Hyperlipidemia and its treatment are currently recognized as important modulators of cardiovascular mortality in the presence of disordered glucose control. On the other hand, the effects of hyperglycemia and its treatment on hyperlipidemia are not widely appreciated. Hyperglycemia is commonly associated with an increase in intestinal lipoproteins and a reduction in high-density lipoprotein (HDL). This could be a consequence of hyperglycemia-induced glycation of lipoproteins, which reduces the uptake and catabolism of the lipoproteins via the classical low-density lipoprotein (LDL) receptor. A high dietary carbohydrate load increases the glycation of intestinal lipoproteins, prolongs their circulation, and increases their plasma concentration. Hyperglycemia also leads to inhibition of lipoprotein lipase, further aggravating hyperlipidemia. Circulating advanced glycation end-products (AGEs) also bind lipoproteins and delay their clearance, a mechanism that has particularly been implicated in the dyslipidemia of diabetic nephropathy. As uptake via scavenger receptors is not inhibited, glycation increases the proportion of lipoproteins that are taken up via inflammatory cells and decreases the proportion taken up by hepatocytes via classical LDL receptors. This promotes the formation of atheromatous plaques and stimulates inflammation. Hyperglycemia increases the formation of oxidized LDL and glycated LDL, which are important modulators of atherosclerosis and cardiovascular death. The risk of cardiovascular death is increased by even short-term derangement of blood sugar control, owing perhaps to the glycation of lipoproteins and other critical proteins. Glycated LDL could prove very useful in measuring the effect of hyperglycemia on cardiovascular disease, its risk factors, and its complications. Comparing different glucose-lowering and lipid-lowering drugs in respect to their influence on glycated LDL could increase knowledge of the mechanism by which they alter cardiovascular risk.
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References
1.
Kanters SD, Banga JD, Stolk RP, et al: Incidence and determinants of mortality and cardiovascular events in diabetes mellitus: A meta-analysis. Vasc Med4:67-75, 1999.
2.
Fontbonne A, Eschwege E: Insulin-resistance, hypertriglyceridaemia and cardiovascular risk: The Paris Prospective Study. Diabetes Metab17(1 Pt 2):93-95, 1991.
3.
Jeffrey S: CARDS study halted due to benefit of atorvastatin in patients with type 2 diabetes. From www.theheart.org [HeartWire > News]; Jun 18, 2003. Accessed at http://www.theheart.org/viewArticle.do?primaryKey=347771 on July 16, 2004.
4.
Vijan S, Hayward RA, and the American College of Physicians: Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: Background paper for the American College of Physicians. Ann Intern Med140:650-658, 2004.
5.
Deedwania PC, Hunninghake DB, Bays H: Effects of lipid-altering treatment in diabetes mellitus and the metabolic syndrome. Am J Cardiol93:18C-26C, 2004.
6.
Heldgaard PE, Olivarius Nde F, Hindsberger C, et al: Impaired fasting glycaemia resembles impaired glucose tolerance with regard to cardiovascular risk factors: Population-based, cross-sectional study of risk factors for cardiovascular disease. Diabet Med21:363-370, 2004.
7.
Keech A, Colquhoun D, Best J, et al, and the LIPID Study Group: Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: Results from the LIPID trial. Diabetes Care26:2713-2721, 2003.
8.
Papadakis JA, Milionis HJ, Mikhailidis DP, et al: Treating dyslipidaemia in non-insulin-dependent diabetes mellitus—a special reference to statins. J Diabetes Complications15:211-226, 2001.
9.
Grundy SM, and the National Cholesterol Education Program (NCEP): The National Cholesterol Guidelines in 2001, Adult Treatment Panel (ATP) III. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol90:11i-21i, 2002.
10.
Siribaddana S, Perera N, Perera S, et al: Prevalence of lipid abnormalities in Sri Lankan patients with non-insulin dependent diabetes mellitus. Ceylon Med J39:22-25, 1994.
11.
