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.
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.
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. 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 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 LpL is stimulated by acute 18 and chronic insulin therapy LpL activity is low in patients with diabetes and is increased with insulin therapy 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. 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 This increased postprandial lipemia is especially marked in women, who generally have less postprandial lipemia than men.
Chylomicron clearance requires several steps Fig. 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 apoB A correlation between postprandial lipemia and atherosclerosis has been found in a number of clinical studies In addition, apoB48 remnants are found in a number of atherogenic animal models made with diets and genetic modifications 27 , 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. 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. In very poorly controlled diabetes LDL receptors may be decreased. Although most patients with poorly controlled diabetes develop hypertriglyceridemia, occasional patients develop severe hyperchylomicronemia.
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 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 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. 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. 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. Conversely, increases in this lipolytic step that accompany weight loss, fibric acid drug therapy, and treatment of diabetes may increase LDL levels.
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.
The core of all lipoproteins contains hydrophobic cholesteryl ester and triglyceride. In the absence of a defect in these enzymes, lipoproteins enriched in triglyceride will be converted to small, denser forms.
Plasma lipid exchange. This triglyceride can then be converted to free fatty acids by the actions of plasma lipases, primarily hepatic lipase. 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 In other studies the concomitant association of hypertriglyceridemia and low HDL appears to obscure any additional risk profiling attributable to LDL size In dietary studies using primates, larger, not smaller, LDL size correlates with atherosclerosis, presumably because each of these LDL carries more cholesterol This can be done by measuring LDL density using an ultracentrifuge or by measuring size using gradient gels or light scattering.
Another method of determining the likelihood of a patient having small dense LDL is by waist measurement, a cheaper and easier test 38 , Obesity and insulin resistance are highly correlated with small dense LDL. Reduced HDL. There are several reasons for the decrease in HDL found in patients with diabetes Fig. Clinical measurements of HDL are of HDL cholesterol; therefore, substitution of triglyceride for cholesteryl ester in the core of the particle leads to a decrease in this measurement.
Moreover, the triglyceride, but not cholesteryl ester, in HDL is a substrate for plasma lipases, especially hepatic lipase that converts HDL to a smaller particle that is more rapidly cleared from the plasma This increases HDL lipid content. An acceptable LDL level is less than mg per dL 3. In patients with clinically evident vascular disease, LDL levels should be less than mg per dL 2.
Whether these lower values should be the target for all patients with diabetes, regardless of whether they manifest vascular disease, has been debated. An HDL level of greater than 45 mg per dL is recommended 1.
Management of hyperlipidemia should begin with improving glycemic control and losing weight. Exercise should be incorporated into a weight-loss program, as it has been shown to enhance weight loss and facilitate weight maintenance.
Weight loss will result in a decrease in triglyceride levels and an increase in HDL levels. Before an exercise program can be recommended, concomitant medical conditions that would increase the risks of exercise should be taken into consideration, including the presence of proliferative retinopathy, neuropathy and foot problems.
It is prudent to recommend an exercise tolerance test to rule out silent myocardial ischemia, particularly in patients older than 35 years. If the goals for lipid levels have not been reached after three to six months of diet, exercise and improved glycemic control, drug therapy should be initiated.
However, drug therapy should be used at the outset in patients with severe hypertriglyceridemia triglyceride level greater than 1, mg per dL [ The type of drug chosen should be based on the lipid abnormality that is present.
In patients with hypercholesterolemia without hypertriglyceridemia, an HMG-CoA reductase inhibitor should be used; in patients with hypercholesterolemia with hypertriglyceridemia, an HMG-CoA reductase inhibitor or gemfibrizol can be used; in patients with hypertriglyceridemia, gemfibrizol can be used. A patient with decreased HDL levels may benefit from taking an HMG-CoA reductase inhibitor or niacin; however, niacin should be used with caution because of a possible adverse effect on glycemic control.
Omega-3 fatty acids fish oils have been shown to reduce lipid levels in healthy patients. However, when fish oils have been used in patients with type 2 diabetes, some adverse effects have been reported, including elevation of fasting and postprandial glucose levels.
Combination drug therapy can be used if hyperlipidemia is unresponsive to monotherapy. An extremely useful example is the combination of low-dose bile acid sequestrants and HMG-CoA reductase inhibitors. The use of an HMG-CoA reductase inhibitor with fibrates or niacin is associated with an increased risk of myopathy. Develop and improve products. List of Partners vendors. A high level of glucose sugar in the bloodstream is associated with a host of complications, including cholesterol abnormalities.
The linking factor: insulin resistance—when cells no longer respond appropriately to the hormone insulin. As a result, a person may develop an abnormal cholesterol profile—low high-density lipoprotein HDL, or "good cholesterol" , high low-density lipoprotein LDL, or "bad cholesterol" , and high triglycerides.
These cholesterol abnormalities then increase a person's risk for heart disease and stroke. With this in mind, managing your pre-diabetes or diabetes is about more than just keeping your blood sugar in check. It's also about working to protect your cardiovascular health. After eating a meal, carbohydrates are broken down into glucose by your digestive system.
This glucose is then absorbed through the wall of your intestines into your bloodstream. Once there, insulin—a hormone, made by your pancreas, that is the primary regulator of carbohydrate metabolism—brings glucose into various cells, so they have the energy to function and do their jobs. Insulin also blocks the breakdown of fat into fatty acids lipolysis within your body. Insulin resistance is when the cells become less responsive to this process.
As a result, blood sugar eventually increases, which is why it's considered a precursor to pre-diabetes and type 2 diabetes. Fats are also broken down within the body at an increased rate, and this ultimately leads to various cholesterol changes. A low HDL level or a high LDL level paired with a high triglyceride level is linked to the buildup of plaque fatty deposits in the walls of arteries. This condition is called atherosclerosis and it increases your risk of developing a heart attack and stroke.
Metabolic syndrome is not a specific disease or condition, even though its name suggests that. Rather, it's a collection of circumstances that increase a person's chances of developing type 2 diabetes and heart disease. This phenomenon is often preceded by insulin resistance and can essentially be considered a possible "next stop" in terms of elevated risk to your cardiac health stemming from high glucose levels.
There are currently no medications to treat high blood sugar from insulin resistance that are approved by the U. That said, research has found that taking metformin a medication that lowers blood sugar may prevent the onset of type 2 diabetes. If you haven't gone in yet for your yearly health check-up, or if you are experiencing potential symptoms of high blood sugar e. Most people with high blood sugar and insulin resistance have no symptoms, which is why regular screening with your healthcare provider is important.
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