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    • Conflicting data concerning the involvement of H

    2022-09-07

    Conflicting data concerning the involvement of H2R on glycaemia has also arisen. Its antagonism was reported to decrease [35], not affect [36], [37] and increase [38], [39] Fmoc-Val-OPfp australia levels. In comparison, the clinical experience with antipsychotic drugs generated clearer evidence for the involvement of the central H1R in the development of a diabetic phenotype [40]. Consistently, it has been found that the intra-ventricle or ⿿hypothalamic administration of an H1R agonist induces satiety evoking an anti-obesity effect [41], [42]. Moreover, a strategy based on the contemporary H1R agonism and H3R antagonism was demonstrated to have the potential to reduce obesity also in patients with comorbidities such as diabetes [43].
    Histamine and diabetes complications As mentioned above, despite the effectiveness of the different anti-diabetic strategies in controlling glycaemic levels, due to the glucose variability, patients are still exposed to a high risk of developing one or more of the longstanding and serious complications [4]. According to the definitions by the World Health Organization, the complications can be divided into macrovascular complications (including coronary artery disease, peripheral arterial disease and stroke) and microvascular complications (including diabetic nephropathy, neuropathy and retinopathy). Notably, for each new case of one given complication, a higher probability to display another one has been clearly documented [44]. Interestingly, a higher content of histamine in the anatomical districts involved in the diabetic longterm complications has been reported in different studies [6], [7]. Independently from the source of histamine within these districts, due to an activation of mast cells, a recruitment of basophils, an imbalance in the amine anabolism/catabolism or all three, the increased histaminergic tone is a common feature of the different complications and deserves to be further clarified. In particular, based on its vascular actions, histamine has been suggested to be a key triggering stimulus for the functional microangiopathy in diabetes mellitus, from retinopathy to nephropathy. However, its complete functional contribution to diabetes microvascular complications is yet to be elucidated.
    Conclusion Is it really the time to reconsider the functional contribution of histamine in diabetes? Indeed, although still far from conclusive, different elements point to a clear role of histamine in diabetes and diabetic complications etiopathogenesis. The evidence is strong in some cases, sometimes independent, but sometimes contradictory; despite this heterogeniety, when viewing the timeline of interest for histamine involvement in this disease (Fig. 1) it appears phasic with a clear upturn and renewal in interest in the last couple of years, thanks to the very recent discovery of a direct effect of histamine on glycaemia [13], [16], [17] as well as a profound up-regulation of both H3R and H4R in the diabetic animal kidney [33], [146]. As a whole, the revisit of the literature herein clearly shows growing independent lines of evidence for a bidirectional connection between histamine and diabetes (Table 1). Therefore, a pathophysiological role for this amine cannot be discounted anymore and new studies specifically aimed to assess its function in the onset and progression of the longstanding diabetes complications are strictly warranted. The state of the art on histamine in diabetes is recapitulated in Fig. 1. As reported in Table 1, not all the diabetic complications have been provided with the same level of compelling evidence. Many blind spots remain regarding the role of histamine in macrovascular complications where the effect of the amine seems to be mostly related to its general vasoactive properties rather than to a specific function in diabetes. The discrepancies often observed in the literature can be mostly ascribed to the different models adopted as well as to the doses, the administration route and the actual selectivity of the compound used, which could differentially affect the central and peripheral histaminergic system. More notably, the majority of the evidence for histamine involvement in the different diabetes complications arises from studies not directly aimed to assess its role in diabetic disease. This is in particular the case for diabetic peripheral neuropathy where the studies were designed to assess a general role in nociception and/or neuropathic pain. Other fields, such as retinopathy, have found using new strategies, effective and specific pharmacological tools that have downgraded the antihistaminergic approach to a supporting role. However, since many of the investigations were prior to the discovery of the newest histamine receptor members H3R and H4R, [147] there is scope for new insights in histamine and diabetes, and the opportunity to develop new antihistamine drugs to overcome the paucity of effective therapies.