Acanthosis nigricans (AN) was first recognized more than 100 years ago in association with internal malignancy. In 1976, in a landmark study Kahn et al  described what has become today, its commonest association - the link with insulin resistance and type 2 diabetes. Thus individuals with AN are more likely to display risk factors for type 2 diabetes whatever their ethnic or geographic origin [18, 19].
Fifty years ago, it was observed in the course of treating skin diseases with topical glucocorticoids that pallor of the surrounding skin occurred , an observation that has formed the basis of the skin vasoconstrictor assay (SVC). Traditionally used to evaluate the potential efficacy of newer topical glucocorticoid agents, workers have explored the potential of this bioassay to assess glucocorticoid sensitivity as a pathogenetic mechanism for disease [16, 21].
Individual responsiveness to topically applied glucocorticoid varies considerably such that there are individuals who respond with an intense degree of pallor and others who only barely do so or not at all . In a previous study  we were intrigued by the heterogeneity of this biologic response to topically applied glucocorticoid and asked whether a lack of response reflected a more generalized insensitivity to glucocorticoids. We demonstrated that patients defined as having asthma resistant to standard therapeutic doses of systemic glucocorticoid were more likely to demonstrate reduced skin vasoconstrictor responsiveness to potent topically applied glucocorticoid . These findings supported the concept that topical glucocorticoid resistance was an indicator a more generalised phenomenon. In further work, topically applied progesterone or aldosterone failed to produce a SVC response and additionally, the response to potent glucocorticoid was abolished by specific glucocorticoid receptor blocking agents . These observations permitted the conclusion that the SVC response is specifically glucocorticoid receptor mediated and its absence may point to evidence of disturbance of glucocorticoid pharmacodynamics and receptor activation rather than altered glucocorticoid pharmacokinetics. In further support of this idea, there are data which have linked variation in skin vasoconstrictor responsiveness to polymorphism in the glucocorticoid receptor gene .
In the current study, we have now demonstrated a novel clinical observation linking AN to the absence of the SVC response. Thus the greater the degree of AN, the less likely was there an SVC response to beclomethasone dipropionate. There is a number of possible explanations for this finding. Firstly, in AN, the skin is thickened and an absent biologic response could simply be the result of poor bioavailability across thickened skin. Against this idea would be the fact that the agent used in this study, beclomethasone dipropionate, is potent, exhibits high cutaneous bioavailability  and which was, in addition, used in high concentration. It is also noteworthy that the sites of predilection for AN (neck, axillae and groin) were quite remote from the site where the SVC assay was conducted viz., the volar aspect of the forearm. Another possible explanation is that SVC may be diminished in darker skin. However, we have found that SVC was independent of ethnic origin (Study 2) in which peoples of African, South Asian or mixed ancestry participated and which provided a range of skin textures and colours. The alternative explanation is that there is reduced glucocorticoid sensitivity of dermal vasculature among severely insulin -resistant individuals as characterized by high grade AN. Such reduced glucocorticoid action would provide a plausible explanation as to why in the face of increased cortisol exposure in MS [13, 14] characteristic Cushingoid features, notably thin skin and purpura are absent. Differential tissue sensitivity will also explain another paradox.
One of the models of MS that has been recently explored is that relating to over activity of an enzyme, 11beta-hydroxysteroid dehydrogenase type 1, which regenerates the natural active glucocorticoid cortisol in man (corticosterone in rodents) from inactive cortisone (deoxycorticosterone in rodents). Mice over expressing the gene for this enzyme in adipose tissue have metabolic and phenotypic features of MS . Treatment with a specific inhibitor of the enzyme both reverses the metabolic abnormalities of MS as well as also stops atherosclerotic plaque progression . The mouse model of MS in which glucocorticoid is overproduced in some tissues is not mutually exclusive of the findings demonstrated in our study. In man the enzyme 11B-hydroxysteroid dehydrogenase is active in mature adipocytes and hepatocytes and may play a role in increasing glucocorticoid activity locally in obesity syndromes . Our work suggests that in the face of increased glucocorticoid production in the liver and adipose tissue reduced dermal glucocorticoid sensitivity may exemplify a possible adaptive mechanism response to counteract glucocorticoid overexposure i.e. tissue- selective glucocorticoid resistance. In this regard, it is well recognized that tissues can differentially regulate glucocorticoid exposure both by enzyme-mediated  as well as receptor-mediated mechanisms .
Glucocorticoid resistance, even if adaptive, will have consequences. Given the natural anti-inflammatory actions of glucocorticoids one would expect that inflammatory phenomena could arise from this state of reduced glucocorticoid activity. In keeping with this notion, we have shown that not only was SVC an independent predictor of CRP but also those with combined AN and absent SVC have the highest CRP levels (Figure 2). The role of the vasculature in the immune response is well documented  and elevated CRP reflects deficiency of the innate immune system. It should be noted, however, there was no obvious relationship between plasma cytokines IL-1, IL-6 and TNF-alpha and the SVC among the groups here studied. This implies that the exaggerated inflammatory response, though more marked when SVC is absent, is confined to innate or vascular mechanisms without discernible changes involving cytokines.
There were some limitations to our studies. There was an age disparity between subjects carefully selected for having high grade AN in STUDY 1 when compared with controls which could have been a confounding factor. In the multivariate linear model which is based on data from study 1, the interaction between SVC and AN may also be mediated by those other covariates which are imbalanced between the groups with and without AN grade 4. However, in STUDY 2, where subjects were drawn cross-sectionally and in which there were no significant age difference in the groups, the association between AN and absent SVC was sustained. Similarly, analysis of data to evaluate the relationship between SVC and ethnicity would not have been meaningful in Study 1, given the small numbers of Afro-Caribbeans (n = 17) and "Others" (n = 10) but in Study 2 where this was possible, we found SVC to be independent of ethnicity. The prevalence of AN is known to be ethnically related and darker races exhibit higher prevalence . It remains to be seen if the SVC/AN relationship demonstrated among Africans and Asian Indians occurs in other ethnic groups. It should be noted that the frequency of SVC responsiveness also appears to be higher in Caucasians (90%)  than among this sample comprising people with darker skin. It is also unclear whether the absence of SVC response to topical glucocorticoid represents a consequence of inflammation or is indeed the cause of exaggerated inflammation.
The observation that acanthosis nigricans ameliorates with progressive weight reduction  highlights the role of obesity in its pathogenesis. It would be interesting to determine whether SVC alters with weight reduction, which will indicate that glucocorticoid resistance in MS is acquired and not genetic with obvious implications for interventional strategies.
The interactions between stress, inflammation, obesity and the hypothalamic-pituitary-adrenal axis [7–10, 33] are complex and no doubt an evolving story. Differential tissue sensitivity to glucocorticoids adds an additional dimension to the list of abnormalities already known to exist in the hypothalamic-pituitary-adrenal axis [11, 13, 14, 34] in the MS and the skin presents a valuable and practical window through which such interactions can be explored.