Diabetic Foot - Pathology

Ischaemic - updated: 15 March 2008

Manifestations of cutaneous diabetic microangiopathy

Am J Clin Dermatol. 2005;6(4):225-37

Ngo BT, Hayes KD, DiMiao DJ, Srinivasan SK, Huerter CJ, Rendell MS.

The etiologies of a variety of skin conditions associated with diabetes have not been fully explained. One possible etiological factor is diabetic microangiopathy, which is known to affect the eyes and kidneys in patients with diabetes. There are many mechanisms by which diabetes may cause microangiopathy. These include excess sorbitol formation, increased glycation end products, oxidative damage, and protein kinase C overactivity. All of these processes occur in the skin, and the existence of a cutaneous diabetic microangiopathy has been well demonstrated. These microangiopathic changes are associated with abnormalities of skin perfusion. Because the skin plays a thermoregulatory role, there is significant capillary redundancy in normal skin. In diabetic patients, loss of capillaries is associated with a decrease in perfusion reserve. This lost reserve is demonstrable under stressed conditions, such as thermal stimulation. The associated failure of microvascular perfusion to meet the requirements of skin metabolism may result in diverse skin lesions in patients with diabetes. Many skin conditions peculiar to diabetes are fairly rare. Necrobiosis lipoidica diabeticorum (NLD) and diabetic bullae occur very infrequently as compared with diabetic retinopathy and nephropathy. Conversely, there is a correlation between diabetic microvascular disease and NLD. This correlation also exists with more common skin conditions, such as diabetic dermopathy. This relationship suggests that diabetic microangiopathy may contribute to these conditions even if it is not primarily causal. Clinically, the major significance of diabetic cutaneous microangiopathy is seen in skin ulceration which is very common and has a major impact on diabetic patients. Many factors contribute to the development of diabetic foot ulcers. Neuropathy, decreased large vessel perfusion, increased susceptibility to infection, and altered biomechanics all play a role, but there is no doubt that inadequate small blood vessel perfusion is a major cause of the inability to heal small wounds that eventually results in ulcer formation. The accessibility of skin capillaries makes cutaneous diabetic microangiopathy an attractive model for research on the evolution of microvascular disease in diabetic patients.

Publication Types:

• Review

Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors

Circ Res. 2006 Jan 6;98(1):55-62. Epub 2005 Nov 23

Tanii M, Yonemitsu Y, Fujii T, Shikada Y, Kohno R, Onimaru M, Okano S, Inoue M, Hasegawa M, Onohara T, Maehara Y, Sueishi K.

Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-alpha and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.

Publication Types:

• Animal Study

Microvascular changes in the diabetic foot

Int J Low Extrem Wounds. 2006 Sep;5(3):149-59

Schramm JC, Dinh T, Veves A.

Impairment of the microcirculation of diabetic patients may contribute to secondary complications in the lower extremity, such as foot infections and ulcerations. These microcirculatory changes, which are mainly functional rather than structural, are responsible for the impaired ability of the microvasculature to vasodilate in response to injury. Dysfunction of vascular endothelial cells and vascular smooth muscle cells both contribute to the reduction in vasodilation that is observed in diabetic patients. Nerve-axon reflex related microvascular vasodilation is also impaired in the diabetic population, and there is a growing belief that both the failure of the vessels to dilate and the impairment of the nerve axon reflex are major causes for impaired wound healing in diabetic patients. Further studies are necessary to clarify the precise etiology of endothelial and smooth muscle dysfunction in diabetic patients so that potential therapeutic interventions may be identified.

Publication Types:

• Review

Microcirculation of the diabetic foot

Curr Pharm Des. 2005;11(18):2301-

Studies over the last decade have revealed impairment of the microcirculation in the diabetic foot. Endothelial dysfunction along with derangements in numerous biochemical pathways has been implicated as causes of microcirculation impairment. Additionally, reduction or absence of the nerve-axon reflex renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury or infection and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions. Furthermore, these changes appear to be directly related to the presence of diabetic neuropathy. These alterations in the diabetic microcirculation may explain the poor wound healing commonly observed in diabetes.

Publication Types:

• Review

Aetiology of diabetic foot ulceration: a role for the microcirculation?

Diabet Med. 1992 May;9(4):320-9.

Flynn MD, Tooke JE.

Neuropathy, mechanical stress, and macrovascular disease are involved in the pathogenesis of diabetic foot ulceration. Implicit in the development of gangrene and ulceration is the recognition that these factors interact with the microcirculation, resulting in the failure of skin capillary flow to meet nutritive requirements. There is little evidence to associate structural microangiopathy with foot microcirculatory failure. Significant functional abnormalities of the microcirculation have been defined. In accord with the haemodynamic hypothesis early hyperaemia and capillary hypertension promote more sinister late functional abnormalities with increasing duration of diabetes. These late functional abnormalities include loss of autoregulation and reduced hyperaemic responses which interact with loss of neurogenic flow regulation, disturbed endothelial function, and abnormal rheology to produce the familiar clinical picture of the diabetic foot. Ischaemia secondary to multi-segment arterial disease induces additional abnormalities of microcirculatory function which are superimposed on the pre-existing diabetic microvascular structural and functional microangiopathy

Publication Types:

• Review

Publication Types:

• Review