Diabetes and peripheral vascular disease
1999; Elsevier BV; Volume: 30; Issue: 2 Linguagem: Inglês
10.1016/s0741-5214(99)70154-0
ISSN1097-6809
AutoresCameron M. Akbari, Frank W. LoGerfo,
Tópico(s)Cardiovascular Health and Disease Prevention
ResumoDiabetes mellitus is found in as many as 13 million people nationally, or 5.2% of the US population, and more than 650,000 new cases are diagnosed annually.1American Diabetes Association Diabetes: 1993 vital statistics.1993Google Scholar Clinical data that link diabetes to vascular disease are derived from several large epidemiologic studies. The Framingham Study of more than 5000 subjects showed that diabetes is a powerful risk factor for atherosclerotic coronary and peripheral arterial disease, independent of other atherogenic risk factors, with a relative risk averaging two fold for men and three fold for women.2Ruderman NB Haudenschild C. Diabetes as an atherogenic factor.Prog Cardiovasc Dis. 1984; 26: 373-412Abstract Full Text PDF PubMed Scopus (251) Google Scholar The Framingham Study results also confirmed that the risk of stroke is at least 2.5-fold higher in patients with diabetes,3Stokes J Kannel WB Wolf PA Cupples LA D’Agostino RB The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study.Circulation. 1987; 75: 65-73PubMed Google Scholar a finding that has been confirmed in other large epidemiologic studies.4Burchfiel CM Curb JD Rodriguez BL Abbott RD Chiu D Yano K. Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program.Stroke. 1994; 25: 951-957Crossref PubMed Scopus (201) Google Scholar, 5Jorgensen H Nakayama H Raaschou HO Olsen TS. Stroke in patients with diabetes. The Copenhagen Stroke Study.Stroke. 1994; 25: 1977-1984Crossref PubMed Scopus (323) Google Scholar Moreover, diabetes is strongly associated with atherosclerosis of the extracranial internal carotid artery and thus imparts an additional independent risk of stroke.6Yasaka M Yamaguchi T Shichiri M. Distribution of atherosclerosis and risk factors in atherothrombotic occlusion.Stroke. 1993; 24: 206-211Crossref PubMed Scopus (90) Google Scholar Many of the clinical complications of diabetes may be ascribed to alterations in vascular structure and function, with subsequent end-organ damage and death. Specifically, two types of vascular disease are seen in patients with diabetes: a nonocclusive microcirculatory dysfunction involving the capillaries and arterioles of the kidneys, retina, and peripheral nerves, and a macroangiopathy characterized by atherosclerotic lesions of the coronary and peripheral arterial circulation.7Cameron NE Cotter MA. The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications.Diabetes Metab Rev. 1994; 10: 189-224Crossref PubMed Scopus (224) Google Scholar, 8LoGerfo FW Coffman JD. Vascular and microvascular disease of the foot in diabetes.N Engl J Med. 1984; 311: 1615-1619Crossref PubMed Scopus (438) Google Scholar, 9Williamson JR Titlon RG Chang K Kilo C. Basement membrane abnormalities in diabetes mellitus: relationship to clinical microangiopathy.Diabetes Metab Rev. 1988; 4: 339-370Crossref PubMed Scopus (96) Google Scholar, 10LoGerfo FW. Vascular disease, matrix abnormalities, and neuropathy: implications for limb salvage in diabetes mellitus.J Vasc Surg. 1987; 5: 793-796PubMed Scopus (21) Google Scholar The former is relatively unique to diabetes, whereas the latter lesions are morphologically similar in both patients with and without diabetes. Retinopathy is the most characteristic microvascular complication of diabetes, and population-based study results have identified a correlation between its development and the duration of diabetes.11Palmberg P Smith M Waltman S et al.The natural history of retinopathy in insulin-dependent juvenile-onset diabetes.Ophthalmology. 