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Thrombotic risk factors in diabetic patients
154
Pre-congress, Delphi Diabetic dyslipidemia (1)
in non-diabetic subjects matched for race, age and gender. Hypertriglyceridemia is reflected in exaggerated postprandial lipemia and preponderance of small dense LDL which are considered to be metabolic consequences of hypertriglyceridemia. In addition, compositional changes o f HDL due to triglyceride enrichment enhance the catabolic rate of HDL particles. The key question is what are the underlying mechanisms behind elevation of plasma triglycerides in Type 2 diabetic patients. The recognition o f lipoprotein heterogeneity has opened new perspective to the understanding of lipoprotein metabolism and its regulation. We have studied VLDL apo B metabolism using 3-3H leucine to track apo B 100 in large VLDLI (Sf 60400) and small VLDL2 (Sf 20-60) particles in nondiabetic, normolipidemic men and in Type 2 diabetic men. The subjects were studied on two occasions: I. during an 8.5-hour infusion of saline (control study) and 2. during an 8.5hour euglycemic hyperinsulinemic clamp (serum insulin 490 pmol/1). The novel observation was that in normal men acute hyperinsulinemia suppresses VLDLI apo B production but has no effect on VLDL2 production. On average VLDLI apo B production was reduced by 50% during insulin infusion leading also to the reduction of total VLDL apo B production. In contrast to normal men insulin failed to suppress VLDLI production in Type 2 diabetic men. This defect o f insulin action may be the root cause to elevation of triglyceride rich particles (TRLs) in Type 2 diabetes and insulin resistance. The long residence time of TRLs due to the competition o f both chylomicrons and endogenous VLDL particles for common catabolic pathways allows excessive transfer of core lipids between TRLs and LDL and HDL particles. We propose that the physiological role o f insulin is to maintain a balance between intestine derived and liver derived triglyceride rich particles. The failure of this action results in postprandial lipemia, changes of LDL and H DL subfractions and may be the link between diabetic dyslipidemia and CHD.
ATHEROGENICITY OF APO. B-CONTAINING LIPOPROTEINS IN DIABETIC DYSLIPIDEMIA: ROLE OF CETP M. Guerin, L. Steiner, M.J. Chapman. INSERM Unit~ 321. Hdpital de la
Piti~, Paris, France
THROMBOTIC RISK FACTORS IN DIABETIC PATIENTS
H. Milionis, D.P. Mikhailidis. Dept. of Molecular PatholoKv & Clinical Biochemistry, Royal Free & University College Medical School. London. UK Diabetic (DM) patients are at an increased risk of vascular events. Therefore, the prevention of vascular events in these patients is an important goal. This can be achieved by better glucose and blood pressure control. Correcting dyslipidaemias may also be clinically relevant although trial-based evidence is awaited. In this review we focus on the haemostatic system in diabetics. The plasma levels of fibrinogen are often elevated in DM. However, it is not clear if this is affected by the quality of glucose control. There is very strong evidence showing that elevated plasma levels of this coagulation factor are associated with an increased incidence of myocardial infarction and stroke. However, most of this evidence is based on non-DM patients. A decreased fibrinolytic activity may be particularly relevant to noninsulin dependent DM because it is associated with hypertriglyceridaemia, a common lipid abnormality in these patients. There is some evidence indicating that platelet hyperactivity occurs in diabetics. This may be relevant to the accelerated sclerogenesis seen in diabetics because platelets also release growth factors (e.g. platelet derived growth factor and serotonin). Endothelial dysfunction has been reported in diabetics. This abnormality may contribute to the increased prevalence of hypertension in DM, the activation of the coagulation system and platelets as well as to the impaired fibrinolytic activity. From a therapeutic point of view, the Antiplatelet Trialists' Collaboration report (1994) did not show any significant benefit when DM was considered separately. However, this conclusion was based on a total of 1,365 patients. There is no trial-based evidence showing that 'correcting' the coagulation and fibrinolytic activity, on a long-term basis, results in a clinically relevant benefit in diabetics. However, there is indirect evidence supporting this concept. Thus, 'tightening' diabetic control is both of clinical benefit and will normalise the circulating levels of coagulation and fibrinolytic factors. THE TREATMENT OF DIABETIC DYSLIPIDAEMIA
