Diabetic Dyslipidemia: Causes and Consequences

More cardiovascular disease occurs in patients with either type 1 or 2 diabetes. The link between diabetes and atherosclerosis is, however, not completely understood. Among the metabolic abnormalities that commonly accompany diabetes are disturbances in the production and clearance of plasma lipoproteins. Moreover, development of dyslipidemia may be a harbinger of future diabetes. A characteristic pattern, termed diabetic dyslipidemia, consists of low high density lipoprotein (HDL), increased triglycerides, and postprandial lipemia. This pattern is most frequently seen in type 2 diabetes and may be a treatable risk factor for subsequent cardiovascular disease. The pathophysiological alterations in diabetes that lead to this dyslipidemia will be reviewed in this article. Defects in insulin action and hyperglycemia could lead to changes in plasma lipoproteins in patients with diabetes. Alternatively, especially in the case of type 2 diabetes, the obesity/insulin-resistant metabolic disarray that is at the root of this form of diabetes could, itself, lead to lipid abnormalities exclusive of hyperglycemia. Type 1 diabetes, previously termed insulin-dependent diabetes mellitus, provides a much clearer understanding of the relationship among diabetes, insulin deficiency, and lipid/lipoprotein metabolism. In poorly controlled type 1 diabetes and even ketoacidosis, hypertriglyceridemia and reduced HDL commonly occur (1). Replacement of insulin in these patients may correct these abnormalities, and well controlled diabetics may have increased HDL and lower than average triglyceride levels. The lipoprotein abnormalities commonly present in type 2 diabetes, previously termed noninsulin-dependent diabetes mellitus, include hypertriglyceridemia and reduced plasma HDL cholesterol. In addition, low density lipoprotein (LDL) are converted to smaller, perhaps more atherogenic, lipoproteins termed small dense LDL (2). In contrast to type 1 diabetes, this phenotype is not usually fully corrected with glycemic control. Moreover, this dyslipidemia often is found in prediabetics, patients with insulin resistance but normal indexes of plasma glucose (3). Therefore, abnormalities in insulin action and not hyperglycemia per se are associated with this lipid abnormality. In support of this hypothesis, some thiazoladinediones improve insulin actions on peripheral tissues and lead to a greater improvement in lipid profiles than seen with other glucose-reducing agents (4). Several factors are likely to be responsible for diabetic dyslipidemia: insulin effects on liver apoprotein production, regulation of lipoprotein lipase (LpL), actions of cholesteryl ester transfer protein (CETP), and peripheral actions of insulin on adipose and muscle. A number of studies using tracer kinetics in humans have demonstrated that liver production of apolipoprotein B (apoB), the major protein component of very low density lipoprotein (VLDL) and LDL, is increased in type 2 diabetes. ApoB is a large (>500-kDa) protein whose production is not modulated at the level of protein synthesis. In animals and cultured liver cells, transcription of the apoB gene is not remarkably altered by dietary changes and diabetes. Rather, a large amount of newly synthesized protein is degraded either during or immediately after translation. This degradation is prevented when lipid is added to the protein; this occurs via the actions of microsomal triglyceride transfer protein (the protein that is defective in patients with apobetalipoproteinemia). Thus, lipid regulates apoB production. Increased lipolysis in adipocytes due to poor insulinization results in increased fatty acid release from fat cells. The ensuing increase in fatty acid transport to the liver, which is a common abnormality seen in insulin-resistant diabetes, may cause an increase in VLDL secretion. Tissue culture (5), animal experiments (6), and human studies (7) suggest that fatty acids modulate liver apoB secretion. A second regulatory process may be a direct effect of insulin on liver production of apoB and other proteins involved in degradation of circulating lipoproteins. In some studies insulin directly increased degradation of newly synthesized apoB (8). Therefore, insulin deficiency or hepatic insulin resistance may increase the secretion of apoB. Insulin may modulate the production of a number of other proteins that affect circulating levels of lipoproteins. These include apoCIII (9), a small apoprotein that may increase VLDL by preventing the actions of LpL and inhibiting lipoprotein uptake via the LDL receptor-related protein (LRP). Hepatic lipase is an enzyme synthesized by hepatocytes that hydrolyzes phospholipids and triglycerides on HDL and remnant lipoproteins. Some (10, 11), but not all (12), studies suggest that