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Diabetic Neuropathy and Microcirculation
Chantel Hile, MD, and Aristidis Veves, MD, DSc*
‘Small-vessel Disease’: An Outdated Term
For the purpose of clarity in discussing microcirculation, the concept of “small-vessel disease” must be eliminated. Early retrospective pathologic studies in diabetic patients who underwent amputation led to the misconception that abnormalities in the microcirculation are occlusive in nature, socalled “small-vessel disease.” It was postulated that such occlusions occur even in the absence of any macrovascular occlusive problem and cause ischemic lesions and impairment of wound healing. This idea originated from the histologic existence of periodic acid-Schiff-positive material occluding the medium-sized or small arteries in amputated limb specimens [11]. However, subsequent physiologic studies [12] and other prospective staining and arterial casting studies [13,14] have demonstrated the absence of such occlusive lesions. Furthermore, the term “small-vessel disease” initially referred to medium or small size arteries, not to the microcirculation. Therefore, as it stands, the phrase creates confusion and should no longer be used.
Address *Microcirculation Laboratory, Palmer 317, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215, USA. E-mail: [email protected] Current Diabetes Reports 2003, 3:446–451 Current Science Inc. ISSN 1534-4827 Copyright © 2003 by Current Science Inc.

The microcirculation in diabetic and neuropathic feet is subject to the same changes found in other end organs of diabetic patients, such as the retina or the kidney. Complications such as foot ulceration lead to further morbidity and hospitalizations. Research into the causes of microcirculatory dysfunction has revealed an interplay of numerous factors. The most prominent findings are impaired endothelium-dependent and -independent vasodilation and reduced or absent nerve-axon reflex-related vasodilation. This renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury, and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions.

Structural Changes Introduction
Diabetic foot problems are major contributors to health care costs and hospitalizations. Fifteen percent of diabetic patients will suffer foot ulceration, a clear risk factor for limb loss, during their lifetimes. The main causes of ulceration are diabetic neuropathy and vascular disease of both the macro- and microcirculation. A complete understanding of how the disease process works is essential in learning how to best prevent and treat these complications. Abnormalities of the microcirculation occur early in the course of diabetes [1–4]. Eventual manifestations of altered microcirculation, such as retinopathy, nephropathy, and neuropathy, are related to the duration and severity of diabetes [5,6]. In the DCCT (Diabetes Control and Complications Trial), intensive glycemic control was found to significantly delay the development and progression of these microvascular complications in type 1 diabetic patients, with similar results reported in type 2 diabetic patients [6–9]. The capillary microcirculation to foot skin undergoes changes that are similar to that of the retina, nerves, and kidneys, and has shown signs of significant impairment in diabetic patients, especially when metabolic control is poor [10]. Over the past two decades, it has become clear that metabolic alterations in diabetes cause both structural and functional changes in multiple areas within the arteriolar and capillary systems [15,16]. The most characteristic structural changes of the capillary circulation in diabetic patients are a reduction in the capillary size and thickening of basement membranes [17,18]. The density of skin capillaries, however, does not differ from that of healthy subjects [19]. The changes in capillary size and basement membrane thickness are most pronounced in the legs, especially in diabetic patients with poorly controlled blood sugar levels [20]. It is currently believed that increased hydrostatic pressure and shear force in the microcirculation in the lower extremities evoke an injury response in the microvascular endothelium. The injury may result in proliferation of extravascular matrix proteins, leading to capillary basement membrane thickening and arteriolar hyalinosis [21,22]. Thickened membranes impair the migration of leukocytes and hamper the hyperemic response to injury, increasing the susceptibility of the diabetic foot to infection [23,24]. These structural modifications also decrease the elastic properties of the capillary vessel walls, limiting their capacity for vasodilatation, and may eventually result in a significant loss of the autoregulatory capacity [25]. It is of interest that these changes do

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not result in narrowing or occlusion of the capillary lumen; on the contrary, the arteriolar blood flow may be normal or even increased [26]. Another factor that is probably involved in the impaired vasodilatory capacity of diabetic patients is the increased stiffness of precapillary vessel walls due to increased glycosylation and formation of nonenzymatic advanced glycosylation end products (AGEs). Irreversible chemical processes occur slowly as these compounds accumulate over time [27]. The idea that AGEs contribute to the development of diabetic microangiopathy is supported by the fact that diabetic patients have higher serum and arterial wall concentrations of AGEs than healthy subjects [27]. Diabetic patients with nephropathy have even more striking elevations in AGE concentrations as compared to healthy subjects [28]. A study of the effect of AGEs on endothelial function in experimental animals showed that the presence of AGEs inhibits endothelium-dependent vasodilatation, an effect that can be reversed by an AGE inhibitor [29].

thelial function is one of the main mechanisms that lead to the development of the long-term complications of diabetes, such as neuropathy and retinopathy.