Non-insulin-dependent diabetes mellitus (NIDDM) is frequently associated with hypertriglyceridemia and premature atherosclerosis. Moreover, a predominance o f small dense LDL particles is characteristic of NIDDM. Plasma cholesteryl ester transfer protein (CETP) facilitates intravascular lipoprotein remodeling by promoting the heteroexchange of neutral lipids, i.e. triglycerides and cholesteryl esters. NIDDM is characterized by an accelerated rate of cholesteryl ester transfer as a result of increased plasma VLDL levels. In order to determine whether plasma triglyceride levels may influence the CETP-mediated redistribution of cholesteryl esters between atherogenic plasma lipoprotein particles, we measured cholesteryl ester mass transfer from HDL to apoB-containing lipoproteins in the plasma o f NIDDM subjects (n = 32). In parallel, we investigated the potential relationship between cholesteryl ester transfer and the appearance of an atherogenic LDL profile in NIDDM. In the present study, the diabetic population was divided into three groups according to fasting plasma triglyceride levels: Group I (GI): TG < l g/I; Group II (GIl): I g/1 < TG < 2 g/l and Group Ill (GIII): TG > 2 g/1. The rate of cholesteryl ester mass transfer from HDL to apoB-containing lipoproteins was significantly enhanced in the hypertriglyceridemic NIDDM group (GIII) in comparison with the mildly hypertriglyceridemic (GII) or normotriglyceridemic NIDDM (GI) groups (41.8+8.1 p.g CE transferred/lffml; 34.94-4.6 p.g CE transferred/hlml and 27.0+3.0 p.g CE transferred/h/ml in Gill, GII and GI respectively; p < 0.0001 GIIl vs GI, p = 0.0001 GII vs GI and p = 0.0183 GII vs GIII). Moreover, we observed a marked difference between groups in the relative capacity of VLDL and LDL to act as acceptors of cholesteryl esters from HDL. Indeed, the VLDL fraction acquired 25.74-8.7%, 45.94-9.0% and 68.1+8.7% o f CE from HDL whereas the LDL fraction accumulated 74.3%, 54.1% and 31.9% o f the total cholesteryl ester transferred from HDL in GI, GII and Gill respectively (p < 0.0001 GII and GIll vs GI and Gll vs GtII). Analysis o f the density distribution o f LDL subspecies mass revealed that NIDDM patients displayed an asymmetric LDL profile in which the dense LDL subfractions, LDL-4 (d = 1.039-1.050 g/ml) and LDL-5 (d ffi 1.050-1.063 g/ml), predominated. The relative proportion of dense LDL subspecies were closely related to plasma TG levels. Indeed, denser LDL subspecies accounted for 38%, 42% and 48% of total LDL mass in normotriglyceridemic, mildly hypertriglyceridemic and hypertriglyceridemic NIDDM patients, respectively. In conclusion, our data reveal that CETPdependent CE transfer to VLDL in NIDDM is intimately associated with progressive appearance of atherogenic dense LDL in these patients.
P.N. Durrington. University of Manchester, Department of Medicine, Manchester Royal Infirmary, Manchester MI 3 9WL, UK Although the principal abnormality of lipoprotein metabolism in diabetes is hypertriglyceridaemia the major clinical trial evidence of benefit from lipid-lowering is for cholesterol. Serum cholesterol carries a greater risk of coronary heart disease (CHD) in diabetes than in non-diabetic people. In secondary prevention lowering cholesterol in diabetes with statin drugs when it is >5 mmol/I decreases the relative CHD risk by at least as much as in non-diabetic people and absolute risk by more. This could be seen as the greatest therapeutic advance in diabetes treatment since insulin was introduced in 1923. The high absolute risk in many diabetic patients even before they have clinically evident CHD also justifies the use of statin drugs in primary prevention at an absolute risk of _>15% over the next 10 years. The mechanism by which serum cholesterol is more atherogenic in diabetes is likely to be because of the high levels of triglycerides with which it is frequently associated and the high rate of transfer of cholesteryl ester into this expanded circulating triglyceride pool from HDL (causing low HDL cholesterol in NIDDM) and from LDL (causing increased small dense LDL which is not readily appreciated from the routine lipoprotein profile provided in most laboratories). These abnormalities can be reversed to a large extent with fibrate drugs and these too have their place in combination with statins in high risk patients with a combined increase in cholesterol and triglycerides and as monotherapy in patients with type V and type Ill hyperlipoproteinaemia. The use of lipid-lowering drugs in hypertriglyceridaemia associated with serum cholesterol levels < 5 mmol/I is not supported by current evidence. Evidence that glycaemic control will reduce CHD risk is poor and although there are other reasons for attempting to optimise it, treatment of the dyslipoproteinaemia of diabetes using lipidlowering drugs is more clinically effective at least in NIDDM.
