Specific lipid lowering therapy in the management of diabetes.
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Clinical Trials as Topic↗
Biomedical subjects
P N Durrington
Publications and source records attributed to P N Durrington.
Clinical value of apolipoprotein measurement.
Low density and very low density lipoproteins contain apolipoprotein B100 which is synthesized in the liver. Chylomicrons have apolipoprotein B48, which consists of part of the apolipoprotein B100 sequence, and which is produced in the gut by the same gene that encodes for apolipoprotein B100. Both apolipoprotein B100 and apolipoprotein B48 are important for the secretion of triglyceride-rich lipoproteins whereas apolipoprotein B100, which can bind to the low density lipoprotein receptor, is also important for low density lipoprotein catabolism. Apolipoprotein (a) has structural homology with plasminogen and exists as a complex with apolipoprotein B100 in lipoprotein (a). Apolipoprotein AI is the main lipoprotein in high density lipoproteins, whilst apolipoprotein E, present in chylomicrons and intermediate density lipoproteins, plays a major role in their catabolism. Serum apolipoprotein B and apolipoprotein AI have potential in the evaluation of coronary risk. Apolipoprotein B may be of particular value in patients with hypertriglyceridaemia and normal low density lipoprotein cholesterol levels. Apolipoprotein (a) has also been reported to be an important indicator of coronary risk, especially in the presence of elevated apolipoprotein B. Lack of standardization and the limited availability of prospective data at present limit the routine use of apolipoprotein B, AI and (a) measurements. The determination of apolipoprotein E phenotypes has proved useful in the diagnosis of remnant (type III) hyperlipoproteinaemia.
Apolipoproteins↗
Serum esterase activities and hyperlipidaemia in the streptozotocin-diabetic rat.
The levels of activity of four serum esterases were measured in control and streptozotocin-diabetic rats for a period of 6 months. Pseudocholinesterase activity was significantly elevated in the diabetic rats at all time points tested, reaching 250% of the control activity at 6 months. Levels of paraoxonase activity progressively decreased with time in the diabetic rats, being 36% lower than in controls at 6 months. No significant differences in either serum arylesterase or carboxylesterase activity between control and diabetic rats were observed.
Animals↗
Investigation of lipid transfer in human serum leading to the development of an isotopic method for the determination of endogenous cholesterol esterification and transfer.
The rate at which radioactivity appeared in cholesteryl esters (CE) in whole serum and in very low density lipoproteins (VLDL) and low density lipoproteins (LDL) when radioactively labelled free cholesterol (FC) was incubated with serum was investigated. At 4 degrees C equilibration of radioactive FC with native FC occurred, but there was no conversion to CE. At 37 degrees C CE mass increased in parallel with radioactivity in CE both in whole serum and VLDL/LDL. Incubation at 37 degrees C with an inhibitor of lecithin cholesterol acyl transferase (LCAT) abolished the increase in the total CE radioactivity and mass in serum. Transfer of CE from high density lipoprotein (HDL) to VLDL/LDL, however, continued to occur. An assay for LCAT and for cholesteryl ester transfer protein (CETP) was developed, which employed the increases in radioactive CE in whole serum and VLDL/LDL during a single incubation as indices of LCAT and CETP activity, respectively. Determination of the initial serum FC concentration allowed the expression of these activities in nmol/ml per h. References ranges were established in 62 fasting normolipidaemic men and women and increases in both LCAT and CETP were found following a fatty meal. The experiments thus provided further information about the carrier-mediated transfer of CE from its site of esterification on HDL to VLDL/LDL and formed the basis of a relatively simple assay, which has advantages over previously published methods and which may be used in clinical and epidemiological studies to elucidate the role of CETP and LCAT in atherosclerosis.
Apolipoproteins↗
Lipoprotein (a): structure, properties and possible involvement in thrombogenesis and atherogenesis.
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Animals↗
Hyperlipidaemia and renal disease.
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Cholesterol↗
Coronary risk factors: value of screening and preventive strategies in general practice.
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Coronary Disease↗
Secondary hyperlipidaemia.
Secondary hyperlipidaemia is common and occurs frequently in disorders such as obesity, alcoholism, diabetes mellitus, hypothyroidism, liver and renal diseases and as a side-effect of drug therapy, particularly for hypertension. Its management may be important to prevent complications such as coronary heart disease and acute pancreatitis. Its study provides many fascinating insights into lipoprotein pathophysiology.
Alcoholism↗
Elevation of skeletal muscle isoform of serum creatine kinase in heterozygous familial hypercholesterolaemia.
Serum creatine kinase (CK) is an important adjunct in the diagnosis of myocardial infarction or in monitoring for the side-effects of drugs. We report elevation of CK in patients with untreated heterozygous familial hypercholesterolaemia (FH) with no evidence of myocardial infarction. Of a group of 30 patients, 60% had elevated CK values on one occasion. In 40% of patients elevated CK activity was observed on most occasions. This was not related to exercise or previous lipid-lowering therapy. These observations are of importance in view of the potential for misdiagnosis of myocardial infarction or premature withdrawal of lipid-lowering therapy.