Functional Changes
In addition to the structural changes produced by diabetes on the microcirculation, techniques that allow the measurement of skin blood flow have highlighted functional disturbances as well. Using these techniques, researchers have observed that diabetic patients have reduced maximal hyperemic response to heat, even in the early stages of the disease [30]. The idea that impaired capillary microcirculation could be a major contributing factor in the development of diabetic foot pathology has encouraged more indepth research in this direction [14,23,31]. Evaluating the microcirculation to peripheral tissues has expanded the understanding of these functional changes and their role in altering the microvascular blood flow.

Expression of eNOS and diabetic neuropathy Endothelial nitric oxide synthetase (eNOS) plays a crucial role in the production of nitric oxide from arginine. One possible mechanism for impairment of endothelial function in diabetic neuropathy is a reduction in the expression of eNOS activity [35••]. We have tested this hypothesis by evaluating the immunohistochemistry staining for eNOS in biopsies taken from foot skin of diabetic neuropathic patients with peripheral vascular disease (PVD), diabetic neuropathic patients without PVD, and healthy subjects [35••]. The results showed reduced staining for eNOS in the diabetic patients (with or without PVD) as compared to the healthy subjects. Similar results have been reported by other investigators using immunohistochemistry and western blotting techniques [36]. Therefore, these data indicate that reduced expression of eNOS may be related to the development of diabetic neuropathy and techniques that increase its expression may be helpful in preventing or treating nerve dysfunction. Changes in the microcirculation in the neuropathic foot The classic description of the diabetic neuropathic foot as warm and red, with palpable pulses and distended veins, indicates increased blood flow in the affected limb. Studies exploring this presentation found that despite appearances the blood flow in the nutritional skin microcirculation is stable or even reduced [37], indicating a functional ischemia of the skin microcirculation and maldistribution of blood flow to the foot [10]. It was also suggested that both structural and functional changes in the skin microcirculation result in a significant shift of blood flow away from nutritional capillaries toward subpapillary arteriovenous shunts of a much lower resistance [38]. As these shunts are innervated by sympathetic nerves [39], coexisting autonomic neuropathy and sympathetic denervation seen in diabetic patients with severe neuropathy may lead to an opening of these shunts, augmentation of the maldistribution of blood between the nutritional capillaries and subpapillary vessels [40,41], and consequent aggravation of microvascular ischemia. Studies using venous occlusion plethysmography, Doppler sonography, and venous oxygen tension measurements support this concept [41,42]. These disturbances in nutritive microcirculation may be important in the development of diabetic foot complications and may help explain why the diabetic foot is more susceptible to the effect of pressure and has impaired ulcer healing. To evaluate the relation between changes in microcirculation and neuropathy in the presence or absence of PVD, the skin microcirculation of foot was thoroughly investigated using both single-point laser imaging and laser scanning techniques in five groups [35••]. The first

Endothelial function and diabetes The endothelium plays an important role in maintaining the vascular tone by the balanced secretion of vasoconstrictors and vasodilators, the most important of which is nitric oxide. Using the technique of measuring capillary blood flow by laser Doppler flowmetry has enabled the evaluation of the endothelial function in diabetic limbs more precisely. Early application of this technique showed a reduced hyperemic response to heat stimulus and pointed to the role of endothelial dysfunction as the cause of impaired vascular reactivity at the microcirculatory level [30]. Such dysfunction was shown to occur early in the course of diabetes and may even predict diabetic microand macrovascular complications [3,32,33]. More recently, endothelial dysfunction was also reported in patients with impaired glucose tolerance and in relatives of type 2 diabetic patients [34•], suggesting that changes in the microcirculation occur early in the course of the metabolic syndrome, before any changes in the metabolism of glucose. It is currently believed that impairment of the endo-

