Tips From Other Journals - American Family Physician
That patients with familial hypercholesterolemia have a significantly reduced risk Distinguish the relationship between statins and the risk for type 2 diabetes. Pathophysiology of hyperlipidemia in diabetes mellitus. Abbate SL(1), Brunzell JD. Author information: (1)Department of Medicine, University of Washington. Hyperlipidaemia is common in type 2 diabetes and contributes There is a relationship between the incidence of CHD and the . Hypercholesterolaemia and HDL cholesterol may improve, but triglycerides may worsen.
Several factors are likely to be responsible for diabetic dyslipidemia: Insulin regulation of liver apoproteins and lipid-metabolizing proteins A number of studies using tracer kinetics in humans have demonstrated that liver production of apolipoprotein B apoBthe 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 5animal experiments 6and 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 1011but not all 12studies 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.
Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus
Several steps in the production of biologically active LpL may be altered in diabetes, including its cellular production 1516 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. Specific lipoprotein abnormalities Postprandial lipemia. Compared with normal subjects, patients with type 2 diabetes have a slower clearance of chylomicrons from the blood after dietary fat 142223 ; 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 25and 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. View large Download slide 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.
Pathophysiology of hyperlipidemia in diabetes mellitus.
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.
Exercise should be incorporated into a weight-loss program, as it has been shown to enhance weight loss and facilitate weight maintenance.
- Diabetic Hyperlipidemia: Managing High Cholesterol When You Have Diabetes
- Pathophysiology of hyperlipidemia in diabetes mellitus.
- Hyperlipidemia in Patients with Type 2 Diabetes
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. While not contraindicated, this combination should be used with caution. The authors conclude that hyperlipidemia is partly responsible for the increased vascular disease that occurs in patients with diabetes.
Hypertriglyceridemia and reduced LDL levels should be aggressively managed in these patients. Effective treatment includes a combination of pharmacologic and nonpharmacologic therapy.