This project will identify risk factors for diabetic foot ulcer by studying the relationship
between endothelial dysfunction and foot ulcer risk. A fundamental defect in type 1 and 2
diabetic subjects is impaired vasodilatory reserve which is reflected in the dysfunction of
endothelium-dependent vasodilation. Findings thus far point to an important role of the
microvasculature in the development of diabetic foot ulcer and amputation.
In this study a a well-characterized cohort of 750 diabetic veterans without foot ulcer will
be followed over 3-years.
Prevention of foot ulcer should result in a reduction in the risk of lower limb amputation.
We propose to identify risk factors for diabetic foot ulcer by studying the relationship
between endothelial dysfunction and foot ulcer risk. It has been proposed that impaired
vasoregulation in diabetic patients leads to the development and perpetuation of chronic
foot ulceration via failure of the normal hyperemic response to injury. A fundamental defect
that has been demonstrated in type 1 and 2 diabetic subjects is impaired vasodilatory
reserve, which reflects dysfunction of endothelium-dependent vasodilation. Our findings thus
far point to an important role of the microvasculature in the development of diabetic foot
ulcer and amputation, with our demonstration of higher foot ulcer and lower-limb amputation
risk in relation to lower dorsal foot transcutaneous oxygen level. The role of endothelial
dysfunction in relation to diabetic foot ulcer risk has not previously been studied.
We will follow a well-characterized cohort of 750 diabetic veterans without foot ulcer over
3-year after obtaining baseline measures of endothelial function using iontophoretic
application of acetylcholine to induce cutaneous endothelium-dependent vasodilation on the
dorsal foot. Iontophoresis permits noninvasive delivery of ionic drugs cutaneously without
damage to the skin or systemic effects. Change in microvascular flow will be measured using
a laser Doppler imager (Moor LDI) over a 4x4 cm area divided into 18496 measurement sites.
Endothelial function will be defined as the difference between readings before and after the
iontophoretic application of a 1% acetylcholine solution at a current of 0.2 mA for 1
minute, with higher readings reflecting better endothelial function. These techniques are
the accepted standard method for assessment of endothelium-dependent vasodilation in the
cutaneous microvasculature. Additional measurements will be obtained on other ulcer risk
factors to assess whether endothelial dysfunction independently influences foot ulcer risk,
or whether it is merely a marker for different pathophysiologic conditions responsible for
higher risk (eg., sensory neuropathy). Possible confounding factors considered will include
sensory and autonomic neuropathy; dorsal foot transcutaneous oximetry; macrovascular
function assessed with Doppler blood pressures; diabetes characteristics; in-shoe plantar
pressure (F-scan), medication use, and foot deformity.
Diabetic patients with foot ulcers
John Fryer, Ph.D. Asst. Director
Program Analysis and Review Section (PARS), Rehabilitation Research & Development Service