Paterson JR, Pettigrew AR, Dominiczak MH, et al: Screening for hyperlipidaemia in diabetes mellitus. Relationship to glycaemic control. Ann Clin Biochem28(Pt 4):354-358, 1991.
12.
Kohler C, Temelkova-Kurktschiev T, Schaper F, et al: [Prevalence of newly diagnosed type 2 diabetes, impaired glucose tolerance and abnormal fasting glucose in a high risk population. Data from the RIAD study using new diagnostic criteria for diabetes.] Dtsch Med Wochenschr124:1057-1061, 1999.
13.
Hu G, Qiao Q, Tuomilehto J, et al, and the DECODE Study Group: Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med164:1066-1076, 2004.
14.
Ford ES: The metabolic syndrome and mortality from cardiovascular disease and all-causes: Findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis173:309-314, 2004.
15.
Cheal KL, Abbasi F, Lamendola C, et al: Relationship to insulin resistance of the adult treatment panel III diagnostic criteria for identification of the metabolic syndrome. Diabetes53:1195-1200, 2004.
16.
Rewers M, Zaccaro D, D’Agostino R, et al, and the Insulin Resistance Atherosclerosis Study Investigators. Insulin sensitivity,,insulinemia, and coronary artery disease: The Insulin Resistance Atherosclerosis Study. Diabetes Care27:781-787, 2004.
17.
Liljeberg H, Bjorck I: Effects of a low-glycaemic index spaghetti meal on glucose tolerance and lipaemia at a subsequent meal in healthy subjects. Eur J Clin Nutr54:24-28, 2000.
18.
Frost G, Keogh B, Smith D, et al: The effect of lowglycemic carbohydrate on insulin and glucose response in vivo and in vitro in patients with coronary heart disease. Metabolism45:669-672, 1996.
19.
Frost PH, Verter J, Miller D: Serum lipids and lipoproteins after myocardial infarction: Associations with cardiovascular mortality and experience in the Aspirin Myocardial Infarction Study. Am Heart J113:1356-1364, 1987.
20.
Yaari S, Goldbourt, Even-Zohar S, et al: Associations of serum high-density lipoprotein and total cholesterol with total, cardiovascular, and cancer mortality in a 7-year prospective study of 10,000 men. Lancet1:1011-1015, 1981.
21.
Wilson PW, Abbott RD, Castelli WP: High-density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis8:737-741, 1988.
22.
Temelkova-Kurktschiev T, Hanefeld M: The lipid triad in type 2 diabetes—prevalence and relevance of hypertriglyceridaemia/low high-density lipoprotein syndrome in type 2 diabetes. Exp Clin Endocrinol Diabetes112:75-79, 2004.
23.
Glader CA, Birgander LS, Stenlund H, et al: Is lipoprotein(a) a predictor for survival in patients with established coronary artery disease? Results from a prospective patient cohort study in northern Sweden. J Intern Med252:27-35, 2002.
24.
Berg K, Dahlen G, Christophersen B, et al: Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study. Clin Genet52:254-261, 1997.
25.
Packard CJ, Saito Y: Non-HDL cholesterol as a measure of atherosclerotic risk. J Atheroscler Thromb11:6-14, 2004.
26.
Karpe F, Taskinen MR, Nieminen MS, et al: Remnant-like lipoprotein particle cholesterol concentration and progression of coronary and vein-graft atherosclerosis in response to gemfibrozil treatment. Atherosclerosis157:181-187, 2001.
27.
McNamara JR, Shah PK, Nakajima K, et al: Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: Results from the Framingham Heart Study. Atherosclerosis154:229-236, 2001.
28.
Morishita E, Asakura H, Jokaji H, et al: Hypercoagulability and high lipoprotein(a) levels in patients with type II diabetes mellitus. Atherosclerosis120:7-14, 1996.
29.
Watanabe N, Taniguchi T, Taketoh H, et al: Elevated remnant-like lipoprotein particles in impaired glucose tolerance and type 2 diabetic patients. Diabetes Care22:152-156, 1999.