1981; 88: 613-618Abstract Full Text PDF PubMed Scopus (170) Google Scholar Similar correlations have been found with nephropathy, neuropathy, and diabetes,12Pirart J. Diabetes mellitus and its degenerative complications: A prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care. 1978; 1 (252-61): 168-188Google Scholar with perhaps the strongest evidence coming from the Diabetes Control and Complications Trial. The results from the Diabetes Control and Complications Trial clearly showed a delay in the development and progression of these microvascular complications with intensive glycemic control, thus supporting the direct causal relationship between hyperglycemia, diabetes, and its microvascular sequelae.13DCCT Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (21159) Google Scholar These and other clinical trials have provided the rationale for experimental studies investigating the fundamental pathophysiology of microvascular and macrovascular disease in diabetes mellitus. Microvascular dysfunction in diabetes is manifested by an increased vascular permeability and impaired autoregulation of blood flow and vascular tone. These changes culminate into nephropathy, retinopathy, and neuropathy and most likely contribute to the cardiovascular complications of diabetes. Although multiple theories have been postulated as to the cause of accelerated microangiopathy, it is likely that several biochemical derangements exist in the presence of hyperglycemia and diabetes and that these mechanisms work synergistically to cause microvascular dysfunction. These metabolic alterations produce functional and structural changes at multiple areas within the arteriolar and capillary level, including the basement membrane,9Williamson JR Titlon RG Chang K Kilo C. Basement membrane abnormalities in diabetes mellitus: relationship to clinical microangiopathy.Diabetes Metab Rev. 1988; 4: 339-370Crossref PubMed Scopus (96) Google Scholar the smooth muscle cell,14Vanhoutte PM The endothelium—modulator of vascular smooth-muscle tone.N Engl J Med. 1988; 319: 512-513Crossref PubMed Scopus (242) Google Scholar and, in particular, the endothelial cell.15Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus.Circulation. 1993; 87: V67-V76Google Scholar One of the greatest impediments in understanding vascular disease in patients with diabetes is the misconception that they have an untreatable occlusive lesion in the microcirculation.8LoGerfo FW Coffman JD. Vascular and microvascular disease of the foot in diabetes.N Engl J Med. 1984; 311: 1615-1619Crossref PubMed Scopus (438) Google Scholar This idea originated from a retrospective histologic study that showed the presence of periodic-acid-Schiff-positive material occluding the arterioles in amputated limb specimens from patients with diabetes.16Goldenberg SG Alex M Joshi RA Blumenthal HT. Nonatheromatous peripheral vascular disease of the lower extremity in diabetes mellitus.Diabetes. 1959; 8: 261-273Crossref PubMed Scopus (184) Google Scholar However, subsequent prospective staining and arterial casting studies17Strandness Jr, DE Priest RE Gibbons GE. Combined clinical and pathologic study of diabetic and nondiabetic peripheral arterial disease.Diabetes. 1964; 13: 366-372PubMed Google Scholar, 18Conrad MC. Large and small artery occlusion in diabetics and nondiabetics with severe vascular disease.Circulation. 1967; 36: 83-91Crossref PubMed Google Scholar and physiological studies19Bamer HB Kaiser GC Willman VL. Blood flow in the diabetic leg.Circulation. 1971; 43: 391-394Crossref PubMed Scopus (72) Google Scholar have shown the absence of an arteriolar occlusive lesion. Dispelling the notion of “small vessel disease” is fundamental to the principles of limb salvage in patients with diabetes because arterial reconstruction is almost always possible in these patients. Although there is no occlusive lesion in the diabetic microcirculation, other structural changes do exist, most notably, a thickening of the capillary basement membrane. This alteration in extracellular matrix may represent a response to the metabolic changes related to diabetes and hyperglycemia. However, this does not lead to narrowing of the capillary lumen and arteriolar blood flow may be normal or even increased despite these changes.20Parving HH Viberti GC Keen H Christiansen JS Lassen NA. Hemodynamic factors in the genesis of diabetic microangiopathy.Metabolism. 