this enzyme is reduced by insulin deficiency. One effect of hepatic lipase deficiency is to decrease the clearance of postprandial remnant lipoproteins (see below). LpL is the major enzyme responsible for conversion of lipoprotein triglyceride into free fatty acids. This protein has an unusual intercellular transport; LpL is synthesized primarily by adipocytes and myocytes, but must be transferred to the luminal side of capillary endothelial cells, where it can interact with circulating triglyceride-rich lipoproteins such as VLDL and chylomicrons (13). Humans with both type 1 and type 2 diabetes have been reported to have reduced LpL activity measured in postheparin blood (14); the enzyme is released from the capillary walls and into the circulation by heparin. Several steps in the production of biologically active LpL may be altered in diabetes, including its cellular production (15, 16) and possibly its transport to and association with endothelial cells (17). LpL is stimulated by acute (18) and chronic insulin therapy (19). LpL activity is low in patients with diabetes and is increased with insulin therapy (20). The release of stored fatty acids from adipocytes requires conversion of stored triglyceride into fatty acids and monoglycerides that can be transferred across the plasma membrane of the cell. The primary enzyme that is responsible for this is hormone-sensitive lipase (HSSL). HSSL is inhibited by insulin, which decreases phosphorylation of HSSL and its association with the stored lipid droplet (21). Postprandial lipemia. Compared with normal subjects, patients with type 2 diabetes have a slower clearance of chylomicrons from the blood after dietary fat (14, 22, 23); in treated type 1 patients, abnormalities in the postprandial period may not be found (24). This increased postprandial lipemia is especially marked in women, who generally have less postprandial lipemia than men. Chylomicron clearance requires several steps (Fig. 1). After chylomicrons enter the bloodstream via the thoracic duct, apoCII, the activator of LpL, is transferred to these particles primarily from HDL. The particle then interacts with LpL on capillary lumenal endothelial cells of cardiac and skeletal muscle and adipose tissue. Released fatty acids are taken up by those tissues, perhaps via the fatty acid transporter, CD36 (25), and a smaller triglyceride-depleted particle, a chylomicron remnant, is created. Chylomicrons contain a truncated form of apoB termed apoB48. This protein is 48% of full-length apoB and lacks the portion of apoB that interacts with the LDL receptor. A correlation between postprandial lipemia and atherosclerosis has been found in a number of clinical studies (26). In addition, apoB48 remnants are found in a number of atherogenic animal models made with diets and genetic modifications (27, 28). It is generally accepted that remnant lipoproteins, in addition to LDL, are atherogenic. Effects of diabetes on postprandial lipemia. A defect in removal of lipids from the bloodstream after a meal is common in patients with diabetes. Chylomicron metabolism requires that these lipoproteins obtain apoCII after they enter the bloodstream from the thoracic duct. Triglyceride within the particles can then be hydrolyzed by LpL, which is found on the wall of capillaries. LpL activity is regulated by insulin, and its actions are decreased in diabetes. Triglyceride-depleted remnant lipoproteins are primarily degraded in the liver. This requires them to be trapped by liver heparan sulfate proteoglycans (HSPG) and then internalized by lipoprotein receptors, LDL receptor and LRP. Because remnants contain a truncated form of apoB, apoB48, that does not interact with these receptors, this uptake is mediated by apoE. Remnant lipoproteins can be removed from the bloodstream via several pathways, some of which appear to be modulated by diabetes. Liver is the major, although not exclusive, site of remnant clearance. As these particles percolate through the liver, they are trapped by association with the negatively charged proteoglycans within the space of Disse. This process may be aided by the presence of apoE and hepatic lipase, proteins that bind to both lipid particles and proteoglycans. Both hepatic lipase and heparan sulfate proteoglycan production (29) may be reduced in diabetes. The second step in remnant clearance is via cellular internalization and degradation of the particles. Some of the remnants may be directly internalized along with cell surface proteoglycans. Most remnant uptake is via receptors. ApoE is a ligand for both the LDL receptor and LRP. Lipase enzymes (LpL and hepatic lipase) also interact with the LRP. In very poorly controlled diabetes LDL receptors may be decreased. Although LRP may be regulated by insulin in cultured macrophages (30), liver LRP is not decreased in