30.
Schaefer EJ, McNamara JR, Shah PK, et al, and the Framingham Offspring Study: Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study. Diabetes Care2002;25:989-994.
31.
Robins SJ, Collins D, Wittes JT, et al, and the VA-HIT Study Group: Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: A randomized controlled trial. JAMA285:1585-1591, 2001.
32.
Brownlee M, Vlassara H, Cerami A: Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med101:527-537, 1984.
33.
Friedman EA: Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care22(suppl 2):B65-B71, 1999.
34.
Sobal G, Menzel J, Sinzinger H: Why is glycated LDL more sensitive to oxidation than native LDL? A comparative study. Prostaglandins Leukot Essent Fatty Acids63:177-186, 2000.
35.
Sanchez-Quesada JL, Perez A, Caixas A, et al: Effect of glycemic optimization on electronegative low-density lipoprotein in diabetes: Relation to nonenzymatic glycosylation and oxidative modification. J Clin Endocrinol Metab86:3243-3249, 2001.
36.
Khan M, Pelengaris S, Cooper M, et al: Oxidized lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages. Atherosclerosis171:21-29, 2003.
37.
Thorne SA, Abbot SE, Winyard PG, et al: Extent of oxidative modification of low-density lipoprotein determines the degree of cytotoxicity to human coronary artery cells. Heart75:11-16, 1996.
38.
Sakata N, Uesugi N, Takebayashi S, et al: Glycoxidation and lipid peroxidation of low-density lipoprotein can synergistically enhance atherogenesis. Cardiovasc Res49:466-475, 2001.
39.
Picard S, Talussot C, Serusclat A, et al: Minimally oxidized LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. Diabetes Metab22:25-30, 1996.
40.
Fornasieri A, Perugini C, Seccia M, et al: Circulating antibodies recognising oxidatively-modified low-density lipoproteins in patients with IgA nephropathy, membranous glomerulonephritis and focal glomerulosclerosis. J Nephrol15:349-357, 2002.
41.
Brown BG, Zhao XQ, Chait A, et al: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345:1583-1592, 2001. Summary for patients in: Curr Cardiol Rep4:486, 2002.
42.
de Gaetano G, and the Collaborative Group of the Primary Prevention Project: Low-dose aspirin and vitamin E in people at cardiovascular risk: A randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 357:89-95, 2001. Erratum in: Lancet357:1134, 2001.
43.
Matsui J, Onuma T, Tamasawa N, et al: Effects of advanced glycation endproducts on the generation of macrophage-mediated oxidized low-density lipoprotein. J Diabetes Complications11:338-342, 1997.
44.
Galle J, Schneider R, Winner B, et al: Glycoxidized LDL impair endothelial function more potently than oxidized LDL: Role of enhanced oxidative stress. Atherosclerosis138:65-77, 1998.
45.
Posch K, Simecek S, Wascher TC, et al: Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide synthesis by inhibition of shear stress-activated L-arginine uptake in endothelial cells. Diabetes. 48:1331-1337, 1999.
46.
Ren S, Lee H, Hu L, et al: Impact of diabetes-associated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells. J Clin Endocrinol Metab87:286-291, 2002.
47.
Zhang J, Ren S, Sun D, et al: Influence of glycation on LDL-induced generation of fibrinolytic regulators in vascular endothelial cells. Arterioscler Thromb Vasc Biol18:1140-1148, 1998.
48.
Wen Y, Skidmore JC, Porter-Turner MM, et al: Relationship of glycation, antioxidant status and oxidative stress to vascular endothelial damage in diabetes. Diabetes Obes Metab4:305-308, 2002.
49.
Artwohl M, Graier WF, Roden M, et al: Diabetic LDL triggers apoptosis in vascular endothelial cells. Diabetes52:1240-1247, 2003.
50.
Takeda H, Yano T, Kishikawa H, et al: Abnormalities in platelets and vascular endothelial cells induced by glycated lipoproteins. Intern Med31:746-751, 1992.