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Figure 1. A, The maximal hyperemic response to heating of foot skin at 44°C for at least 20 minutes (expressed as the percentage of increase over baseline flow measured by a single-point laser probe) is reduced in the diabetic with neuropathy (DN) and in diabetic patients with neuropathy and peripheral vascular disease (DI) when compared with diabetic patients with Charcot arthropathy (DA), diabetic patients without complications (DC), and normal control subjects (C) (P < 0.001). B, The response to iontophoresis of acetylcholine and sodium nitroprusside (SNP) (expressed as the percentage of increase over baseline flow measured by laser scanner imager). The response to acetylcholine is equally reduced in the DN, DI, and DA groups when compared with the DC and C groups (P < 0.001). The response to SNP was more pronounced in the DI group and was also reduced in the DN and DA groups compared with the DC and C groups (P < 0.001).

group included diabetic patients with neuropathy (DN), the second group included diabetic patients with both neuropathy and peripheral vascular disease (DI), the third group included diabetic patients with Charcot arthropathy (DA), the fourth group included diabetic patients without complications (DC), and the fifth group included healthy control subjects (C) (Fig. 1). The percentage of increase in blood flow over baseline in response to heating the skin to 44°C was reduced in the diabetic neuropathic and ischemic patients (DN, DI), whereas no difference existed among the remaining three groups. Conversely, employing laser Doppler imaging to measure the vasodilatory response to iontophoresis (a noninvasive method of introducing soluble ions into skin), it was shown that the endothelium-dependent vasodilatation (response to iontophoresis of acetylcholine) was reduced in diabetic patients with neuropathy, vascular disease, and arthropathy. The endothelium-independent vasodilatation (response to iontophoresis of sodium nitroprusside) was more severely reduced in the ischemic-neuropathic patients compared with other groups and was reduced in the neuropathic groups with or without Charcot disease compared to the control subjects. These findings substantiate the close association between diabetic neuropathy and microcirculatory impairment in the form of reduced endothelium-dependent and endotheliumindependent vasodilation at the foot level even in the absence of large-vessel PVD. They also imply that the presence of neuropathy may be an important contributing factor in microcirculatory dysfunction, because the coexistence of neuropathy and PVD did not result in a greater decrease in endotheliumdependent vasodilation than that due to neuropathy alone.

PARP role in impaired vascular reactivity Recently, data have emerged showing poly (ADP-ribose) polymerase (PARP) to be involved in endothelial dysfunction as well. PARP is a nuclear enzyme that responds to oxidative DNA damage by activating an inefficient cellular metabolic cycle, often leading to cell necrosis. In a study done in our unit, nondiabetic control subjects were compared to three groups: those with type 2 diabetes, those with glucose intolerance only, and those with a family history of type 2 diabetes but no intolerance themselves. PARP activation was higher in all three diabetes-associated groups than in the healthy control subjects [43]. The activation of PARP was associated with changes in the vascular reactivity of the skin microcirculation in forearm biopsies taken from these subjects, supporting the hypothesis that PARP activation contributes to changes in microvascular reactivity. Further study is required to prove this association and the possible benefits from inhibiting this activation. The role of the nerve-axon reflex in vasodilation In healthy subjects, the ability to increase blood flow depends on the existence of normal neurogenic vascular response. The normal neurovascular response is conducted through the Cnociceptive nerve fibers. Stimulation of these nerve fibers leads to antidromic stimulation of adjacent C fibers, which secrete substance P, calcitonin gene-related peptide, and histamine, causing vasodilatation and increased blood flow to the injured tissues, thereby promoting wound healing (Lewis' triple flare response, Fig. 2). In cases of diabetic neuropathy, this neurovascular response is impaired, leading to a significant reduction of blood flow under conditions of stress (eg, injury

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Figure 2. Neurogenic vascular response. Stimulation of the C-nociceptive nerve fibers leads to antidromic stimulation of the adjacent C fibers, which secrete substance P, calcitonin gene-related peptide (CGRP), and histamine that cause vasodilatation and increased blood flow.