71st EAS Congress and Satellite Symposia
Pre-congress, Delphi Diabetic dyslipidemia (1)
in non-diabetic subjects matched for race, age and gender. Hypertriglyceridemia is reflected in exaggerated postprandial lipemia and preponderance of small dense LDL which are considered to be metabolic consequences of hypertriglyceridemia. In addition, compositional changes o f HDL due to triglyceride enrichment enhance the catabolic rate of HDL particles. The key question is what are the underlying mechanisms behind elevation of plasma triglycerides in Type 2 diabetic patients. The recognition o f lipoprotein heterogeneity has opened new perspective to the understanding of lipoprotein metabolism and its regulation. We have studied VLDL apo B metabolism using 3-3H leucine to track apo B 100 in large VLDLI (Sf 60400) and small VLDL2 (Sf 20-60) particles in nondiabetic, normolipidemic men and in Type 2 diabetic men. The subjects were studied on two occasions: I. during an 8.5-hour infusion of saline (control study) and 2. during an 8.5hour euglycemic hyperinsulinemic clamp (serum insulin 490 pmol/1). The novel observation was that in normal men acute hyperinsulinemia suppresses VLDLI apo B production but has no effect on VLDL2 production. On average VLDLI apo B production was reduced by 50% during insulin infusion leading also to the reduction of total VLDL apo B production. In contrast to normal men insulin failed to suppress VLDLI production in Type 2 diabetic men. This defect o f insulin action may be the root cause to elevation of triglyceride rich particles (TRLs) in Type 2 diabetes and insulin resistance. The long residence time of TRLs due to the competition o f both chylomicrons and endogenous VLDL particles for common catabolic pathways allows excessive transfer of core lipids between TRLs and LDL and HDL particles. We propose that the physiological role o f insulin is to maintain a balance between intestine derived and liver derived triglyceride rich particles. The failure of this action results in postprandial lipemia, changes of LDL and H DL subfractions and may be the link between diabetic dyslipidemia and CHD.
ATHEROGENICITY OF APO. B-CONTAINING LIPOPROTEINS IN DIABETIC DYSLIPIDEMIA: ROLE OF CETP M. Guerin, L. Steiner, M.J. Chapman. INSERM Unit~ 321. Hdpital de la
Piti~, Paris, France
THROMBOTIC RISK FACTORS IN DIABETIC PATIENTS
H. Milionis, D.P. Mikhailidis. Dept. of Molecular PatholoKv & Clinical Biochemistry, Royal Free & University College Medical School. London. UK Diabetic (DM) patients are at an increased risk of vascular events. Therefore, the prevention of vascular events in these patients is an important goal. This can be achieved by better glucose and blood pressure control. Correcting dyslipidaemias may also be clinically relevant although trial-based evidence is awaited. In this review we focus on the haemostatic system in diabetics. The plasma levels of fibrinogen are often elevated in DM. However, it is not clear if this is affected by the quality of glucose control. There is very strong evidence showing that elevated plasma levels of this coagulation factor are associated with an increased incidence of myocardial infarction and stroke. However, most of this evidence is based on non-DM patients. A decreased fibrinolytic activity may be particularly relevant to noninsulin dependent DM because it is associated with hypertriglyceridaemia, a common lipid abnormality in these patients. There is some evidence indicating that platelet hyperactivity occurs in diabetics. This may be relevant to the accelerated sclerogenesis seen in diabetics because platelets also release growth factors (e.g. platelet derived growth factor and serotonin). Endothelial dysfunction has been reported in diabetics. This abnormality may contribute to the increased prevalence of hypertension in DM, the activation of the coagulation system and platelets as well as to the impaired fibrinolytic activity. From a therapeutic point of view, the Antiplatelet Trialists' Collaboration report (1994) did not show any significant benefit when DM was considered separately. However, this conclusion was based on a total of 1,365 patients. There is no trial-based evidence showing that 'correcting' the coagulation and fibrinolytic activity, on a long-term basis, results in a clinically relevant benefit in diabetics. However, there is indirect evidence supporting this concept. Thus, 'tightening' diabetic control is both of clinical benefit and will normalise the circulating levels of coagulation and fibrinolytic factors. THE TREATMENT OF DIABETIC DYSLIPIDAEMIA