diabetic mice (29). Although most patients with poorly controlled diabetes develop hypertriglyceridemia, occasional patients develop severe hyperchylomicronemia. Triglyceride levels exceeding 1000 mg/dL lead to visibly lipemic serum. At higher levels the patients can develop eruptive xanthomas, lipemia retinalis, and pancreatitis. Most of these patients have an underlying lipid disorder, such as heterozygous LpL deficiency, that is then exacerbated by diabetes (31). The relationship between severe hypertriglyceridemia and diabetes is sometimes obscured because primary LpL deficiency can lead to recurrent pancreatitis and insulin deficiency. In contrast to this, recent experimental data have shown that the LpL is expressed in the islet cells, and it has been postulated that this enzyme may promote fat-induced toxicity leading to defective insulin secretion (32). Increased plasma VLDL. Patients with diabetes, especially type 2 diabetes, have increased VLDL production (1). Insulin infusion will correct this abnormality (7) either because of the concomitant reduction in plasma fatty acids or because of direct effects of insulin on the liver (Fig. 2). Effects of diabetes on VLDL production. Poorly controlled type 1 diabetes and type 2 diabetes are associated with increased plasma levels of VLDL. Two factors may increase VLDL production in the liver: the return of more fatty acids due to increased actions of hormone-sensitive lipase (HSL) in adipose tissue and insulin actions directly on apoB synthesis. Both of these processes will prevent the degradation of newly synthesized apoB and lead to increased lipoprotein production. VLDL, like chylomicrons, requires LpL to begin its plasma catabolism, leading to the production of LDL or the return of partially degraded lipoprotein to the liver. Both the composition and the size of VLDL determine its metabolic fate. In diabetes greater amounts of fatty acids returning to the liver are reassembled into triglycerides and secreted in VLDL. A greater content of triglyceride leads to the production of larger particles. Not all VLDL are equally likely to be converted to LDL. A greater proportion of large lighter VLDL return to the liver without complete conversion to LDL (33); this pathway is akin to that of chylomicrons. Like chylomicrons, apoE may be the ligand that mediates liver uptake of these particles. Thus, VLDL metabolism is a competition between liver uptake of partially catabolized lipoproteins and intracapillary lipolysis, a process that may require several steps to complete VLDL conversion to LDL. LDL are not usually increased in diabetes. In part this may represent a balance of factors that affect LDL production and catabolism. A necessary step in LDL production is hydrolysis of its precursor VLDL by LpL. A reduction in this step due to LpL deficiency or excess surface apoproteins (C1, C3, or possibly E) decreases LDL synthesis. Conversely, increases in this lipolytic step that accompany weight loss, fibric acid drug therapy, and treatment of diabetes may increase LDL levels. In diabetes a reduction in LDL production may be counterbalanced by decreases in LDL receptors and/or the affinity of LDL for those receptors. Both glycosylated LDL and small, dense LDL bind to LDL receptors less avidly than does normal LDL. Occasionally diabetic patients, especially those with very poor glycemic control, may have increased LDL that is reduced by treatment of their diabetes. This is due to effects on either the LDL or the receptor. Increased small dense LDL. Heterogeneity exists in the size and composition of all classes of lipoproteins. The ratio of lipid to denser protein varies, and this determines both the buoyancy and the size of the particle, as the lipids are primarily contained in the core. In the case of VLDL and HDL, the particles also differ in their content of apoproteins, especially in the amounts of apoCs and apoE on the particle. The core of all lipoproteins contains hydrophobic cholesteryl ester and triglyceride. The proportions of these lipids are determined by CETP-mediated exchange of lipids (Fig. 3) and the actions of lipases that remove triglyceride by converting it into monoglycerides, glycerol, and free fatty acids. In the absence of a defect in these enzymes, lipoproteins enriched in triglyceride will be converted to small, denser forms. This is true for both HDL and LDL. Plasma lipid exchange. In the presence of increased concentrations of VLDL in the circulation, CETP will exchange VLDL triglyceride for cholesteryl ester in the core of LDL and HDL. This triglyceride can then be converted to free fatty acids by the actions of plasma lipases, primarily hepatic lipase. The net effect is a decrease in size and an increase in density of both LDL and HDL. A decrease in the size and an increase in density of LDL are