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    • Introduction Glucose dependent insulinotropic polypeptide

    2022-01-15

    Introduction Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secreted postprandially from enteroendocrine K cells in response to ingestion of either fat [1], protein [2], or carbohydrates [3]. GIP is primarily known for its glucose-dependent insulinotropic actions mediated via the GIP receptor (GIPR) expressed on pancreatic β-cells [4], [5], [6], a property it shares with the other incretin hormone glucagon-like peptide-1 (GLP-1), secreted from enteroendocrine L cells [7]. GIP regulates glucagon secretion from the pancreatic α-cells in a glucose-dependent manner by stimulating glucagon secretion at hypoglycemic conditions [8], [9], but not during hyperglycemia [10]. Thus, there is a clear glucose-dependent duality regarding its stimulation of both insulin and glucagon secretion from the pancreatic islets. The lipogenic effect of GIP has drawn much attention after the generation of the GIPR knockout (GIPR−/−) mouse which was resistant to diet-induced obesity [11]. Consistent with this, a study of mice lacking intestinal GIP secreting cells demonstrated resistance to diet-induced obesity [12]. However, studies of the effects on adipocyte metabolism have shown conflicting results as GIP has been shown both to have anabolic and catabolic effects in adipose tissue [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. The GIPR is widely expressed in various tissues such as the pancreas, adipose tissue, bone, lungs and NHS-SS-Biotin [24] and belongs to class B GPCRs which is structurally characterized by a large N-terminal extracellular domain which is important for ligand binding [25]. GPCRs are especially known for their interaction with G proteins resulting in either activation or inhibition of second messengers [26]. They also signal through G protein-independent signaling pathways by interaction with e.g. β-arrestins [27] which has given rise to the study of biased signaling. Coupling to β-arrestins is primarily associated with the termination of G protein-dependent signaling and subsequent receptor desensitization and internalization, but may also initiate signaling pathways [28]. In patients with type 2 diabetes (T2D), the incretin effect of GIP is attenuated [29], [30]. As the secretion of GIP in these patients seems to be unaltered [31] this may point towards an alteration of GIPR signaling pathways such as e.g. an increased receptor desensitization. However, this still remains to be clarified. We have previously described that the naturally occurring GIPR antagonist, GIP(3-30)NH2, is a highly potent competitive antagonist of the human GIPR with regard to GIP-mediated G protein-dependent signaling [32]. Importantly, GIP(3-30)NH2, is a more potent antagonist compared to the other naturally occurring GIPR antagonist GIP(3-42) [32], [33]. Like exendin(9-39), being a specific GLP-1 receptor (GLP-1R) antagonist with an indispensable role in the study of human GLP-1 physiology, GIP(3-30)NH2 represents a comparable tool for the studies of human GIP physiology and pathophysiology. As such, we have shown that GIP(3-30)NH2 efficiently inhibits GIP-potentiated glucose-stimulated insulin secretion [34] and triacylglycerol (TAG) uptake in adipose tissue in humans [35]. Until now, GIP(3-30)NH2’s ability to inhibit different GIPR-mediated signaling pathways has not been studied. Understanding the GIPR inhibition mechanism of GIP(3-30)NH2 is of considerable importance when using it as a tool to study GIP physiology in humans but also in relation to potential drug development strategies. In the present study we examine if GIP(3-30)NH2 inhibits different G protein-independent pathways. We also investigate if it inhibits the GIP-mediated effects in adipocytes to probe for cell signaling differences. Finally, using a palette of metabolically relevant GPCRs, we screen for whether GIP(3-30)NH2 is a specific antagonist for the human GIPR. Taken together, these experiments contribute to the understanding of the different physiological actions of GIP such as its lipogenic effects and attenuated effects in patients with T2D.