Tooke JE: Microvascular function in human diabetes: a physiological perspective. .Diabetes 44::721. ,1995. .
Williamson JR, Ido Y: The Vascular Cellular Consequences of Hyperglycemia, Oxford University Press, New York. ,1999. .
Tooke JE: A Pathophysiological Framework for the Pathogenesis of Diabetic Microangiopathy, Oxford University Press, New York. ,1999. .
Tooke JE: Methodologies used in the study of the microcirculation in diabetes mellitus. .Diabetes Metab Rev 9::57. ,1993. .
LoGerfo FW, Coffman JD: Current concepts: vascular and microvascular disease of the foot in diabetes: implications for foot care. .N Engl J Med 311::1615. ,1984. .
Diabetes Control and Complications Trial: The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. .Diabetes 44::968. ,1995. .
Bouche C, Serdy S, Kahn CR, et al: The cellular fate of glucose and its relevance in type 2 diabetes. .Endocr Rev 25::807. ,2004. .
Grant PJ: Inflammatory, atherothrombotic aspects of type 2 diabetes. .Curr Med Res Opin 21: (suppl 1):S5. ,2005. .
Flynn MD, Tooke JE: Aetiology of diabetic foot ulceration: a role for the microcirculation?. Diabet Med 9::320. ,1992. .
Algenstaedt P, Schaefer C, Biermann T, et al: Microvascular alterations in diabetic mice correlate with level of hyperglycemia. .Diabetes 52::542. ,2003. .
Myers BD: Pathophysiology of proteinuria in diabetic glomerular disease. .J Hypertens Suppl 8::S41. ,1990. .
Flynn MD: The Diabetic Foot, Oxford University Press, New York. ,1999. .
Pham HT, Economides PA, Veves A: The role of endothelial function on the foot: microcirculation and wound healing in patients with diabetes. .Clin Podiatr Med Surg 15::85. ,1998. .
Poston L: The Endothelium in Diabetes, Oxford University Press, New York. ,1999. .
Williamson JR, Kilo C: Current status of capillary basement-membrane disease in diabetes mellitus. .Diabetes 26::65. ,1977. .
Parving HH, Noer I, Deckert T, et al: The effect of metabolic regulation on microvascular permeability to small and large molecules in short-term juvenile diabetics. .Diabetologia 12::161. ,1976. .
Williamson JR, Vogler NJ, Kilo C: Regional variations in the width of the basement membrane of muscle capillaries in man and giraffe. .Am J Pathol 63::359. ,1971. .
Tooke JE: Microcirculation and diabetes. .Br Med Bull 45::206. ,1959. .
Ajjam ZS, Barton S, Corbett M, et al: Quantitative evaluation of the dermal vasculature of diabetics. .Q J Med 54::229. ,1985. .
Parving HH, Viberti GC, Keen H, et al: Hemodynamic factors in the genesis of diabetic microangiopathy. .Metabolism 32::943. ,1983. .
Sandeman DD, Shore AC, Tooke JE: Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control. .N Engl J Med 327::760. ,1992. .
Trap-Jensen J, Lassen NA: Increased capillary diffusion capacity for small ions in skeletal muscle in long-term diabetics. .Scand J Clin Lab Invest 21::116. ,1968. .
Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al: Albuminuria reflects widespread vascular damage: the Steno hypothesis. .Diabetologia 32::219. ,1989. .
Cameron 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 10::189. ,1994. .
Hayden MR, Tyagi SC: Neural redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus, and diabetic neuropathy. .Med Sci Monit 10::RA291. ,2004. .
McMillan DE, Utterback NG, Stocki J: Low shear rate blood viscosity in diabetes. .Biorheology 17::355. ,1980. .
Ernst E, Matrai A: Altered red and white blood cell rheology in type II diabetes. .Diabetes 35::1412. ,1986. .
MacRury SM, Lowe GD: Blood rheology in diabetes mellitus. .Diabet Med 7::285. ,1990. .
Lowe GD, Ghafour IM, Belch JJ, et al: Increased blood viscosity in diabetic proliferative retinopathy. .Diabetes Res 3::67. ,1986. .
Leiper JM, Lowe GD, Anderson J, et al: Effects of diabetic control and biosynthetic human insulin on blood rheology in established diabetics. .Diabetes Res 1::27. ,1984. .
Jaap AJ, Lowe GD: Blood Rheological Changes in Diabetes, Oxford University Press, New York. ,1999. .
Poston L, Taylor PD: Glaxo/MRS Young Investigator Prize: endothelium-mediated vascular function in insulin-dependent diabetes mellitus. .Clin Sci (Lond) 88::245. ,1995. .
Hassan AA, Tooke JE: Mechanism of the postural vasoconstrictor response in the human foot. .Clin Sci (Lond) 75::379. ,1988. .
Tooke JE: Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes. .J Diabetes Complications 14::197. ,2000. .
Quigley FG, Faris IB, Duncan HJ: A comparison of Doppler ankle pressures and skin perfusion pressure in subjects with and without diabetes. .Clin Physiol 11::21. ,1991. .
Singleton JR, Smith AG, Russell JW, et al: Microvascular complications of impaired glucose tolerance. .Diabetes 52::2867. ,2003. .
Schmitz O, Romer FK, Alberti KG, et al: Angiotensin-converting enzyme in diabetes mellitus dependence on metabolic aberration. .Diabetes Metab 9::179. ,1983. .