1983; 32: 943-949Abstract Full Text PDF PubMed Scopus (283) Google Scholar Capillary basement membrane thickening is the dominant structural change in both diabetic retinopathy and neuropathy. In the kidney, nonenzymatic glycosylation reduces the charge on the basement membrane, which may account for transudation of albumin, an expanded mesangium, and albuminuria.21Morgensen CE Schmitz A Christensen CR. Comparative renal pathophysiology relevant to IDDM and NIDDM patients.Diabetes Metab Rev. 1988; 4: 453-483Crossref PubMed Scopus (55) Google Scholar Similar increases in vascular permeability occur in the eye and probably contribute to macular exudate formation and retinopathy. In the diabetic foot, basement membrane thickening may theoretically impair the migration of leukocytes and the hyperemic response after injury and thus may increase the susceptibility of the diabetic foot to infection.22Flynn MD Tooke JE. Aetiology of diabetic foot ulceration: a role for the microcirculation?.Diabetes Med. 1992; 8: 320-329Crossref Scopus (113) Google Scholar, 23Rayman G Williams SA Spencer PD et al.Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes.Br Med J. 1986; 292: 1295-1298Crossref PubMed Scopus (179) Google Scholar Although resting total skin microcirculatory flow is similar in both patients with and without diabetes, the capillary blood flow is reduced in diabetes, indicating a maldistribution and functional ischemia of the skin.24Jorneskog G Brismar K Fagrell B. Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications.Diabetologia. 1995; 38: 474-480Crossref PubMed Scopus (111) Google Scholar Moreover, study results of skin microvascular flow have shown reduced maximal hyperemic response to heat in patients with diabetes, suggesting that a functional microvascular impairment is a major contributing factor for diabetic foot problems. All of these changes result in an inability to vasodilate and achieve maximal blood flow after injury. Diabetes also affects the axon reflex. Injury directly stimulates nociceptive C fibers, which results in both orthodromic conduction to the spinal cord and antidromic conduction to adjacent C fibers and other axon branches. One function of this axon reflex is the secretion of several active peptides, such as substance P and calcitonin gene-related peptide, which directly and indirectly (through mast cell release of histamine) cause vasodilation and increased permeability. This neurogenic vasodilatory response is impaired in diabetes, further reducing the hyperemic response when it is most needed: that is, under conditions of injury and inflammation.25Parkhouse N LeQueen PM. Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions.N Engl J Med. 1988; 318: 1306-1309Crossref PubMed Scopus (170) Google Scholar The previous changes contribute to an early functional impairment in vascular reserve in the peripheral, coronary, and cerebral circulation of patients with diabetes. With positron emission tomography, myocardial blood flow may be measured at rest and after vasodilator administration, and thus coronary flow reserve (as a measure of endothelial function) may be calculated. Reduced coronary flow reserve and impaired coronary reactivity has been observed in patients with diabetes with angiographically normal coronary arteries and no other detectable microvascular complications, which suggests an early endothelial dysfunction.26Yokoyama I Ohtake T Momomure S et al.Hyperglycemia rather than insulin resistance is related to reduced coronary flow reserve in NIDDM.Diabetes. 1998; 47: 119-124Crossref PubMed Google Scholar, 27Pitkanen OP Nuutila P Raitakari OT et al.Coronary flow reserve is reduced in young men with IDDM.Diabetes. 