This cross-sectional study assesses the association between type 2 diabetes prevalence and familial hypercholesterolemia. That patients with familial hypercholesterolemia have a significantly reduced risk Distinguish the relationship between statins and the risk for type 2 diabetes. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. Besseling J(1), Kastelein JJ(1), Defesche JC(2).
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.
Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.
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 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.
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: 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.
Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus
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. In patients with diabetes, coronary artery disease is the most common cause of death.
Lipid abnormalities are commonly associated with diabetes, particularly in those with type 2 diabetes formerly known as non—insulin-dependent diabetes. The most common lipid abnormalities in these patients include hyper-triglyceridemia and reduced high-density lipoprotein HDL cholesterol levels.
While lipid abnormalities typically improve with better glycemic control, normalization does not usually occur. Because there is a strong relationship between all forms of vascular disease in patients with type 2 diabetes and hyperlipidemia, it is important to screen for and treat these lipid abnormalities.
O'Brien and associates review recent studies of the evaluation and management of this problem. Annual screening for lipid abnormalities in adults with diabetes is recommended.
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Such screening should include measurements of total cholesterol, HDL, low-density lipoprotein LDL and triglyceride levels. 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.