or infection). This increases the vulnerability of the neuropathic limb [44]. Evidence that diabetic neuropathy contributes to vasodilatory impairment is provided by studies in our laboratory that evaluate the nerve-axon–related vasodilatory response. We found that the nerve-axon–related vasodilatory response to iontophoresis of acetylcholine was significantly reduced in diabetic patients with neuropathy, diabetic patients with neuropathy and PVD, and diabetic patients with Charcot arthropathy, when compared with healthy subjects or diabetic patients without complications [45]. Further evidence is provided by a study designed to evaluate the role of the C-nociceptive nerve fibers in nerve-axon reflex-related vasodilation. In this study, nerve-axon reflex-related vasodilation was measured in three groups: diabetic neuropathic, diabetic non-neuropathic, and healthy control subjects. Measurements were first taken on the forearm and the foot of each subject. Then, after blocking the C-nociceptive nerve fibers with dermal anesthesia, measurements were repeated. A clear reduction in nerve-axon reflex-related vasodilation occurred in all three groups on the forearm but only in the two non-neuropathic groups on the foot, indicating that Cnociceptive fiber function is the main factor that influences nerve-axon reflex-related vasodilation [46]. The contribution of the nerve-axon reflex-related vasodilatation response to the total endothelium-dependent and endothelium-independent vasodilation was also studied in a group of diabetic patients versus a control group at both the forearm and foot levels [47••]. The nerve-axon–related response in healthy subjects was found to be 35% of the total response at the forearm level and 29% at the foot level. In the presence of neuropathy, the nerve-axon–related response was significantly reduced, at a level of only 8% of the total response. The neuropathic response correlates to the response of healthy skin to sodium nitroprusside, a substance that does not specifically excite the C-nociceptive fibers. These findings indicate that although the neurovascular response is an important factor in skin microcirculation, it is not the sole or even the dominant pathway through which vasodilation is achieved [48]. The abnormality in nerve-axon–related vascular reactivity is believed to further aggravate the abnormalities in the microcirculation and contribute to a vicious cycle of

injury [35••]. It becomes apparent that involvement of Cnociceptive fibers in diabetes not only impairs pain perception leading to injury and inflammation, but also contributes to impaired vasodilation, depriving the injured area of increased blood flow and healing factors.

Differences between forearm and foot microcirculation As mentioned previously, erect posture may lead to differences in the microcirculation at the foot level when compared to other parts of the body that are closer to the heart and, therefore, have a reduced hydrostatic pressure. In order to test this hypothesis, we have examined the differences in the foot and forearm skin microcirculation in healthy subjects and in diabetic patients with or without neuropathy. No differences were found in the maximal hyperemic response between the forearm and foot levels in any of the three groups, although the response in the neuropathic group was significantly lower at both levels in comparison to the diabetic non-neuropathic and healthy control subjects. The endothelium-dependent and endothelium-independent vasodilatation was significantly lower at the foot level when compared to the forearm level in all groups. The neuropathic group showed a significantly lower response at both forearm and foot levels when compared to the non-neuropathic and control groups. Evaluation of the nerve-axon–mediated vasodilatation response also revealed a significantly lower response at the foot level versus the forearm level in the three groups [45]. These results indicate that the microcirculation at the foot level is compromised even in healthy subjects when compared to the forearm level. The presence of diabetes may further compromise the microcirculation to a level that creates a hypoxic environment and allows the development of neuropathic changes. These factors may also explain why neuropathy initially occurs in the lower extremities of diabetic patients [48,49]. Microvascular changes in diabetic foot with Charcot arthropathy The diagnosis of Charcot neuroarthropathy is made when gross destruction of the joints in the mid-foot results in significant foot deformity. The skin temperature of Charcot feet is usually higher due to increased blood flow in arteriovenous

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shunts, as discussed earlier. Although the endothelial-dependent and endothelial-independent vasodilatation is impaired in Charcot patients, the maximal hyperemic response to heat is preserved. These findings indicate that the hyperemic response in Charcot disease is present but is probably unregulated and results in the excessive bone resorption that leads to gross deformity of the foot shape. These findings are consistent with clinical observations that the development of Charcot neuroarthropathy is extremely rare in the presence of PVD [50]. Poor blood flow to the extremity would prevent much of a hyperemic response, protecting the foot from bone resorption and deformation, although certainly contributing to other microcirculatory derangement.