1998; 47: 248-254Crossref PubMed Google Scholar Similarly, cerebrovascular reactivity and reserve capacity may be assessed with transcranial Doppler scanning and acetazolamide, which causes vasodilatation of the brain resistance vessels. Impaired cerebrovascular reserve is also noted in patients with diabetes, particularly among those patients with other microvascular complications.28Fulesdi B Limburg M Bereczki D et al.Impairment of cerebrovascular reactivity in long-term type I diabetes.Diabetes. 1997; 46: 1840-1845Crossref PubMed Google Scholar The normal endothelium plays an important role in blood vessel wall function and homeostasis by synthesizing and releasing substances, such as prostacyclin, endothelin, prostaglandins, and nitric oxide, which modulate vasomotor tone and prevent thrombosis.29Vane JR Anggard EE Botting RM. Regulatory functions of the vascular endothelium.N Engl J Med. 1990; 323: 27-36Crossref PubMed Scopus (1722) Google Scholar There is substantial evidence that endothelial function is abnormal in animal models of diabetes mellitus30Gupta S Sussman I McArthur CS Tomheim K Cohen RA Ruderman NB. Endothelium-dependent inhibition of Na+ - K+ ATPase activity in rabbit aorta by hyperglycemia. Possible role of endothelium-derived nitric oxide.J Clin Invest. 1992; 90: 727-732Crossref PubMed Scopus (115) Google Scholar, 31Pieper GM Meier DA Hager SR. Endothelial dysfunction in a model of hyperglycemia and hyperinsulinemia.Am J Physiol. 1995; 269: H845-H850PubMed Google Scholar, 32Tesfamarian B Brown ML Cohen RA. Elevated glucose impairs endotheliurla-dependent relaxation by activating protein kinase C.J Clin Invest. 1991; 87: 1643-1648Crossref PubMed Scopus (391) Google Scholar and in patients with both insulin-dependent and non–insulin-dependent diabetes mellitus,33Williams SB Cusco JA Roddy M Johnstone MY Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.J Am Coll Cardiol. 1996; 27: 567-574Abstract Full Text PDF PubMed Scopus (851) Google Scholar, 34Johnstone MT Creager SJ Scales KM Cusco JA Lee BK Creager MA. Impaired endothelium dependent vasodilation in patients with insulin-dependent diabetes mellitus.Circulation. 1993; 88: 2510-2516Crossref PubMed Scopus (979) Google Scholar thus directly implicating either hyperglycemia or hyperinsulinemia as a possible mediator of abnormal endothelium-dependent responses. A variety of mechanisms responsible for vascular dysfunction have been proposed, principally abnormalities in the nitric oxide pathway, abnormal production of vasoconstrictor prostanoids, intracellular signaling, reduction in Na+,K+–adenosine triphosphatase (ATPase) activity, and advanced glycosylated end products.15Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus.Circulation. 1993; 87: V67-V76Google Scholar, 27Pitkanen OP Nuutila P Raitakari OT et al.Coronary flow reserve is reduced in young men with IDDM.Diabetes. 1998; 47: 248-254Crossref PubMed Google Scholar, 28Fulesdi B Limburg M Bereczki D et al.Impairment of cerebrovascular reactivity in long-term type I diabetes.Diabetes. 1997; 46: 1840-1845Crossref PubMed Google Scholar, 35Tesfamarian B Brown ML Deykin D Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta.J Clin Invest. 1990; 85: 929-932Crossref PubMed Scopus (317) Google Scholar, 36Simmons DA Winegrad AI. Elevated extracellular glucose inhibits an adenosine-Na+ - K+ ATPase regulatory system in rabbit aortic wall.Diabetologia. 1991; 34: I57-I163Crossref Scopus (18) Google Scholar, 37Brownlee M Cerami A Vlassare H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.N Engl J Med. 1988; 318: 1315-1321Crossref PubMed Scopus (2271) Google Scholar In 1980, Furchgott and Zawadzki38Furchgott RF Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (9605) Google Scholar discovered that arterial vasodilation was dependent on an intact endothelium and its release of a substance they called endothelium-derived relaxing factor, which causes arterial smooth muscle relaxation in response to acetylcholine and other vasodilators.38Furchgott RF Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (9605) Google Scholar Later identified as endothelial-derived nitric oxide (EDNO), it activates vascular smooth muscle guanylate cyclase, elevates cyclic guanosine monophospate levels, and may increase Na+,K+-ATPase activity.39Palmer RM Ferrige AG Moncada S. Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor.Nature. 1987; 327: 524-526Crossref PubMed Scopus (8979) Google Scholar A variety of substances other than acetylcholine may cause EDNO-mediated vasodilation. Several in vivo studies with NG-monomethyl-L -arginine (L -NMMA), an arginine analogue and competitive inhibitor of EDNO synthesis, have shown that the vasodilatory effects of insulin are nitric oxide dependent40Scherrer U Randin D Vollenweider P Vollenweider L Nicod P Nitric oxide release accounts for insulin’s vascular effects in humans.J Clin Invest. 1994; 94: 2511-2515Crossref PubMed Scopus (668) Google Scholar, 41Taddei S Virdis A Mattei P Natali A Ferrannini E Salvetti A. Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension.Circulation. 1995; 92: 2911-2918Crossref PubMed Scopus (166) Google Scholar and that insulin mediates EDNO-dependent vasodilation by modulating the synthesis and release of EDNO. Impaired endothelial-dependent vasodilatation in certain insulin-resistant states may be instrumental in the pathogenesis of atherosclerosis and hypertension and is postulated to be the result of diminished insulin-mediated EDNO production and release.42Baron AD. The coupling of glucose metabolism and perfusion in human skeletal muscle. The potential role ofendothelium-derived nitric oxide.Diabetes. 1996; 45: S105-S109Crossref PubMed Google Scholar Studies of patients with insulin-dependent and non–insulin-dependent diabetes have shown impaired endothelium-dependent responses to acetylcholine in both groups but an intact response to exogenous nitric oxide donors (ie, sodium nitroprusside) in insulin-dependent diabetes only.33Williams SB Cusco JA Roddy M Johnstone MY Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.J Am Coll Cardiol. 1996; 27: 567-574Abstract Full Text PDF PubMed Scopus (851) Google Scholar, 34Johnstone MT Creager SJ Scales KM Cusco JA Lee BK Creager MA. Impaired endothelium dependent vasodilation in patients with insulin-dependent diabetes mellitus.Circulation. 1993; 88: 2510-2516Crossref PubMed Scopus (979) Google Scholar It thus appears that abnormal nitric oxide release or synthesis predominates in insulin-dependent diabetes, whereas non–insulin-dependent diabetes may be characterized by either a diminished response of smooth muscle to EDNO or increased inactivation of nitric oxide. Although there is considerable controversy regarding the role of free radicals in diabetic vascular disease,43Oberly LW. Free radicals in diabetes.Free Radic Biol Med. 1988; 5: 113-124Crossref PubMed Scopus (898) Google Scholar an increased production of oxygen-derived free radicals has been described in diabetes and may contribute to endothelial dysfunction.44Wolff SP Dean RT. Glucose autoxidation and protein modification: the role of oxidative glycosylation in diabetes.Biochem J. 1987; 245: 234-250Crossref Scopus (1107) Google Scholar Superoxide anions and other oxygen-derived free radicals directly inactivate endothelium-derived nitric oxide.45Gryglewski RJ Palmer RM Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.Nature. 1986; 320: 454-456Crossref PubMed Scopus (2134) Google Scholar In animal models, endothelium-derived free radicals impair EDNO-mediated vasodilatation and administration of superoxide dismutase and other free radical scavengers normalize EDNO-dependent relaxation in diabetic arteries.46Diederich D Skopec J Diederich A Dai FX. Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals.Am J Physiol. 1994; 266: H1153-H1161PubMed Google Scholar Defective endothelium-dependent relaxation in diabetic rat aorta is significantly attenuated by vitamin E, a potent free radical scavenger.47Keegan A Walbank H Cotter MA Cameron NE. Chronic vitamin E treatment prevents defective endothelium-dependent relaxation in diabetic rat aorta.Diabetologia. 