characteristic of most hypertriglyceridemic states, including diabetes. Because of this, small dense LDL is considered by many to be one of the hallmarks of diabetic dyslipidemia rather than the expected companion of reduced HDL and increased triglyceride levels (2). The special designation given to LDL size, rather than HDL and VLDL size, is based on a large amount of clinical and experimental data implying that these particles confer additional atherosclerotic risk. In vitro, small dense LDL can be oxidized more easily, the particles do not interact with LDL receptors as well, and they may associate with proteoglycans on the surface of cells or in matrix more readily. Although several human studies imply that small dense LDL are an additional marker for atherosclerosis development (34), this observation may be restricted to patients with increased levels of apoB and decreased HDL (35). In other studies the concomitant association of hypertriglyceridemia and low HDL appears to obscure any additional risk profiling attributable to LDL size (36). In dietary studies using primates, larger, not smaller, LDL size correlates with atherosclerosis, presumably because each of these LDL carries more cholesterol (37). Although one could question the need to search for additional risk factors in diabetic patients who are at increased risk of many and do LDL density and/or This can be by LDL density using an or by size using or of the of a small dense LDL is by a and and insulin resistance are with small dense LDL. HDL. are several for the decrease in HDL found in patients with diabetes (Fig. Increased concentrations of plasma VLDL the exchange of triglyceride from VLDL for the cholesteryl found in HDL. Thus, the of the hypertriglyceridemia and reduced HDL can be CETP-mediated exchange of VLDL triglyceride for HDL cholesteryl is in the presence of hypertriglyceridemia of HDL are of HDL of triglyceride for cholesteryl ester in the core of the particle leads to a decrease in this Moreover, the but not cholesteryl in HDL is a for plasma lipases, especially hepatic lipase that HDL to a smaller particle that is more from the plasma to HDL is the surface lipid from triglyceride-rich particles that are transferred to HDL during VLDL and chylomicron This increases HDL lipid lipolysis leads to reduced HDL production. Effects of diabetes on HDL metabolism. HDL production requires the addition of lipid to small particles. This lipid via hydrolysis of VLDL and chylomicrons with transfer of surface lipids and free cholesterol via the actions of transfer protein A second pathway is via of cellular free cholesterol a process that the newly and of this cholesterol by the enzyme cholesterol HDL may occur through several Hepatic lipase and are found in the liver and in cells. HDL lipid can be by these tissues without degradation of HDL In the HDL protein without perhaps by the 2 a number of additional enzymes and receptors have been that are of HDL metabolism and presumably the effects of HDL on It is not hyperglycemia or insulin is an of these One of the steps in HDL production is the addition of lipid to the small, newly HDL particles in the liver and transfer protein may be for lipid transfer from triglyceride-rich lipoproteins In addition, newly HDL cholesterol from the most of these tissues for atherosclerosis development be the wall and Several have the gene responsible for a defect associated with very low levels of HDL and of cholesterol in the and other a of a of is defective in this disease This protein appears to be necessary for transfer of excess cholesterol of cells and into HDL. is an that be expected to on the surface of a cholesterol into its hydrophobic ester it to enter the core of the lipoprotein particle. LDL, but more akin to triglyceride-rich lipoproteins, HDL protein and lipid metabolism are sometimes is the for and and can obtain HDL lipid without uptake and degradation of the This process the return of cholesterol to the liver, this receptor appears to an in models of atherosclerosis are a major site of degradation of the major protein component of HDL. This appears to occur due to of this protein when it is from HDL acids may be for this these fatty acids may be from hepatic lipase hydrolysis of HDL triglyceride of diabetic dyslipidemia to atherosclerotic risk. of glucose reduction have that glucose is the to preventing diabetic These however, to a marked of glucose on disease. are several this could have The of the effects of diabetes on of large and small and may be of underlying disease may require a of or may a than that for small the processes are disease of diabetic patients occurs in both type 1 and type 2 diabetes and does not occur in It is to the defective glucose control. atherosclerosis is not a disorder, it is in patients with however, processes to diabetes must be