Non-insulin-dependent diabetes mellitus (NIDDM) is frequently associated with hypertriglyceridemia and premature atherosclerosis. Moreover, a predominance o f small dense LDL particles is characteristic of NIDDM. Plasma cholesteryl ester transfer protein (CETP) facilitates intravascular lipoprotein remodeling by promoting the heteroexchange of neutral lipids, i.e. triglycerides and cholesteryl esters. NIDDM is characterized by an accelerated rate of cholesteryl ester transfer as a result of increased plasma VLDL levels. In order to determine whether plasma triglyceride levels may influence the CETP-mediated redistribution of cholesteryl esters between atherogenic plasma lipoprotein particles, we measured cholesteryl ester mass transfer from HDL to apoB-containing lipoproteins in the plasma o f NIDDM subjects (n = 32). In parallel, we investigated the potential relationship between cholesteryl ester transfer and the appearance of an atherogenic LDL profile in NIDDM. In the present study, the diabetic population was divided into three groups according to fasting plasma triglyceride levels: Group I (GI): TG < l g/I; Group II (GIl): I g/1 < TG < 2 g/l and Group Ill (GIII): TG > 2 g/1. The rate of cholesteryl ester mass transfer from HDL to apoB-containing lipoproteins was significantly enhanced in the hypertriglyceridemic NIDDM group (GIII) in comparison with the mildly hypertriglyceridemic (GII) or normotriglyceridemic NIDDM (GI) groups (41.8+8.1 p.g CE transferred/lffml; 34.94-4.6 p.g CE transferred/hlml and 27.0+3.0 p.g CE transferred/h/ml in Gill, GII and GI respectively; p < 0.0001 GIIl vs GI, p = 0.0001 GII vs GI and p = 0.0183 GII vs GIII). Moreover, we observed a marked difference between groups in the relative capacity of VLDL and LDL to act as acceptors of cholesteryl esters from HDL. Indeed, the VLDL fraction acquired 25.74-8.7%, 45.94-9.0% and 68.1+8.7% o f CE from HDL whereas the LDL fraction accumulated 74.3%, 54.1% and 31.9% o f the total cholesteryl ester transferred from HDL in GI, GII and Gill respectively (p < 0.0001 GII and GIll vs GI and Gll vs GtII). Analysis o f the density distribution o f LDL subspecies mass revealed that NIDDM patients displayed an asymmetric LDL profile in which the dense LDL subfractions, LDL-4 (d = 1.039-1.050 g/ml) and LDL-5 (d ffi 1.050-1.063 g/ml), predominated. The relative proportion of dense LDL subspecies were closely related to plasma TG levels. Indeed, denser LDL subspecies accounted for 38%, 42% and 48% of total LDL mass in normotriglyceridemic, mildly hypertriglyceridemic and hypertriglyceridemic NIDDM patients, respectively. In conclusion, our data reveal that CETPdependent CE transfer to VLDL in NIDDM is intimately associated with progressive appearance of atherogenic dense LDL in these patients.
P.N. Durrington. University of Manchester, Department of Medicine, Manchester Royal Infirmary, Manchester MI 3 9WL, UK Although the principal abnormality of lipoprotein metabolism in diabetes is hypertriglyceridaemia the major clinical trial evidence of benefit from lipid-lowering is for cholesterol. Serum cholesterol carries a greater risk of coronary heart disease (CHD) in diabetes than in non-diabetic people. In secondary prevention lowering cholesterol in diabetes with statin drugs when it is >5 mmol/I decreases the relative CHD risk by at least as much as in non-diabetic people and absolute risk by more. This could be seen as the greatest therapeutic advance in diabetes treatment since insulin was introduced in 1923. The high absolute risk in many diabetic patients even before they have clinically evident CHD also justifies the use of statin drugs in primary prevention at an absolute risk of _>15% over the next 10 years. The mechanism by which serum cholesterol is more atherogenic in diabetes is likely to be because of the high levels of triglycerides with which it is frequently associated and the high rate of transfer of cholesteryl ester into this expanded circulating triglyceride pool from HDL (causing low HDL cholesterol in NIDDM) and from LDL (causing increased small dense LDL which is not readily appreciated from the routine lipoprotein profile provided in most laboratories). These abnormalities can be reversed to a large extent with fibrate drugs and these too have their place in combination with statins in high risk patients with a combined increase in cholesterol and triglycerides and as monotherapy in patients with type V and type Ill hyperlipoproteinaemia. The use of lipid-lowering drugs in hypertriglyceridaemia associated with serum cholesterol levels < 5 mmol/I is not supported by current evidence. Evidence that glycaemic control will reduce CHD risk is poor and although there are other reasons for attempting to optimise it, treatment of the dyslipoproteinaemia of diabetes using lipidlowering drugs is more clinically effective at least in NIDDM.
71st EAS Congress and Satellite Symposia