1995; 38: 1475-1478Crossref PubMed Scopus (124) Google Scholar In human studies, administration of vitamin C restores and improves endothelium-dependent vasodilation, but not endothelium-independent responses, in patients with both insulin-dependent and non–insulin-dependent diabetes mellitus, thus further suggesting that oxygen-derived free radicals may decrease the bioavailability of EDNO.48Timimi FK Ting HH Haley EA Roddy M Ganz P Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.J Am Coll Cardiol. 1998; 31: 552-557Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar A potentially treatable source of oxygen-derived free radicals is hyperlipidemia. Increased levels of low density lipoprotein (LDL) and very low density lipoprotein are common in patients with diabetes. Hyperglycemia promotes the oxidation and nonenzymatic glycation of LDL, which has been strongly implicated in atherogenesis by a variety of mechanisms.49Witzum JL. The oxidation hypothesis of atherosclerosis.Lancet. 1994; 344: 793-795Abstract PubMed Scopus (1237) Google Scholar In animal models of hypercholesterolemia, the vascular endothelium produces several free radicals, presumably through xanthine oxidase activation, and these endothelial-derived free radicals inactivate EDNO.50Ohara Y Peterson TE Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest. 1993; 91: 2546-2551Crossref PubMed Scopus (1608) Google Scholar Moreover, flow-mediated vasodilatation and reactive hyperemia (endothelium-dependent) are more impaired in patients with insulin-dependent diabetes and elevated LDL cholesterol levels, which further supports the relationship of hypercholesterolemia, free radicals, and EDNO.51Clarkson P Celermajer DS Donald AE et al.Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels.J Am Coll Cardiol. 1996; 28: 573-579Abstract Full Text PDF PubMed Google Scholar Advanced glycosylation end products (AGEs) have also been implicated in the pathogenesis of diabetic microvascular complications.37Brownlee M Cerami A Vlassare H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.N Engl J Med. 1988; 318: 1315-1321Crossref PubMed Scopus (2271) Google Scholar These are formed from a reversible reaction between glucose and protein to form Schiff bases, which then rearrange to form stable Amadori-type early glycosylation products. Some of these reversible early glycosylation products may undergo complex rearrangements to form irreversible AGEs. In experimental diabetes, AGEs impair the actions of EDNO and cause an impaired endothelium-dependent response, which is ameliorated by the administration of an AGE inhibitor.52Bucala R Tracey KJ Cerami A. Advanced glycosylation end products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.J Clin Invest. 1991; 87: 432-438Crossref PubMed Scopus (1025) Google Scholar AGEs also displace disulfide crosslinkages in collagen and scleral proteins, accounting for the diminished charge in the capillary basement membrane. This may contribute to the increased vascular permeability of diabetes because blockade of a specific receptor for AGE reverses diabetes-mediated vascular hyperpermeability.53Wautier JL Zoukourian C Chappey O. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.J Clin Invest. 1996; 97: 238-243Crossref PubMed Scopus (480) Google Scholar Moreover, the presence of AGE receptors on both endothelial cells and monocytes, along with AGE deposition in the subendothelium, suggests monocyte deposition into the subendothelial space and secondary complications.54Schmidt AM Hori O Brett J Yan SD Wautier JL Stem D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions.Arterioscler Thromb. 