Factors were studied that may initiate macroangiopathy or enhance or aggravate its patho genesis in patients with type 2 diabetes mellitus. A total of 151 diabetics were compared with healthy controls (n = 50); all patients and subjects were normotensive and without renal failure. Plasma endothelin-1 and free radical levels were measured. In addition, plasma prosta cyclin levels were assessed by assaying its stable, spontaneous, breakdown product 6-keto prostaglandin-F1a. Diabetics were divided into three groups: those with clinically evident macroangiopathy and those with early or without atherosclerosis (as determined by the carotid intima-media thickness. Plasma endothelin-1 levels were increased in all diabetics with atherosclerosis. Plasma free radical levels were increased in diabetics with macroan giopathy when compared with control subjects. The plasma levels of 6-keto-prostaglandin-F 1a were slightly, but significantly, decreased in the diabetics with macroangiopathy when compared with control subjects. The carotid intima-media thickness was significantly greater in diabetics without macroangiopathy when compared with the controls. Furthermore, the intima-media thickness increased significantly in this group of diabetics but not in the controls over a 30-month follow-up period. Several factors may contribute to atherogenesis in diabetics. These include increased plasma endothelin-1 and free radical levels as well as a defi ciency of prostacyclin. These factors may become targets for intervention as well as markers of disease progression.
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References
1.
Tkac I., Molcanyiova A.: Fibrinogen and albuminuria are related to the presence and severity of peripheral arterial disease in women with type 2 diabetes mellitus. Angiology48:715-719, 1997.
2.
Ross R.: Atherosclerosis—An inflammatory disease. N Engl J Med340:115-126, 1999.
3.
Bertello P., Veglio F., Pinna G., et al: Plasma endothelin in NIDDM patients with and without complications . Diabetes Care17:574-576, 1994.
4.
Ferri C., Bellini C., Desideri G., et al: Endogenous insulin modulates circulating endothelin-1 concentrations in humans. Diabetes Care19:504-506, 1995.
5.
Ferri C., Laurenti O., Bellini C., et al: Circulating endothelin-1 levels in lean non-insulin-dependent diabetic patients. Am J Hypertens8:40-47, 1995.
6.
Moncada S., Vane JR: Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmac Rev30:292-331, 1979.
7.
Marx JL: Oxygen free radicals linked to many diseases. Science235:529-531, 1987.
8.
Kanters Sdjm , Algra A., Banga JD: Carotid intima-media thickness in hyperlipidemic type I and type II diabetic patients. Diabetes Care20:276-280, 1997.
9.
Peppa-Patrikiou M., Scordili M., Antoniou A., et al: Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors. Diabetes Care21:1004-1007, 1998.
10.
Davis M., Atwal AS, Nair DR, et al: The effect of short term lipid lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: A pilot study. Curr Med Res Opin16:198-204, 2000.
11.
Smilde TJ, van Wissen S., Wollersheim H., et al: Effect of aggressive versus conventional lipid lowering on atherosclerosis in familial hypercholesterolaemia (ASAP): A prospective, randomised, double-blind trial. Lancet357:577-581, 2001.
Pignoli P., Tremoli E., Poli A., et al: Intimal plus medial thickness of the arterial wall: A direct measurement with ultrasound imaging. Circulation74:1399-1406, 1986.
14.
Hendriks T. , Assmann R.: On the fluorometric assay of circulating lipoperoxides. Clin Chim Acta174 :263-270, 1988.
15.
Yagi K.: Assay for blood plasma or serum. In: Oxygen Radicals In Biological Systems. Methods in Enzymology, ed. by Packer L.New York: Academic Press, 1984, pp 328-331.
16.
Yanagisawa M., Kurihara H., Kimura S., et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature332:411-415, 1988.
17.
Schwartz C. , Valente A., Sprague E.: Pathogenesis of the atherosclerotic lesions: Implication for diabetes mellitus. Diabetes Care15:1156-1167, 1992.
18.
Brownlee M. : Glycation and diabetic complications. Diabetes43:836-841, 1994.
19.
Yamauchi T. , Ohnaka K., Takayanagi R., et al: Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine aortic endothelial cells. FEBS Lett267:16-18, 1990.
20.
Perfetto F. , Tarquini R., De-Leonardis V., et al: Angiopathy affects circulating endothelin-1 levels in type 2 diabetic patients. Acta Diabetol32:263-267, 1995.
21.
Perfetto F. , Tarquini R., Tapparini L., et al: Influence of non-insulin-dependent diabetes mellitus on plasma endothelin-1 levels in patients with advanced atherosclerosis. J Diabetes Complications12:187-192, 1998.