51.
Lyons TJ, Li W, Wells-Knecht MC, et al: Toxicity of mildly modified low-density lipoproteins to cultured retinal capillary endothelial cells and pericytes. Diabetes43:1090-1095, 1994.
52.
Galle J, Winner B, Conzelmann E, et al: Impairment of endothelial function induced by glyc-oxidized lipoprotein a [Lp(a)]. Cell Mol Biol (Noisy-le-grand)44:1035-1045, 1998.
53.
Gempel KE, Gerbitz KD, Olgemoller B, et al: In-vitro carboxymethylation of low-density lipoprotein alters its metabolism via the high-affinity receptor. Horm Metab Res25:250-252, 1993.
54.
Wang X, Bucala R, Milne R: Epitopes close to the apolipoprotein B low-density lipoprotein receptor-binding site are modified by advanced glycation end products. Proc Natl Acad Sci USA95:7643-7647, 1998.
55.
Yamamoto Y, Tahara Y, Cha T, et al: Radioimmunoassay of glycated serum protein using monoclonal antibody to glucitollysine and coomassie-brilliant-blue-coated polystyrene beads. Diabetes Res11:45-49, 1989.
56.
Bucala R, Makita Z, Vega G, et al: Modification of low-density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci USA91:9441-9445, 1994.
57.
Pruneta-Deloche V, Sassolas A, Dallinga-Thie GM, et al: Alteration in lipoprotein lipase activity bound to triglyceride-rich lipoproteins in the postprandial state in type 2 diabetes. J Lipid Res45:859-865, 2004. Epub 2004 Feb 16.
58.
Mamo JC, Szeto L, Steiner G: Glycation of very low-density lipoprotein from rat plasma impairs its catabolism. Diabetologia33:339-345, 1990.
59.
Phillips C, Murugasu G, Owens D, et al: Improved metabolic control reduces the number of postprandial apolipoprotein B-48-containing particles in type 2 diabetes. Atherosclerosis148:283-291, 2000.
60.
Edwards IJ, Terry JG, Bell-Farrow AD, et al: Improved glucose control decreases the interaction of plasma low-density lipoproteins with arterial proteoglycans. Metabolism51:1223-1229, 2002.
61.
Klein RL, Laimins M, Lopes-Virella MF: Isolation, characterization, and metabolism of the glycated and nonglycated subfractions of low-density lipoproteins isolated from type I diabetic patients and nondiabetic subjects. Diabetes44:1093-1098, 1995.
62.
Helmersson J, Vessby B, Larsson A, et al: Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation109:1729-1734, 2004. Epub 2004.
63.
Mangge H, Schauenstein K, Stroedter L, et al: Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis. Exp Clin Endocrinol Diabetes112:378-382, 2004.
64.
Sigurdardottir V, Fagerberg B, Hulthe J: Preclinical atherosclerosis and inflammation in 61-year-old men with newly diagnosed diabetes and established diabetes. Diabetes Care27:880-884, 2004.
65.
Sidhu JS, Cowan D, Kaski JC: The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol42:1757-1763, 2003.
66.
Malmberg K, Norhammar A, Wedel H, et al: Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation99:2626-2632, 1999.
67.
Gaus K, Hall EA: Short peptide receptor mimics for atherosclerosis risk assessment of LDL. Biosens Bioelectron18:151-164, 2003.
68.
Gaus K, Basran A, Hall EA: Assessment of the fifth ligand-binding repeat (LR5) of the LDL receptor as an analytical reagent for LDL binding. Analyst126:329-336, 2001.
69.
Laffont I, Shuvaev VV, Briand O, et al: Early-glycation of apolipoprotein E: Effect on its binding to LDL receptor, scavenger receptor A and heparan sulfates. Biochim Biophys Acta1583:99-107, 2002.
70.
Hudgins LC, Hellerstein MK, Seidman CE, et al: Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res41:595-604, 2000.
71.
