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    • br Histamine and glycaemia Histamine is

    2022-01-20


    Histamine and glycaemia Histamine is involved in a wide variety of pathophysiological events mostly related to the inflammatory response through four receptors, namely H1-4Rs. The first studies of PFI 3 synthesis and diabetes date back to the 1950s. Since that time the involvement of histamine in diabetes was related to its well-known vasoactive properties and permeability leakage effects correlated to microvascular complications. In particular, the first evidence for a correlation between histamine and diabetes came in 1989 through the work of Gill and colleagues when they reported an increase in plasma and leucocyte histamine content which was claimed to contribute to the underlying pathogenesis evoking endothelial permeability [6]. These findings were in keeping with in vivo studies of experimental diabetes suggestive of an increased histaminergic tone in diabetic rodents. Indeed, histamine was found to be increased in plasma, kidney, brain, lung, heart, pancreas and intestine [6], [7] of diabetic rats. Independent evidence also suggested a parallel imbalance of the anabolism and catabolism of this amine with an increased synthesis and a simultaneous decreased catabolism [8], [9], [10], [11]. For instance, a significant drop in intestinal diamine oxidase (DAO) activity [7] as well as an increase of histidine decarboxylase (HDC) activity in various tissues [12] were observed, thus providing evidence for a nascent histamine pool. The very recent observation of a reduced prevalence of hyperglycemia in HDC⿿/⿿ NOD mice (an animal model of spontaneous type 1 diabetes) in comparison with the wild-type counterpart [13] strongly lends weight to this original hypothesis. More intriguingly, it has been reported that histamine plasma and aortic synthesis [10] in diabetic rats are reduced when insulin is administrated [14], thus strongly supporting the hypothesis for an interconnection between histamine and glycaemic status. This hypothesis is further strengthened by the study of Azevedo and colleagues reporting an increase of pancreatic islet histamine content in streptozotocin (STZ)-induced diabetes rats [15]. Interestingly, recent data suggest the involvement of the peripheral H3R in the insulin-histamine loop (Supplementary Fig. 1). Indeed, Nakamura and colleagues provided the first evidence for a potential diabetogenic effect of the pancreatic H3R, through reporting the presence of functional histamine H3R in this tissue. In particular, it has been demonstrated that H3R activation in pancreatic beta cells by imetit (PubChem CID 3692) inhibits the insulin secretion associated with high glucose levels in MIN6 cells [16]. Moreover, the same authors reported H3R expression in pancreatic alpha cells, indicating that H3R activation may reduce glucagon production by αTC1.6 cells in a non-hyperglycemic condition [17]. Notably, although the H3R has been known to play a critical role in homeostatic regulatory functions, such as control of food intake and maintenance of body weight [18], its contribution to diabetes is controversial [18], [19], [20], [21], [22], [23], [24] and still far from being fully understood. Indeed, the H3R inverse agonist clobenoprit (PubChem CID 2790) has been demonstrated to increase the hypothalamic histamine release and reduce the energy intake in normal and leptin-resistant mice with diet-induced obesity (DiO) [25]. So far, some newly synthesized H3R antagonists have been specifically tested in diabetic animal models demonstrating an effectiveness in reducing non-fasting glucose levels by potentially blocking the increase of HbA1 [26]. More interestingly, the strategy of an H3R antagonism combined with a phenylsulfonylurea (well-known insulinotropic drugs) moiety has been explored [27]; although an effective prototype remains elusive. On the contrary, the activation of H3Rs in mice has been reported to decrease food intake and increase energy expenditure. Chronic dosing with a H3R agonist reduces body weight, fat mass, hyperleptinemia, and hyperinsulinemia in DiO mice [28]. Conversely, the protean H3R agonist proxyfan (PubChem CID 6421522) in mice improves glucose excursion increasing plasma insulin levels without affecting plasma glucagon levels [29]. Furthermore, the mildly obese H3R-deficient mice also demonstrate leptin and insulin resistance with impaired glucose tolerance [28]. Notably, the majority of these data were obtained before the clear demonstration of H3R peripheral expression [16], [30], [31], [32], [33], [34]. In particular, the pancreatic localization of the H3R raises the question of contradictory effects mediated by peripheral and central H3R.