Jensen T, Bjerre-Knudsen J, Feldt-Rasmussen B, et al: Features of endothelial dysfunction in early diabetic nephropathy. .Lancet 1::461. ,1989. .
Stehouwer CD, Stroes ES, Hackeng WH, et al: von Willebrand factor and development of diabetic nephropathy in IDDM. .Diabetes 40::971. ,1991. .
Fasching P, Veitl M, Rohac M, et al: Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus. .J Clin Endocrinol Metab 81::4313. ,1996. .
Lim SC, Caballero AE, Smakowski P, et al: Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria. .Diabetes Care 22::1865. ,1999. .
Chen JW, Gall MA, Deckert M, et al: Increased serum concentration of von Willebrand factor in non-insulin dependent diabetic patients with and without diabetic nephropathy. .BMJ 311::1405. ,1995. .
Satchell SC, Mathieson PW: Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology. .J Nephrol 16::168. ,2003. .
Hsueh WA, Anderson PW: Systemic hypertension and the renin-angiotensin system in diabetic vascular complications. .Am J Cardiol 72::14H. ,1993. .
Giustina A, Perini P, Desenzani P, et al: Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients. .Diabetes 47::423. ,1998. .
Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. .Nature 288::373. ,1980. .
Naseem KM: The role of nitric oxide in cardiovascular diseases. .Mol Aspects Med 26::33. ,2005. .
Bitar MS, Wahid S, Mustafa S, et al: Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. .Eur J Pharmacol 511::53. ,2005. .
Vincent AM, Feldman EL: New insights into the mechanisms of diabetic neuropathy. .Rev Endocr Metab Disord 5::227. ,2004. .
Bucala R, Vlassara H: Advanced glycosylation end products: role in diabetic and nondiabetic vascular disease. .Drug Dev Res 325::836. ,1999. .
Vincent AM, Russell JW, Low P, et al: Oxidative stress in the pathogenesis of diabetic neuropathy. .Endocr Rev 25::612. ,2004. .
Esposito C, Gerlach H, Brett J, et al: Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. .J Exp Med 170::1387. ,1989. .
Kirstein M, Brett J, Radoff S, et al: Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. .Proc Natl Acad Sci U S A 87::9010. ,1990. .
Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. .J Clin Invest 87::432. ,1991. .
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 U S A 91::9441. ,1994. .
Davi G, Falco A, Patrono C: Lipid peroxidation in diabetes mellitus. .Antioxid Redox Signal 7::256. ,2005. .
Widlansky ME, Gokce N, Keaney JF Jr, et al: The clinical implications of endothelial dysfunction. .J Am Coll Cardiol 42::1149. ,2003. .
Zeiher AM, Drexler H, Wollschlager H, et al: Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. .Circulation 84::1984. ,1991. .
Gokce N, Keaney JF Jr, Hunter LM, et al: Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. .Circulation 105::1567. ,2002. .
Gokce N, Keaney JF Jr, Hunter LM, et al: Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. .J Am Coll Cardiol 41::1769. ,2003. .
Hsueh WA, Law R: The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. .Am J Cardiol 92::3J. ,2003. .
Caballero AE, Saouaf R, Lim SC, et al: The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial. .Metabolism 52::173. ,2003. .
Kwak BR, Mulhaupt F, Mach F: Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. .Autoimmun Rev 2::332. ,2003. .
Walter DH, Zeiher AM, Dimmeler S: Effects of statins on endothelium and their contribution to neovascularization by mobilization of endothelial progenitor cells. .Coron Artery Dis 15::235. ,2004. .
Hsueh WA, Quinones MJ: Role of endothelial dysfunction in insulin resistance. .Am J Cardiol 92::10J. ,2003. .
Ebskov B, Josephsen P: Incidence of reamputation and death after gangrene of the lower extremity. .Prosthet Orthot Int 4::77. ,1980. .
American Diabetes Association: Preventive foot care in people with diabetes. .Diabetes Care 23: (suppl 1):S55. ,2000. .
Arora S, Smakowski P, Frykberg RG, et al: Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy. .Diabetes Care 21::1339. ,1998. .
Veves A, Akbari CM, Primavera J, et al: Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. .Diabetes 47::457. ,1998. .
Park TS, Park JH, Baek HS: Can diabetic neuropathy be prevented?. Diabetes Res Clin Pract 66: (suppl 1):S53. ,2004. .
Koitka A, Abraham P, Bouhanick B, et al: Impaired pressure-induced vasodilation at the foot in young adults with type 1 diabetes. .Diabetes 53::721. ,2004. .
Arora S, Pomposelli F, LoGerfo FW, et al: Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. .J Vasc Surg 35::501. ,2002. .
Low PA, Nickander KK, Tritschler HJ: The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. .Diabetes 46: (suppl 2):S38. ,1997. .
Microvascular dysfunction is an important component of the pathologic processes that occur in diabetic foot disease. The endothelial abnormalities observed in patients with diabetes mellitus are poorly understood, and evidence suggests that endothelial dysfunction could be involved in the pathogenesis of diabetic macroangiopathy and microangiopathy. With the advent of insulin replacement in the early 1900s and increased efforts toward metabolic control of diabetes, long-term complications of this disease have become apparent. These late-term complications are primarily disorders of the vascular system. This article reviews the process of microvascular dysfunction and how it may relate to the pathogenesis of diabetic foot problems. (J Am Podiatr Med Assoc 96(3): 245–252, 2006)