22.
Mangiafico RA, Malatino LS, Santonocito M., et al: Plasma endothelin-1 concentrations in non-insulin-dependent diabetes mellitus and non-diabetic patients with chronic arterial obstructive disease of the lower limbs. Int Angiol17:97-102, 1998.
23.
Jagroop IA, Berwanger CS, Stansby G., et al: Plasma endothelin-1 concentrations in non-insulin-dependent diabetes mellitus and nondiabetic patients with chronic arterial obstructive disease of the lower limbs. Int Angiol18:77-79, 1999.
24.
Lerman A., Edwards BS, Hallet JW, et al: Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med325:997-1001, 1991.
25.
Wollesen F. , Berglund L., Berne C.: Plasma endothelin-1 and total insulin exposure in diabetes mellitus. Clin Sci97:149-156, 1999.
26.
Hedblad B., Nilsson P., Janzon L., et al: Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmo, Sweden. Diab Med17:299-307, 2000.
27.
Gobel H., Ihling C., Dentz J., et al: Increased tissue endothelin-1-like immunoreactivity in the internal mammary artery of patients with diabetes or hypercholesterolemia modulates the graft flow in the peri-operative period. Eur J Cardiovasc Thor Surg14 :367-372, 1998.
28.
Guvener N., Aytemir K., Aksoyek S., et al: Plasma endothelin-1 levels in non-insulin dependent diabetes mellitus patients with macrovascular disease. Coron Artery Dis8:253-258, 1997.
29.
Haffner SM, Agil A., Mykkanen L., et al: Plasma oxidizability in subjects with normal glucose tolerance, impaired glucose tolerance, and NIDDM. Diabetes Care18:646-653, 1995.
30.
Nourooz-Zadeh J., Tajaddini-Sarmadi J., McCarthy S., et al: Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes44:1054-1058, 1995.
31.
Lawrence JR, Campbell GR, Barrington H., et al: Clinical and biochemical determinants of plasma lipid peroxide levels in type 2 diabetes. Ann Clin Biochem35 (pt 3) :387-392, 1998.
32.
Nuttall SL, Dunne F., Kendall MJ, et al: Age-independent oxidative stress in elderly patients with non-insulin-dependent diabetes mellitus. QJM92:33-38, 1999.
33.
Paolisso G. , Tagliamonte MR, Barbieri M., et al: Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients. J Clin Endocrinol Metab85:109-115, 2000.
34.
Dyer RG, Stewart MW, Mitcheson J., et al: 7-ketocholesterol, a specific indicator of lipoprotein oxidation, and malondialdehyde in non-insulin dependent diabetes and peripheral vascular disease. Clin Chim Acta260:1-13, 1997.
35.
Leaf A., Weber PC: Cardiovascular effects of n-3 fatty acids. N Engl J Med318:549-557, 1988.
36.
Colwell JA, Lopes-Virella MF: A review of the development of large-vessel disease in diabetes mellitus . Am J Med85:113-118, 1988.
37.
Oriji GK: Endothelin-induced prostacyclin production in rat aortic endothelial cells is mediated by protein kinase C. Prostaglandins Leukot Essent Fatty Acids60:263-268, 1999.
38.
Jeremy JY, Mikhailidis DP, Dandona P.: Simulating the diabetic environment modifies in vitro prostacyclin synthesis . Diabetes32:217-221, 1983.
39.
Jeremy JY, Mikhailidis DP, Dandona P.: Vascular trauma and prostacyclin release. Microcirc Endothel Lymph1:629-644, 1984.
40.
Jeremy JY, Thompson CS, Mikhailidis DP, et al: Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: Pathological implications. Diabetologia28:365-368, 1985.
41.
Barradas MA , Mikhailidis DP, Dandona P.: The effect of non-esterified fatty acids on ADP-degrading enzyme activity. Diab Res Clin Pract3:9-19, 1987.
42.
Jeremy JY, Angellini GD, Khan MA, et al: Platelets, oxidant stress and erectile dysfunction: A hypothesis . Cardiovasc Res46:50-54, 2000.
43.
Mumtaz FH, Khan MA, Sullivan ME, et al: Potential role of endothelin and nitric oxide in the physiology and pathophysiology of the lower urinary tract. Endothelium7:1-9, 1999.
44.
Sullivan ME , Dashwood MR, Thompson CS, et al: Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: Potential relevance to the pathogenesis of erectile dysfunction. J Urol158:1966-1972, 1997.
