Diabetic Neuropathy - Pathology

Micro Vascular - updated: 15 March 2008

Diabetic neuropathy: vascular disease?

Rev Neurol. 2003 Oct 1-15;37(7):658-61

Otero-Siliceo E, Ruano-Calderón LA.

INTRODUCTION: The major neurologic complications of diabetes are: 1) Neuropathy, both peripheral and autonomic, with principal manifestations in the lower limbs; 2) Microvascular disease, mainly affecting the retina, resulting in blindness; and 3) Macrovascular disease, presenting with atherosclerosis in the cerebral arteries causing ischemic cerebrovascular disease and stroke. METHOD: The definition of diabetic neuropathy has changed over the last 50 years. Over the last 20 years there have been three main pathogenetic theories to explain diabetic neuropathy: the polyol pathway theory, the microvascular theory, and the glycosylation end product theory. It is apparent that several pathophysiologic factors probably operate simultaneously, and it may be too simplistic to attempt to explain the many clinical and pathologic findings of diabetic neuropathy through a single theory. Diabetic peripheral neuropathy is not caused by large vessel peripheral vascular disease, however, it does appear that small vessel disease plays a role. CONCLUSION: It seems likely, that microangiopathy on the one hand and changes of various metabolic pathways due to hyperglycemia on the other hand are much more related to each other than it was suggested previously.

Publication Types:

• Review

Mechanisms of disease: Pathway-selective insulin resistance and microvascular complications of diabetes

Nat Clin Pract Endocrinol Metab. 2005 Dec;1(2):100-10

Groop PH, Forsblom C, Thomas MC.

Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes. To the extent that insulin resistance leads to hyperglycemia, dyslipidemia and hypertension, this association is not surprising. It is now clear that insulin also has direct actions in the microvasculature that influence the development and progression of microvascular disease. In the healthy state, insulin appears to have only minor effects on vascular function, because of the activation of opposing mediators such as nitric oxide and endothelin-1. Diabetes and obesity, however, are associated with selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, which leads to reduced synthesis of nitric oxide, impaired metabolic control and compensatory hyperinsulinemia. By contrast, insulin signaling via extracellular signal-regulated kinase dependent pathways is relatively unaffected in diabetes, tipping the balance of insulin's actions so that they favor abnormal vasoreactivity, angiogenesis, and other pathways implicated in microvascular complications and hypertension. In addition, preferential impairment of nonoxidative glucose metabolism leads to increased intracellular formation of advanced glycation end products, oxidative stress and activation of other pathogenic mediators. Despite a strong temporal association, a causal link between pathway-selective insulin resistance and microvascular damage remains to be established. It is possible that this association reflects a common genotype or phenotype. Nonetheless, insulin resistance remains an important marker of risk and a key target for intervention, because those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes.

Publication Types:

• Review

Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56

Rask-Madsen C, King GL.

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.

Publication Types:

• Review

The effect of polyneuropathy on foot microcirculation in Type II diabetes

Diabetologia. 2002 Aug;45(8):1164-71. Epub 2002 Jul 3

Nabuurs-Franssen MH, Houben AJ, Tooke JE, Schaper NC.

AIMS/HYPOTHESIS: The aim of this study was to investigate the influence of peripheral polyneuropathy (PNP) on skin microcirculation and foot swelling rate in the feet of patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: 38 Type II diabetic patients, 24 with PNP (PNP+), 14 without PNP (PNP-), and 16 healthy control subjects were studied, first supine and subsequently sitting with the foot dependent for 50 mn. RESULTS: In patients with PNP, foot skin temperature was higher, (p<0.04) and capillary blood cell velocity (CBV, nailfold capillary microscopy), was lower compared to patients without PNP (222 vs 313 micro m/s respectively, p<0.03). Compared to the control subjects, the percentage reduction in skin blood flux, (LDF, laser-Doppler fluxmetry), after 10 min was higher in the PNP- and PNP+ patients (3% vs 18% and 26% respectively, p<0.02). These disturbances were most pronounced in PNP+ patients with a history of a foot ulcer. Foot swelling rate (mercury strain gauge plethysmography) in the first 10 min of dependency, was lower in patients with PNP+ compared to the control subjects (0.00165 vs 0.00286 ml.100 ml(-1)s respectively, p<0.01). In addition, we found a negative correlation (r=-0.41; p<0.01) between Valk-score (severity of PNP) and FSR. CONCLUSION/INTERPRETATION: Type II diabetes PNP is associated with multiple abnormalities in the (skin) microcirculation of the foot, characterised by reduced capillary blood flow, an enhanced reduction in skin blood flux and impaired fluid filtration after sitting up. The most severe abnormalities were observed in patients with a history of foot ulceration.

Publication Types:

• Review