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    • With an ever increasing incidence rate

    2022-04-20

    With an ever-increasing incidence rate of type 2 diabetes and obesity, it is imperative to develop new therapeutic regimes that may provide a benefit both in terms of efficacy and tolerability. The existing portfolio of drugs for the treatment of metabolic disorders, primarily type 2 diabetes and obesity, suffers from a range of limitations in terms of efficacy, safety and tolerability. The mutual progression of type 2 diabetes and obesity, with insulin resistance as an adjunct, highlights the need for a single therapeutic modality for addressing the issues associated with both of these disorders, without compromising safety and tolerability. The existing classes of drugs either address the extensive glycemic control through different mechanisms or are meant for weight control. With the discovery of the bile Erismodegib australia receptor TGR5 and its involvement in different facets of glucose and energy homeostasis through different mechanisms of actions-, D2 iodinase and GLP-1 respectively, it seems likely that TGR5 agonists may be able to address the issues associated with both type 2 diabetes and obesity (Figure 3). Further, with an expression profile of TGR5 in immune cells-(monocytes and macrophages), TGR5 has been implicated in the regulation of immunomodulation by bile acids [19]. The potential involvement of TGR5 in the regulation of pathophysiology of metabolic disorders such as obesity, insulin resistance and diabetes is, however, strengthened by the above fact, since chronic inflammation associated with visceral obesity contributes to the development of insulin resistance, leading to peripheral insulin resistance in many tissues [53]. The exact role of TGR5 in immunoregulation and its involvement in inflammatory response is not, however, clear. Amongst its other activities, the activation of TGR5 by bile acids in liver macrophages (Kupffer cells) and sinusoidal endothelial cells appears to exert protective effects over liver through a cAMP-dependent anti-apoptotic mechanism and the activation of endothelial nitric oxide synthase (eNOS) 54, 55. This mechanism may scavenge bile acid induced reactive oxygen species and protect the liver against lipid peroxidation and bile acid induced injury (Figure 2, Figure 3). The development of diabetes in patients with cirrhosis is well-recognized, but evidence is emerging that the development of chronic liver disease and progression to cirrhosis may occur after the diagnosis of diabetes and that diabetes plays a role in the initiation and progression of liver injury [56]. Endothelial nitric oxide synthase (eNOS) function is impaired in diabetes as a result of increased vascular generation of reactive oxygen species 57, 58, 59 and, henceforth, the augmentation of nitric oxide through eNOS activation mediated by TGR5 agonists may protect against hepatic ischemia-reperfusion (I-R) injury in type 2 diabetes mellitus (Figure 2, Figure 3). It is too early, however, to draw any conclusion regarding the clinical efficacy and tolerability of TGR5 agonists, until synthetic agonists provide the proof of principle for such preclinical and clinical end points. The only evidence, so far, for the efficacy of small molecule TGR5 agonists has emerged from the preliminary screening data from Takeda, [60]. The correlation of in vitro to in vivo data for small molecule TGR5 agonists is still not known. Further, the evidence of lack of cholesterol gallstone formation in mice lacking the TGR5 receptor, while being fed a lithogenic diet [61] may highlight the crucial role played by TGR5 in the formation of gallstones and, hence, raises the potential issue with the use of TGR5 agonists in inducing the gallstone formation in obese and overweight subjects. The direct involvement of TGR5 in the regulation of expression of key genes governing the negative feedback loop of bile acid synthesis remains, however, obscure. The presence of an excess of phospholipids in the gall bladders of TGR5 depleted mice, resulting in a low bile salt/phospholipid ratio makes it highly unfavorable for gallstone formation and is contradictory to the above mentioned finding [61]. Therefore, more research is warranted to address such issues.