Diabete & metabolisme最新文献

High-density lipoproteins (HDL) are believed to protect against atherosclerosis by promoting the process of reverse cholesterol transport. This process involves different steps including efflux of cellular cholesterol, cholesterol esterification and lipid transport and exchange. Apolipoprotein (apo) A-I, the major HDL apolipoprotein, and the HDL-associated enzyme lecithin-cholesterol acyltransferase (LCAT), which uses apo A-I as a cofactor, play a crucial role in reverse cholesterol transport. HDL may be classified into species according to their apolipoprotein content. Recent data concerning HDL particles indicate that lipoproteins containing apo A-I but not apo A-II (LpA-I) are more effective carriers of free cholesterol and are associated with a protective effect against coronary heart disease. In vitro studies have shown that glycosylated HDL are functionally abnormal and may be considered atherogenic. Our study considers the different impacts of non-enzymatic glycosylation of apo A-I or protein-HDL on the reverse cholesterol transport process.

Apolipoprotein A-IV is considered to play a role in triglyceride-rich lipoprotein metabolism, in reverse cholesterol transport, and in facilitation of CETP (Cholesterolyl Ester Transfer Protein) activity. Moreover, apoA-IV is genetically polymorphic in humans, in whom two major isoproteins (apoA-IV 1 and apoA-IV 2) are present and have differences that influence the apoA-IV phenotype in lipid metabolism. In non-insulin-dependent-diabetes, increased apoA-IV levels are found, mainly related to hypertriglyceridemia and to a lesser extent to HDL cholesterol level; apoA-IV phenotype distribution is not different from controls; in the control population, the potential protective lipid profile (characterized by increased HDL and HDL2 cholesterol levels) related to the apoA-IV 1-2 phenotype, is no longer found in NIDDM patients (the metabolic state of NIDDM appears to have effected the potential protective lipid profile related to the apoA-IV 1-2 phenotype); and plasma apoA-IV levels is associated with increased prevalence for macrovascular disease. In non-insulin-dependent diabetes treated with insulin, apoA-IV levels are increased. Unlike results for NIDDM patients undergoing oral treatment, the increase in apoA-IV level is not related to hypetriglyceridemia, so that the effect on lipid metabolism may be different.

Prospects for therapy for hyperlipoproteinaemia are likely to rely more heavily on improvement of known molecules than on development of new ones aimed at various components of the plasma lipid transport system. Promising advances are revealed in both directions. A new synthetic inhibitor of HMG CoA reductase, atorvastatin, lowers plasma low-density lipoprotein (LDL)-cholesterol and triglycerides and increases high-density lipoprotein (HDL)-cholesterol with greater potency than currently available drugs of this class. A highly selective thyromimetic, CGS 26214, virtually devoid of cardiovascular effects, has potent cholesterol-lowering activity in several models, reduces post-prandial response to a fat load in rats and markedly lowers Lp(a) concentrations in monkeys. There is a trend to develop inhibitors of acyl CoA: cholesterol acyltransferase (ACAT) with more than one desirable activity. Thus, ACA-147, which inhibits cholesterol absorption, reduces LDL, prevents their oxidation and increases HDL-cholesterol, was antiatherogenic in cholesterol-fed rabbits. Sch48461 has emerged as an inhibitor of cholesterol absorption by an as yet unknown mechanism unrelated to ACAT inhibition, while a synthetic saponin, CP- 148,623, which prevents the entry of cholesterol into intestinal mucosa, has a potential for combination therapy. Approaches which may find applications in a more distant future include molecular cages to trap cholesterol selectively, "cholesterol vaccination", overexpression of the apolipoprotein E gene in the skin, and gene therapy. With improvements in understanding of the pathophysiology of dyslipoproteinaemias, drug discovery and development may focus more in future on the specific causes of disease.

Cardiovascular diseases are the leading cause of death during diabetes, and qualitative changes in lipoproteins play a role in the pathogenesis of atherosclerosis. Hyperglycaemia induces glycation of lipoproteins, particularly low-density lipoproteins (LDL), preventing the recognition of apoprotein B by the specific receptor and favouring the accumulation of LDL in macrophages and their oxidation. Other effects contribute to increased LDL oxidation in diabetes: higher production (and decreased degradation) of free radicals, the association of hypertriglyceridemia with the presence of small, dense, more easily oxidizable LDL, and high-density lipoprotein anomalies which reduce LDL antioxidant capacities. Glycation- oxidation interactions are complex. Although glycated LDL are more easily oxidizable, antioxidants could also reduce protein glycation independently of glycaemic balance. The role of glyco-oxidative changes in the pathogenesis of atherosclerosis during diabetes is difficult to determine, partly because of methodological problems related to the presence of circulating antioxidants which allow only minimal (and not easily demonstrable) LDL oxidation. The development of measurements sensitive to lipoprotein oxidation should facilitate the determination of LDL oxidative status. The main means of preventing and treating glyco-oxidative alterations are the normalisation of LDL-cholesterol concentrations and the improvement of glycaemic balance. Prospective studies are needed to determine the role of antioxidants in the prevention and/or treatment of atheromatous disease during diabetes.

