become very large. In addition, LDL particles were cholesterolpoor and TG-rich and showed marked polydispersity. 1 will discuss the physiological role of CETP and the atherogenicity of CETP deficiency on the basis of data on the interaction between these abnormal lipoproteins and cells such as macrophages and fibroblasts, as well as the results of epidemiological studies in a city in northern Japan where the gene deficiency is extremely prevalent IIDL vs. triglycerides: which is important in cardiovascular disease? wNE. Dept. of Cardiovascular Biochem., St Bartholomew’s Hosp. Med. COB., Charterhouse Square, London ECIM 6BQ, UK

Fasting and non-fasting plasma triglycerides and HDL-cholesterol am all risk factors for coronary heart disease (CHD), but on multivariate analysis usually only HDL-C has remained an independent predictor. However, in view of the negative correlation between triglycerides and HDLC, and the greater intra-subject variance of triglycerides, such statistical analyses may not accu-

W20 DIABETES

rately reflect causality. Them is evidence that HDL might inhibit atherogenesis via effects on reverse cholesterol transport, fibrinolysis, platelet aggregation and/or LDL oxidation. The existence of a direct anti-atherogeniceffect has been supportedby effects of drugs, selective breeding, genetic engineering and HDL or apo AI infusions in animals, by clinical disorders of HDL metabolism, and by clinical trials of LDL-lowering/HDL-raising drugs in hypercholesterolemic men. But not all inherited hypoalphalipoproteinemias in humans or animals, nor all genetically engineered alterations of HDL-C have reciprocal effects on atherogenesis. Many humans with low HDIX have prolonged postprandial lipemia, possibly leading to activation of the blood coagulation system and/or increased uptake of remnant particles by arterial macrophages. However, not all hypoalphalipoproteinemics have delayed chylomicron clearance, and not all conditions producing fasting hypertriglyceridemia increase CHD risk. On present evidence the high incidence of CHD in the hypertriglyceridemia/low HDL syndrome probably reflects multiple pathogenetic mechanisms involving both lipoprotein classes. Furthermore, delayed lipolysis may itself diminish reverse cholesterol transport, by reducing the production of pm-beta LpA-1 in the proximity of vascular endothelium.

AND ATHEROSCLEROSIS

Diabetes and atherosclerosis: epidemiology and intervention trials mG. Toronto Hosp. (General Division) and Univ. of Toronto, Dept. of Med., 200 Elizabeth St, Toronto, M5G 2C4, Canada

In diabetes (DM) CAD mortality is 3-4 times greater than in the general population. One group of factors that may underlie this is the dyslipoproteinemias, a term used because the abnormalities may be qualitative as well as quantitative. The most frequent quantitative abnormality is an increase in the triglyceride-rich lipoproteins (TRL). DM is not accompanied by an increase in LDL. HDL levels may be variable. There are many qualitative lipoprotein changes in DM (e.g. modification of LDL by oxidation or by nonenzymatic glycation, changes in the size and density distribution of LDL, changes in the lipid and/or the apolipoprotein composition of the TRL and LDL) which might make the lipoproteins more atherogenic. Even though DM is not accompanied by an increase in LDL, cholesterol does pose a risk for atherosclerosis. The curve relating the incidence of CAD mortality to cholesterol level in DM has the same shape as that in a nondiabetic population. However, for any cholesterol level the risk is approximately three times higher in DM. The atherogenic risk effects of the TRL in the general population is still debated. However, in DM hypertriglyceridemia increases CAD risk, perhaps due to an increase in the smaller TRL, IDL. Advice to reduce lipoproteins in order to reduce CAD risk in DM is based on extrapolation from studies that excluded individuals with DM. Proof that this will reduce the incidence of CAD in DM is still lacking. This is the basis of a multinational study, the Diabetes Atherosclerosis Intervention Study (DAIS) that is conducted in cooperation with the WHO. DAIS is an angiographic trial examining whether correction of the dyslipoproteinemias of DM with fenotibrate will reduce the risk of coronary disease in type II diabetic middle-aged men and women. Insulin, lipoproteins and hemostatic function WA. Eriksson P, Karpe F, Silveira A, Atherosclerosis Res. Unit, King Gustaf V Res. Inst.. Karolinska Hosp. and Inst., S-l 71 76 Stockholm Sweden

Epidemiological,

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clinical and experimental studies have sug-

gested that hypertriglyceridemia (HT) involves derangements of both blood coagulation and fibtinolysis, in particular due to elevations of plasma factor VII coagulant activity and levels of plasminogen activation inhibitor-l (PAI-1). The much-debated link between HT and CHD might be partly accounted for by disturbances of the hemostatic system. The nature of factor VII response to fat intake suggests that an association with postprandial lipemia exists and that the activity rather than the concentration of the protein is affected. However, HT is primarily associated with a rise in factor VII concentration. It has recently been proposed that plasma insulin is the major physiological regulator of PAI- activity in plasma, secondary to that of tibrinolytic activity. The mechanism can either be direct or indirect through the effect of insulin on plasma VLDL. However, the relationship of hypetinsulinemia to plasma PAI- activity appears to be complex. Whether the observed associations of hyperinsulinemia with lipoprotein alterations and impaired fibrinolytic function are related to the amount of circulating insulin or proinsulin-like molecules, to insulin resistance, or to some as yet unknown factor is uncertain. Emerging knowledge of the many interactions between insulin, TG-rich lipoproteins and the hemostatic system is likely to influence our views on hypertriglyceridemia as a risk factor for coronary atherosclerosis and thrombosis as well as our policies for intervention. Postprandial lipemia and lipoprotein lipase Q&&&j&, 3rd Dept. of Med., Univ. of Helsinki, Helsinki, Finland

Triglyceride-rich lipoproteins of exogenous origin (chylomicrons and chylomicron remnants) are catabolized in two steps. Chylomicron catabolism begins with the hydrolysis of triglycerides by lipoprotein lipase (LPL). Delipidation of chylomicrons produces remnant particles which are removed by a receptor-mediated pathway in the liver. The importance of LPL is evidenced by the fact that heterozygotes for LPL deficiency have been reported to exhibit marked fat intolerance. To evaluate the role of LPL as a determinant of postprandial lipemia we have studied three cohorts: NIDDM men with and without angiographically defined CAD, healthy men matched for age and BMI with NIDDM men, and nondiabctic men with low HDUmoderate hypertriglyceride-

Atherosclerosis X, Montreal, October I994