1994; 14: 1521-1528Crossref PubMed Google Scholar Makita et al,55Makita Z Radoff S Rayfield El Advanced glycosylation end products in patients with diabetic nephropathy.N Engl J Med. 1991; 325: 836-842Crossref PubMed Scopus (795) Google Scholar with a radioreceptor assay for AGEs in serum and arterial wall, have demonstrated higher AGE levels in patients with diabetes as compared with nondiabetic control subjects, with the highest levels occurring among patients with diabetes with nephropathy.55Makita Z Radoff S Rayfield El Advanced glycosylation end products in patients with diabetic nephropathy.N Engl J Med. 1991; 325: 836-842Crossref PubMed Scopus (795) Google Scholar Because at least part of AGE-induced cellular dysfunction is the result of an oxidant-sensitive mechanism, which is inhibited by antioxidants, it is likely that both oxygen-derived free radicals and AGEs each contribute to cause impaired EDNO-dependent vasodilation in diabetes. Taken together, the effects of AGEs on vascular permeability, subendothelial protein deposition, inactivation of nitric oxide, and modification of LDL provide strong evidence of their important role in diabetic vascular disease. Experimental studies in diabetic animals have also indicated that abnormal endothelial production of vasoconstrictor prostanoids, notably thromboxane A2 and prostaglandin H2 , may be a cause of endothelial cell dysfunction. Increased levels of thromboxane A2 have been isolated only from segments of diabetic aortic tissue with intact endotheliums, which suggests that the endothelium is responsible for the increased release, and impaired relaxation to acetylcholine in these segments is restored by treatment with cyclooxygenase inhibitors.15Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus.Circulation. 1993; 87: V67-V76Google Scholar, 35Tesfamarian B Brown ML Deykin D Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta.J Clin Invest. 1990; 85: 929-932Crossref PubMed Scopus (317) Google Scholar In humans, however, the role of vasoconstrictor prostanoids is less clear. Flow-dependent vasodilation in healthy subjects, which may be used as an index of endothelial function, is abolished by L -NMMA but unaffected by aspirin, thus showing that it is entirely mediated by EDNO and independent of vasoactive prostanoids.56Joannides R Haefeli WE Linder L et al.Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.Circulation. 1995; 91: 1314-1319Crossref PubMed Scopus (1374) Google Scholar Moreover, the attenuated endothelium-dependent vasodilation after acetylcholine administration seen in patients with diabetes is not affected by pretreatment with cyclooxygenase inhibitors.33Williams SB Cusco JA Roddy M Johnstone MY Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.J Am Coll Cardiol. 1996; 27: 567-574Abstract Full Text PDF PubMed Scopus (851) Google Scholar, 34Johnstone MT Creager SJ Scales KM Cusco JA Lee BK Creager MA. Impaired endothelium dependent vasodilation in patients with insulin-dependent diabetes mellitus.Circulation. 1993; 88: 2510-2516Crossref PubMed Scopus (979) Google Scholar Several lines of evidence have indicated that microcirculation is also implicated in the pathogenesis of diabetic neuropathy, and in fact, the cause of diabetic neuropathy is a complex interplay between metabolic and microvascular defects. Hyperglycemia induces an increase in the polyol pathway by which glucose is metabolized to sorbitol via aldose reductase. Increased aldose reductase activity impairs myo-inositol uptake, which leads to decreased Na+,K+ ATPase activity and loss of electrical conduction in neural tissue.57Greene DA Lattimer SA Sima AA. Sorbitol, phosphoinositides, and sodium-potassium ATPase in the pathogenesis of diabetic complications.N Engl J Med. 1987; 316: 599-606Crossref PubMed Scopus (842) Google Scholar, 58Pfeifer MA Schumer MP. Clinical trials of diabetic neuropathy: past, present, and future.Diabetes. 1995; 44: 1355-1361Crossref PubMed Google Scholar There is also a relationship between aldose reductase, Na+,K+-ATPase activity, and nitric oxide in the pathogenesis of diabetic neuropathy. First, Na+,K+-ATPase activity in normal arteries is dependent on an intact endothelium, which suggests a stimulatory action by EDNO.59Simmons DA Winegrad AI. Mechanism of glucose-induced Na+ - K+ ATPase inhibition in aortic wall of rabbits.Diabetologia. 1989; 32: 402-408Crossref PubMed Scopus (46) Google Scholar Second, hyperglycemia causes d
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