Many models of diabetes dyslipidemia are available. Animals with chemically-induced diabetes have been used to study insulin-dependent diabetes. Hypercholesterolemia in streptozotocin-induced diabetes in rats results from increased intestinal absorption and synthesis of cholesterol. Lipoproteins from diabetic rats are oxidized and demonstrate cytotoxicity, a feature which can be prevented by insulin or antioxidant treatment. Diabetic rabbits fed a cholesterol-rich diet do not develop atherosclerotic lesions because accumulated VLDL are apo E-depleted, too large and do not enter into the arterial wall. Models for non-insulin-dependent diabetes (NIDDM) are obtained through selective breeding or dietary conditions. The obese Zucker rat (fa/fa) is characterized by hyperphagy, hyperglycaemia, hyperinsulinemia, insulin-resistance, hypertriglyceridemia and hypercholesteolemia. It responds to dietary, hormonal and drug treatments, but does not develop atherosclerosis spontaneously. It is used as a model for obesity, NIDDM and type IV hyperlipidemia. The JCR:LA cp rat bears the corpulent gene and develops similar characteristics to those of the Zucker rat. However, insulin-resistance is more severe in homozygous males (cp/cp), and cardiovascular lesions are observed. Their appearance is reduced by treatments which decrease hyperinsulinemia and insulin resistance but not by lowering lipid levels alone. The sand rats (Psammomys obesus) develop obesity and NIDDM when fed a laboratory diet. When cholesterol and anti-thyroid drug are added to the diet, they develop cardiovascular lesions. This species constitutes a new model for studying atherosclerosis-related diabetes.

It has been widely accepted that the remnants of the intestinally-derived lipoprotein chylomicrons, i.e., chylomicron remnants (CMR), are cleared from the circulation by a receptor genetically distinct from the well-known LDL-receptor. This second receptor was initially considered as a receptor specific for apo E, in contrast to the LDL-receptor, which binds both apo B and apoE. This article critically examines the current dogma of the putative CMR receptor, as well as both supporting and conflicting evidence for the recently-proposed identity of this receptor with the LDL-receptor related protein (LRP). Next, we introduce the lipolysis-stimulated receptor, LSR, which bears all the biochemical characteristics of the CMR receptor. In addition, the apparent number of LSR expressed in the liver is inversely correlated with nonfasting levels of plasma triglycerides. A change in LSR expression and parallel inverse change in plasma triglycerides is observed in rats treated with hyperlipidemic (retinoic acid) or hypolipidemic (fish oil in MaxEPA) agents, indicating that LSR represents a definite target for pharmacological management of hyperlipidemia. In support of this notion is the observation that MaxEPA, which causes an increase in LSR expression, also reduces both plasma triglyceride and cholesterol levels in the thus far intractable homozygous Watanabe heritable hyperlipidemic rabbit.

Lp(a) has atherogenic and thrombotic properties and is considered to be a major risk factor for the development of atherosclerotic disease. The risk of cardiovascular disease is increased in both insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), and Lp(a) has attracted attention as a potential risk factor in diabetic patients. Lp(a) levels are "probably" elevated in IDDM patients and related to altered metabolic control and increased urinary albumin excretion rate or renal insufficiency, although results are controversial. There appears to be a real difference between the Lp(a) of patients with proliferative diabetic retinopathy and those with or without background retinopathy. The plasma Lp(a) level may therefore be associated with microangiopathy in some IDDM patients. However, data relating Lp(a) to complications of diabetes are limited, and the literature is conflicting. The few available data suggest that Lp(a) is not elevated in NIDDM patients and that there is no strong link between blood glucose control and plasma Lp(a). There is no clear evidence as to whether Lp(a) is related to microalbuminuria in NIDDM patients. There is little evidence for a correlation between increased risk of cardiovascular disease and plasma Lp(a) among diabetic patients. However, some diabetic patients with coronary heart disease have elevated plasma Lp(a), which seems to be correlated with genetic factors (especially the isoforms of apolipoprotein a) rather than to diabetes per se. Lp(a) synthesis and catabolism could be influenced by insulin or by diabetes and its metabolic concomitants. The atherogenic and thrombogenic potential of Lp(a) could also be increased in diabetic patients. Plasma Lp(a) should be measured for both IDDM and NIDDM patients. If the Lp(a) level is elevated, it seems reasonable to check the other major vascular risk factors.

Non-insulin-dependent diabetes (NIDDM) is characterized by overproduction of glucose, decreased effects of insulin on glucose utilization and production, and a defect in glucose-induced insulin secretion. NIDDM is also associated with defects in fatty acid metabolism, i.e. enhanced lipolysis and impaired suppression of adipose tissue lipolysis in response to insulin, and increased plasma free fatty acid levels. It has been suggested that the "glucose-fatty acid cycle" is enhanced in NIDDM and could contribute to disturbed glucose homeostasis. Although the use of intralipid + heparin infusion and inhibitors of lipolysis or fatty acid oxidation indicates that the glucose-fatty acid cycle exists both in normal and NIDDM subjects, it does not seem to be the primary cause of distributed glucose homeostasis in lean NIDDM subjects or their first-degree relatives. However, the glucose-fatty acid cycle could contribute to overproduction of glucose (by stimulating gluconeogenesis) and muscle insulin resistance in obese NIDDM subjects. Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels. The role of the glucose-fatty acid cycle in normal subject must be clarified, and its contribution to decreased glucose-induced insulin secretion in NIDDM requires further investigation.