the most this it may not be that treatment of these other such as and appears to disease more than does glucose control. the of disease in a diabetic with low plasma cholesterol levels is much less than that found in In the metabolic abnormalities associated with the insulin-resistant and increased disease are found in the even the development of hyperglycemia (3). it these abnormalities and not the glucose per se that are A of animal models have been to to the relationship between diabetes and disease. In a to diabetes in In a the diabetic not This atherosclerosis increased with insulin The for this are These that due in part to a marked defect in LpL. chylomicrons not converted to more atherogenic remnant lipoproteins and to the and lead to lipid This pathophysiological is not in human diabetes, for the in which patients are also LpL animal studies have more the in studies have been in made diabetic using in some studies the have increased LDL and reduced HDL develop diabetes and increased atherosclerosis however, plasma LDL more than by the diabetes. Thus, the effects of diabetes be because increased lipoprotein levels increase the genetic has made mice the most animal for the of human disease. this several have the effects of hyperglycemia on atherosclerosis for a small increase in in most of mice do not have most atherosclerosis not increased in mice an atherogenic are well models of atherosclerosis, and all have been diabetic found that diabetes increased size in diabetic mice in an effect that inhibited by the infusion of of the receptor for In these mice the diabetes increased circulating cholesterol perhaps due to a decrease in liver uptake of remnant lipoproteins via the pathway (29). Therefore, the rather than effects of the diabetes itself, have been the primary for the increased LDL receptor mice do not have more atherosclerosis than mice that contain a for of human apoB are more than animals and develop atherosclerotic when a to that by of and of diabetes using and by with adipose mice not increase atherosclerosis in these mice one that hyperglycemia is responsible for atherosclerosis, it appear that the its production of is to diabetic disease. that is with the human data and is with the and other animal models is that of disease requires some additional factors in the One such factor is diabetic of dyslipidemia in patients with diabetes. are to correct lipoprotein abnormalities in patients with diabetes. These are to prevent pancreatitis due to severe hypertriglyceridemia and to the risk of A number of recent have on the of in diabetic patients The of that therapy will be The has clinical for lipoprotein levels in with diabetes are as LDL cholesterol levels less than mg/dL HDL cholesterol levels more than mg/dL and triglyceride levels less than mg/dL The for the LDL is based on the that patients with diabetes and disease appear to have the risk of development of cardiac as who have a cardiac The for patients with disease is LDL levels Most are that to this in most Moreover, data that are for and disease in diabetic The second is to increase HDL to or Although this may be an for many patients and their it is not a This is in the for LDL, are to this especially in patients with diabetic dyslipidemia who begin with HDL cholesterol levels weight loss, and all increase HDL. low in cholesterol and fat to decrease HDL. The most to HDL is A to this is an increase in HDL of which is not to many low HDL levels to the Although can be given to diabetic patients, it is generally because it hyperglycemia. acids and also increase however, their effects are more that those found with Two recent to cardiac disease in with low HDL. HDL to the the studies that are likely to this in most In one with HDL treated with lower LDL associated with cardiac In the termed patients with cardiac disease and average HDL of mg/dL treated with leading to a HDL triglyceride and recurrent Therefore, it is this that to a for HDL at mg/dL is and the of such a are Triglyceride levels mg/dL are termed this appears to this from a The primary and in many to triglyceride reduction is glycemic control. In type 2 patients this also weight Although severe hypertriglyceridemia leads to increased risk for that reduction of triglycerides is of is Several the and several of fibric acid studies as that treatment of triglycerides is can be reduced with fibric high and It be that the of fibric acids to triglyceride along with increases the risk of and be with of the diabetes and dyslipidemia has been Although of diabetic dyslipidemia is likely to be but one of many for the disease in diabetic treatment of lipid abnormalities has the to cardiovascular more than to that are seen in with lower cholesterol and less atherosclerotic This leads to the that treatment of lipid levels will patients with diabetes to lead