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Microvascular Investigationsin Diabetes Mellitus

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Microvascular Investigationsin Diabetes Mellitus Postgrad Med J: first published as 10.1136/pgmj.69.812.419 on 1 June 1993. Downloaded from Postgrad Med J (1993) 69, 419-428 © The Fellowship of Postgraduate Medicine, 1993 Review Article Microvascular investigations in diabetes mellitus Sandra J. Chittenden and Shukri K. Shami Department ofSurgery, University College and Middlesex School ofMedicine, London, UK Summary: This paper reviews the current literature concerning the different investigative modalities available to assess the microcirculation in diabetic microangiopathy. The advantages and disadvantages of the different invasive and noninvasive methods available are presented objectively. We have concentrated on the tests that provide a quantitative assessment of the microcirculation, including laser Doppler fluxmetry, capillary microscopy, plethysmography, transcutaneous oximetry and radioactive isotope clearance. Some of the invasive methods described are now being replaced by noninvasive equivalents, providing similar information with less discomfort and risk to the patient. Introduction The complications resulting from diabetic angio- information about the nature of the microcir- pathy can be severe and debilitating. An enormous culatory fault in diabetic angiopathy may help in amount of research has been undertaken to to try understanding its aetiology and in developing new by copyright. clarify the mechanisms by which microangiopathy treatment strategies. Many of the invasive techni- occurs but has so far yielded no clear answer. The ques for microvascular measurement have been development of microangiopathy is probably superseded by noninvasive techniques, which is multi-factorial in origin and includes genetic sus- clearly advantageous for the investigation ofmicro- ceptibility. Factors that are thought to contribute angiopathy in the diabetic patient. This review towards the formation ofmicroangiopathy include places more emphasis on the noninvasive techni- those shown in Table I(a).' ques available. Unfortunately, by the time microvascular chan- become clinically evident, there is often little macrovascular assessment ges Importance of http://pmj.bmj.com/ that can be done in the way of treatment. It would be advantageous to identify those patients at risk of Care must be used in the interpretation of micro- developing severe retinal and glomerular impair- vascular assessments if macro- and microvascular ment and neuropathic or atherosclerotic lesions. disease coexist, and this is often the case, diabetic Functional microvascular changes may occur early patients being more prone to cardiovascular and on in the development of clinical angiopathy and peripheral arterial disease than non-diabetics.5'6 investigation of the microcirculation might there- The reasons for diabetics being more prone to fore provide a means of detecting angiopathy macroangiopathy are not certain but probably on September 28, 2021 by guest. Protected before it becomes clinically evident. Microvascular include the factors shown in Table I(b).5'7-'5 Oc- measurement techniques are also used clinically in clusive macrovascular disease may impede the the assessment of sympathetic neuropathy2 and ability ofthe microcirculation to respond to a given investigation of the peripheral microcirculation stimulus. It is therefore important to evaluate the may provide a way of detecting neuropathy in its extent of one source of circulatory dysfunction in earliest stages.3'4 order to study the other. In research, microcirculatory investigations might be used to provide an objective test of Microvascular investigations different modes of treatment. In addition, any An investigation of vessel morphology may be informative about angiopathy in its later stages and can help to assess its progression. However, in Correspondence: S.K. Shami, F.R.C.S., M.S., Surgical order to identify microcirculatory problems earlier Studies, Jules Thorn Building, Middlesex Hospital, on in their development, a functional assessment of Mortimer Street, London W1N 8AA, UK. the microcirculation may be more useful. This Accepted: 30 November 1992 usually consists of measuring blood flow, either in Postgrad Med J: first published as 10.1136/pgmj.69.812.419 on 1 June 1993. Downloaded from 420 S.J. CHITTENDEN & S.K. SHAMI Table I Factors of importance in the pathogenesis of diabetic micro- and macroangiopathy (a) Microangiopathy Hyperglycaemia Results in nonenzymic glycosylation of proteins in the vessel walls Insulin-immune complexes Stimulate monocytes and macrophages to produce procoagulant activity' Platelet activation Initiates thrombosis, release of angiogenic factors such as PDGF and the transforming growth factors (TGF)-alpha and TGF-beta, and