References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
1. Malik RA, Tesfaye S, Thompson SD, et al.: Endothelial localization of microvascular damage in human diabetic neuropathy. Diabetologia 1993, 36:454–459. Tesfaye S, Malik R, Ward JD: Vascular factors in diabetic neuropathy. Diabetologia 1994, 37:847–854. Johnstone MT, Creager SJ, Scales KM, et al.: Impaired endothelium-dependent vasodilation in patients with insulindependent diabetes mellitus. Circulation 1993, 88:2510–2516. Stevens MJ, Feldman EL, Greene DA: The etiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. Diabet Med 1995, 12:566–579. Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Metab 1977, 3:97–107. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group [no authors listed]. N Engl J Med 1993, 329:977–986. Jaap AJ, Tooke JE: The pathophysiology of microvascular disease in type 2 diabetes. Clin Sci 1995, 89:3–12. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [no authors listed]. Lancet 1998, 352:837–853. Ohkubo Y, Kishikawa H, Araki E, et al.: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995, 28:103–117. Jorneskog G, Brismar K, Fagrell B: Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications. Diabetologia 1995, 38:474–480. Goldenberg SG, Alex M, Joshi RA, et al.: Nonatheromatous peripheral vascular disease of the lower extremity in diabetes mellitus. Diabetes 1959, 8:261–273. Barner HB, Kaiser GC, Willman VL: Blood flow in the diabetic leg. Circulation 1971, 43:391–394. Strandness DE Jr, Priest RE, Gibbons GE: Combined clinical and pathologic study of diabetic and nondiabetic peripheral arterial disease. Diabetes 1964, 13:366–372. LoGerfo FW, Coffman JD: Vascular and microvascular disease of the foot in diabetes. N Engl J Med 1984, 311:1615–1619. Nathan DM: Long-term complications of diabetes mellitus. N Engl J Med 1993, 328:1676–1685. Cohen RA: Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993, 87:V67–V76. Jaap AJ, Shore AC, Stockman AJ, et al.: Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes. Diabet Med 1996, 13:160–164. Rayman G, Malik RA, Sharma AK, et al.: Microvascular response to tissue injury and capillary ultrastructure in the foot skin of type I diabetic patients. Clin Sci 1995, 89:467– 474. Malik RA, Metcalf I, Sharma AK, et al.: Skin epidermal thickness and vascular density in type 1 diabetes. Diabet Med 1992, 9:263–267. Raskin P, Pietri A, Unger R, Shannon WA Jr: The effect of diabetic control on skeletal muscle capillary basement membrane width in patients with type 1 diabetes mellitus. N Engl J Med 1983, 309:1546–1550.

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Conclusions
Microcirculation to the diabetic foot suffers multiple significant structural and functional derangements. Nerveaxon–related microvascular reactivity is clearly impaired in the diabetic population. There is a growing belief that both the failure of the dysfunctional vessels to dilate and the impairment of the nerve-axon reflex are major causes for impaired wound healing in diabetic patients. Further studies are required to clarify the precise etiology of observed endothelial dysfunction in diabetic and neuropathic patients and to identify the possible potential therapeutic interventions to prevent it or to retard its progression. Studies are also required to examine the vascular changes in the peripheral nerves, rather than in the skin.
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Future Directions
One of the most important concepts currently under investigation is the role of inflammatory states with the development of both vascular disease and diabetes. The hypothesis that inflammatory factors such as vascular cell adhesion molecule, interleukin-1, and tumor necrosis factor-α have a role in the development and progression of atherosclerosis is intriguing. These same inflammatory factors are necessary in the wound healing cascade, presenting a conflict of interest within the injured diabetic body. The factors required for healing a diabetic foot ulcer may actually worsen the atherosclerosis that is preventing adequate blood flow to heal the foot ulcer in the first place. An attempt to break the resulting cycle of injury leading to inflammatory factor response, causing worsening circulation, leading to nonhealing wound, is the next major focus in the field of diabetic microcirculation.
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Ajjam ZS, Barton S, Corbett M, et al.: Quantitative evaluation of the dermal vasculature of diabetics. Q J Med 1985, 215:229–239. 22. Tilton RG, Faller AM, Burkhardt JK, et al.: Pericyte degeneration and acellular capillaries are increased in the feet of human diabetes. Diabetologia 1985, 28:895–900. 23. Rayman G, Williams SA, Spencer PD, et al.: Impaired microvascular hyperaemic response to minor skin trauma in type 1 diabetes. BMJ 1986, 292:1295–1298. 24. Flynn MD, Tooke JE: Aetiology of diabetic foot ulceration: a role for the microcirculation? Diabet Med 1992, 8:320–329. 25. Tooke JE: Microvascular function in human diabetes: a physiological perspective. Diabetes 1995, 44:721–726. 26. Parving HH, Viberti GC, Keen H, et al.: Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 1983, 32:943–949. 27. Mullarkey CJ, Brownlee M: Biochemical basis of microvascular disease. In Chronic Complications of Diabetes. Edited by Pickup JC, Williams G. Oxford: Blackwell Scientific Publications; 1994:20–29. 28. Makita Z, Radoff S, Rayfield EJ, et al.: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 1991, 325:836–842. 29. Bucala 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, 87:432–438. 30. Sandeman DD, Shore AC, Tooke JE: Relation of skin capillary pressure in patients with insulin-dependent diabetes to complications and metabolic control. N Engl J Med 1992, 327:760–764. 31. Shore AC, Price HJ, Sandeman DD, et al.: Impaired microvascular hyperaemic response in children with diabetes mellitus. Diabet Med 1991, 8:619–623. 32. Williams SB, Cusco JA, Roddy M, et al.: Impaired nitric oxidemediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996, 27:567–574. 33. Stehouwer CDA, Fischer HRA, Van Kuijk AWR, et al.: Endothelial dysfunction precedes development of microalbuminuria in IDD. Diabetes 1995, 44:561–564. 34.• Caballero AE, Arora S, Saouaf R, et al.: Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999, 48:1856–1862. One of the first papers to show changes in the endothelial function of both the micro- and macrocirculation in healthy subjects at risk of developing type 2 diabetes. 35.•• Veves A, Akbari CA, Primavera J, et al.: Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 1998, 47:457–463. Examined in detail the changes in the skin microcirculation of the foot in diabetic patients with neuropathy, vascular disease, and Charcot joint neuroarthropathy. In addition, it studied the mechanisms that are related to this, such as the expression of eNOS.