Clinical Enzyme Tests↗
Bezafibrate retard in patients with insulin-dependent diabetes: effect on serum lipoproteins, fibrinogen, and glycemic control.
The effects of a sustained-release preparation of bezafibrate (Bezalip Mono) 400 mg once daily and placebo administered for 3 months were compared in 36 patients with stable type 1 diabetes and hypercholesterolemia and/or hypertriglyceridemia. There was a significant decrease in fasting glucose levels with bezafibrate, but not in glycosylated hemoglobin. The serum cholesterol concentration decreased on bezafibrate [from 7.1 +/- 0.2 (mean +/- SEM) to 6.3 +/- 0.3 mmol/L; p less than 0.05] predominantly due to a reduction in low-density lipoprotein (LDL) cholesterol [from 4.8 +/- 0.3 to 4.2 +/- 0.3 mmol/L; p less than 0.05. There was also a decrease in fasting serum triglycerides with bezafibrate [1.82 to 1.26 mmol/L (geometric mean)] and in very-low-density lipoprotein (VLDL) cholesterol. Plasma fibrinogen decreased significantly with bezafibrate (from 4.1 +/- 0.2 to 2.9 +/- 0.2 g/L; p less than 0.001). Serum apolipoproteins B and A showed no statistically significant changes. Overall, there was no change in high-density lipoprotein (HDL). However, in patients who were initially hypertriglyceridemic, there was a significant increase in the cholesterol content of total HDL and the HDL2 subfraction (both p less than 0.05). It is concluded that in insulin-dependent diabetic patients with hyperlipidemia, bezafibrate is effective in lowering both serum VLDL and LDL. In addition, it has a potentially important action in decreasing plasma fibrinogen levels.
Adolescent↗
Biological variation in serum lipid concentrations.
Individual variations in serum lipid concentrations resulting from laboratory error are often much less than those due to other factors. Thus the coefficient of variation for biological fluctuations in cholesterol is 5-10% and for triglyceride concentration 5-25%. Many of the causes of changing lipid levels are known. Sampling conditions (venous stasis, body position) contribute as does the handling of the blood sample before it reaches the laboratory, for example whether an anticoagulant is used and haemolysis, clearly meals have a major effect on serum triglycerides, but even when fasting there is probably also diurnal variation. Fluctuations in serum lipids occur during the menstrual cycle, cholesterol and triglycerides tending to be highest at midcycle and to decline towards menstruation. Pregnancy produces major increases in both cholesterol and triglyceride levels. There is a well established seasonal variation in cholesterol concentrations which are greatest in autumn and lowest in late spring and early summer. This may be partly due to nutritional changes, but similar findings in laboratory animals suggest that humoral factors may also be important. Age also influences serum lipids. It is frequently not appreciated that both cholesterol and triglycerides are at their lowest in adolescence. Rapid increases in cholesterol may occur in women around the menopause. Lipid concentrations may undergo considerable change during illness. The decrease in LDL and HDL cholesterol and apo B and tendency for increases in triglycerides during acute myocardial infarction are well known but similar alterations can also occur with angina or coronary artery bypass surgery. Other surgical operations and intercurrent illnesses, perhaps even common viral infections, may also influence lipids.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Validation of the Friedewald formula for the measurement of low density lipoprotein cholesterol in insulin-dependent diabetes mellitus.
The Friedewald formula has been widely used in the estimation of the serum LDL cholesterol concentration in diabetic patients. In patients with insulin-dependent diabetes we have compared the serum LDL cholesterol concentrations obtained when VLDL was isolated in the preparative ultracentrifuge and its cholesterol content directly determined with those when the 'Friedewald Formula' assumption that there is a fixed ratio between total serum triglycerides and VLDL cholesterol was used in the calculation of the LDL cholesterol value. Both methods gave similar results which were closely correlated (r = 0.98) with a slope of 0.98 on linear regression analysis for patients with serum triglycerides of less than 2.5 mmol/l. The inclusion of a small number of hypertriglyceridaemic patients (14%) had virtually no impact on these findings.
Adult↗
Apolipoprotein E polymorphism and lipoproteins in insulin-treated diabetes mellitus.