Parks EJ, Krauss RM, Christiansen MP, et al: Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance. J Clin Invest104:1087-1096, 1999.
72.
Daskalopoulou SS, Mikhailidis DP, Elisaf M: Prevention and treatment of the metabolic syndrome. Angiology2004 (in press).
73.
Stern MP: Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes44:369-374, 1995.
74.
Hadjadj S, Coisne D, Mauco G, et al: Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med21:305-310, 2004.
75.
Bolk J, van der Ploeg T, Cornel JH, et al: Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol79:207-214, 2001.
76.
Slowik A, Zwolinska G, Tomik B, et al: [Prognostic significance of transient hyperglycemia in acute phase of ischemic stroke.]Neurol Neurochir Pol32:317-329, 1998.
77.
Nakamura N, Ueno Y, Tsuchiyama Y, et al: Isolated post-challenge hyperglycemia in patients with normal fasting glucose concentration exaggerates neointimal hyperplasia after coronary stent implantation. Circ J67:61-67, 2003.
78.
Willfort-Ehringer A, Ahmadi R, Gessl A, et al: Neointimal proliferation within carotid stents is more pronounced in diabetic patients with initial poor glycaemic state. Diabetologia47:400-406, 2004. Epub 2004.
79.
Estrada CA, Young JA, Nifong LW, et al: Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann Thorac Surg75:1392-1399, 2003.
80.
Pawlak DB, Kushner JA, Ludwig DS: Effects of dietary glycaemic index on adiposity, glucose homoeostasis, and plasma lipids in animals. Lancet364:778-785, 2004.
81.
Brand-Miller JC, Holt SH, Pawlak DB, et al: Glycemic index and obesity. Am J Clin Nutr76:281S-285S, 2002.
82.
Liu S, Manson JE, Buring JE, Stampfer MJ, et al: Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr75:492-498, 2002.
83.
Schulze MB, Manson JE, Ludwig DS, et al: Sugarx-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA292:927-934, 2004.
84.
Rosenbaum P, Peres RB, Zanella MT, et al: Improved glycemic control by acarbose therapy in hypertensive diabetic patients: Effects on blood pressure and hormonal parameters. Braz J Med Biol Res35:877-884, 2002.
85.
Becker A, van der Does FE, van Hinsbergh VW, et al: Improvement of glycaemic control in type 2 diabetes: Favourable changes in blood pressure, total cholesterol and triglycerides, but not in HDL cholesterol, fibrinogen, Von Willebrand factor and (pro)insulin. Neth J Med61:129-136, 2003.
86.
Daly ME: Extending the use of the glycaemic index: Beyond diabetes? Lancet364:736-737, 2004.
87.
Brand-Miller JC: Glycemic index in relation to coronary disease. Asia Pac J Clin Nutr13(suppl):S3, 2004.
88.
Khaw KT, Wareham N, Luben R, et al: Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ322:15-18, 2001.
89.
Stratton IM, Adler AI, Neil Ha, et al: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ321:405-412, 2000.
90.
Stevens RJ, Coleman RL, Adler AI, et al: Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66. Diabetes Care27:201-207, 2004.
91.
Erratum in: Lancet354:602, 1999.
92.
van Praag MC, Pavel S, Menke HE, et al: [Protection from sunlight, particularly for children.]Ned Tijdschr Geneeskd144:830-834, 2000.
93.
Schlebusch H, Liappis N, Sorger M, et al: [Serum fructosamine in healthy and diabetic children and adolescents.]Klin Padiatr203:173-177, 1991.
94.
Langer T, Strober W, Levy RI: The metabolism of low-density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest51:1528-1536, 1972.
95.
Deegan P, Owens D, Collins P, et al: Association between low-density lipoprotein composition and its metabolism in non-insulin-dependent diabetes mellitus. Metabolism48:118-124, 1999.
96.
Okamoto T, Yamagishi S, Inagaki Y, et al: Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J16:1928-1930, 2002. Epub 2002 Oct 4.