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Jude EB, Boulton AJ, Ferguson MW, et al.: The role of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: possible modulatory effects by transforming growth factor beta 1. Diabetologia 1999, 42:748–757. 37. Murray HJ, Boulton A: The pathophysiology of diabetic foot ulceration: Clin Podiatr Med Surg 1995, 12:1–17. 38. Conrad MC, ed: Functional Anatomy of the Circulation to the Lower Extremities. Chicago, IL: Year Book Medical Publishers; 1971. 39. Watkins PJ, Edmonds ME: Sympathetic nerve failure in diabetes. Diabetologia 1983, 25:75–77. 40. Malik RA, Newrick PG, Sharma AK, et al.: Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 1989, 32:92–102. 41. Flynn MD, Tooke JE: Diabetic neuropathy and the microcirculation. Diabet Med 1995, 12:298–301. 42. Edmonds ME, Roberts VC, Watkins PJ: Blood flow in the diabetic neuropathic foot. Diabetologia 1982, 22:141–147. 43. Szabo C, Zanchi A, Komjati K, et al.: Poly(ADP-ribose) polymerase is activated in subjects at risk of developing type 2 diabetes and is associated with impaired vascular reactivity. Circulation 2002, 106:2680–2686. 44. Walmsley D, Wiles PG: Early loss of neurogenic inflammation in the human diabetic foot. Clin Sci 1991, 80:605–610. 45. Arora S, Smakowski P, Frykberg RG, et al.: Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy. Diabetes Care 1998, 21:1339–1344. 46. Caselli A, Rich J, Hanane T, et al.: Role of C-nociceptive fibers in the nerve axon reflex-related vasodilation in diabetes. Neurology 2003, 60:297–300. 47.•• Hamdy O, Abou-Elenin K, Smakowski P, et al.: The contribution of nerve axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care 2001, 24:344–349. Shows that the nerve-axon reflex-related vasodilation is equal to about one third of the maximal vasodilation that can be achieved by the direct stimulation of the endothelial cell. 48. Veves A, Uccioli L, Manes C, et al.: Comparisons of risk factors for foot problems in diabetic patients attending teaching hospitals outpatient clinics in four different European states. Diabet Med 1994, 11:709–713. 49. Ward JD: Upright posture and the microvasculature in human diabetic neuropathy: a hypothesis. Diabetes 1997, 46(suppl 2):S94–S97. 50. Kozak GP, Campbell DR, Frykberg RG, eds: The diabetic Charcot foot. In Management of Diabetic Foot Problems, edn 2. Philadelphia, PA: WB Saunders; 1994:88–97.

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