Apolipoprotein E (apo E), a component of VLDL, HDL and chylomicron remnants, is inherited at a single genetic locus with 3 common alleles (epsilon 2, epsilon 3 and epsilon 4). epsilon 2 homozygosity is found in 0-2% of healthy populations, but in 75-100% of subjects with type III hyperlipoproteinaemia, in whom an increased prevalence of glucose intolerance has previously been reported. The lipoprotein abnormality associated with diabetes mellitus has features in common with type III hyperlipoproteinaemia and both conditions lead to accelerated atherogenesis with a similar anatomical distribution. We have therefore examined the frequency of apo E genotypes in 120 subjects with insulin-treated diabetes mellitus (ITDM) and 107 healthy controls, and examined the effect of apo E polymorphism on lipoproteins in the diabetic group. As in the general population, the apo E phenotype in ITDM was a significant determinant of the total serum and LDL cholesterol concentrations which were lowest in patients possessing the epsilon 2 allele, intermediate in those homozygous for epsilon 3 and highest in those with an epsilon 4 allele. The observed gene frequencies of epsilon 2 (0.091), epsilon 3 (0.780) and epsilon 4 (0.130) were similar to those of the healthy control group and those in the general population. However, there was an unexpected increase (P less than 0.0002) in epsilon 2 homozygosity of 6.7% compared to a prevalence of 0.8% predicted both from the Hardy-Weinberg equilibrium and the 0.9% prevalence observed in the healthy control group. This suggests either that epsilon 2 homozygosity increases susceptibility to the development of ITDM or that the two conditions are genetically linked.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Does residual insulin secretion (assessed by C-peptide concentration) affect lipid and lipoprotein levels in insulin-dependent diabetes mellitus?
1. Residual endogenous insulin secretion can be assessed by the circulating C-peptide concentration and is present in up to 15% of subjects with established insulin-dependent diabetes mellitus (IDDM). Its role in lipid metabolism in IDDM is not clearly defined. We examined the relationships between serum lipid and lipoprotein concentrations and the response of circulating C-peptide to a test meal in 205 subjects with IDDM. 2. Lipid and lipoprotein levels and glycaemic control did not differ significantly between patients with undetectable, low or high C-peptide responses. 3. High density lipoprotein (HDL) cholesterol and its subfractions were inversely related to concentrations of serum triacylglycerols (P less than 0.01-0.001), but not to C-peptide or glycated haemoglobin (HbA1) levels. Levels of HbA1 and triacylglycerols were correlated with one another (P less than 0.01). Analysis of variance revealed that differences in gender and triacylglycerol concentrations were the most important determinants of HDL and HDL2 cholesterol levels. C-peptide only exerted a weak effect on HDL2 cholesterol levels and no significant predictors of HDL3 cholesterol were found. 4. It is concluded that endogenous insulin secretion (assessed by C-peptide concentration) is relatively unimportant in modifying HDL metabolism in IDDM and that associated clinical features, in particular ambient hypertriglyceridaemia, are of greater importance.
Adolescent↗
Borderline hypercholesterolaemia: when to introduce drugs.
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Adult↗
The prevalence of hyperlipidaemia and related clinical features in insulin-dependent diabetes mellitus.
The prevalence of hyperlipidaemia and related clinical features was examined in 205 individuals with insulin-dependent diabetes mellitus. Overall, 40 per cent (82) of the individuals had hyperlipidaemia. Whilst the prevalence of hypertriglyceridaemia and combined hyperlipidaemia was greater in patients with insulin-dependent diabetes mellitus than non-diabetics, this was not the case for hypercholesterolaemia. Hyperlipidaemia was present in older patients, and the daily insulin dose and levels of HbA1 were highest in those with combined hyperlipidaemia. In addition normolipidaemic subjects had the lowest levels of serum creatinine. Triglyceride levels were predicted (in order of importance) by insulin dose, age at diagnosis, HbA1 and body mass index, whilst cholesterol levels were predicted by the age at the time of study, body mass index, urinary protein excretion, and levels of fasting blood glucose and HbA1. Hyperlipidaemia is common in insulin-dependent diabetes mellitus, and may be particularly apparent in older patients and/or those with early renal dysfunction or poor glycaemic control.
Adult↗
Therapeutic aspects of hyperlipidaemia in diabetes.
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Coronary Disease↗
Apolipoproteins (a), AI, and B and parental history in men with early onset ischaemic heart disease.
Middle-aged men who had had a myocardial infarction were compared with controls matched for social background, age, cigarette-smoking, blood pressure, and alcohol consumption. Serum cholesterol, triglycerides, very low density lipoprotein, low density lipoprotein, high density lipoprotein (HDL), HDL2 and HDL3 cholesterol, and serum apolipoproteins (apo) (a), AI, and B were measured. Discriminant analysis showed that the combination of these variables that best distinguished patients from controls was provided by apo AI and apo B and a knowledge of parental history of early cardiac death, the most discriminating single factor being apo B. No other variable contributed more than these. Apo (a), however, could be substituted for parental history, which had a major influence on the serum concentration of apo (a). Apo (a) concentration accounted for much of the familial predisposition to cardiac ischaemia. These findings may prove valuable in the clinical assessment of genetic susceptibility to myocardial infarction. They also support the hypothesis that serum apo (a) concentration is a genetic trait that predisposes to arterial thrombosis. Apo B emerged as the main lipoprotein determinant of coronary disease risk.
Apolipoprotein A-I↗