the release of vasoconstrictor substances such as thromboxane A2 Endothelial activation Results in increased permeability and release of vasoactive substances Macrophage and monocyte Produces free radicals (superoxides, hydroxyl radicals and peroxides) and activation cytokines and causes vascular damage (b) Macroangiopathy Hyperglycaemia A risk factor in atherogenesis5 which increases adherence of monocytes and macrophages to the vessel walls7'8 and may result in local accumulation of vasoactive substances, increased proliferation of endothelium due to the release of growth factors, and damage to the vessel wall by free radicals Free radicals Increased free radical activity is seen in diabetes9"0 and may be involved in microvascular damage"'12 Lipoproteins Concentrations of low density lipoproteins and very low density lipo- proteins are high in patients with poorly controlled diabetes1314 and this may be important in atherogenesis. High density lipoproteins are said to have a protective role in atherogenesis and are lower in some diabetics'5 Hypertension Not considered a 'very important factor in vascular disease in diabetes' by most authors Other factors Including: hyperinsulinaemia, rheological factors, growth factors, reduced physical activity, obesity and genetic factors PDGF = platelet-derived growth factor. by copyright. the steady state or in response to some provoca- entrainment studies suggest that the central and tion. The resting skin blood flow in diabetic local regulatory mechanisms provide coarse and patients is often shown to be normal and yet the fine microvascular control respectively.26 It is maximal flows are impaired.16"7 Since there has therefore important to investigate the different been some difficulty in finding abnormal data at systems separately, using both contralateral and rest (possibly because of some redundancy in the local stimuli. It is also desirable to study flow in control oflocal flow'8) many studies use some kind both the arterio-venous shunt vessels and the ofprovocation in order to expose a latent problem, nutritional capillaries in the skin. Unfortunately, http://pmj.bmj.com/ for example, looking at blood flow either during most studies to date are unable to distinguish exercise, while raising body temperature, after between flow in these different vessels. administering vasoactive substances'9 or following It may be meaningful to study the effects of tissue ischaemia. The actual pattern of the blood microcirculatory changes on the chemical milieu of flow response to a challenge such as ischaemia may the tissues, including oxygen tension, to determine be important.2 In diabetes mellitus, return of whether observed microvascular alterations have blood flow after ischaemia is impaired in the skin of any functional significance. Nuclear magnetic on September 28, 2021 by guest. Protected the toes21 and in the nailfold22 (although it occurs resonance (NMR) spectroscopy may be employed more rapidly in leg muscle'6). The cold recovery to study this by examining the redox status within time of skin blood flow is also longer.23 the tissues. One approach, which has not been Another way to study the function of the micro- exploited as yet, might be to study the fluorescence circulation is to evaluate reflexes such as the of the mitochondria as their metabolic state reduction of blood flow normally seen on standing changes. (the veno-arteriolar reflex). This is impaired in patients with diabetic neuropathy.24 Similarly, in the retina, the vasoconstriction normally caused by Investigative techniques high oxygen tension is blocked by hyperglycae- mia.'6'25 Care must be taken in interpreting the Blood tests and other nonspecific tests changes in blood flow induced by such stimuli since there are various controlling influences that may be It would be useful if a simple clinical examination at work. These include sympathetic nerve activity, or a laboratory test carried out on the blood or local autoregulatory mechanisms, venous reflexes urine samples routinely taken from diabetic pa- and the status of arterio-venous shunts. Thermal tients could show or predict the development of MICROVASCULAR INVESTIGATIONS IN DIABETES 421 Postgrad Med J: first published as 10.1136/pgmj.69.812.419 on 1 June 1993. Downloaded from angiopathy. It is known that hyperglycaemia has at order to study capillary permeability and blood- least a permissive role in the aetiology of diabetic tissue exchange, it is usually necessary to introduce lesions, such as retinopathy and nephropathy.27 labelled tracer substances invasively. However, Monitoring the levels of glucose or glycosylated their movement can now be monitored non- haemoglobin in the blood and attempting optimal invasively, so reducing the trauma presented by the glycaemic control may therefore help in preventing investigation.
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