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  • Our results revealed that when subjected to intravenous

    2022-06-24

    Our results revealed that when subjected to intravenous glucose tolerance tests, the RIP-Gcgr mice showed enhanced glucose tolerance and increased beta cell function, which is in agreement with the findings of Gelling et al. [6]. However, we also show that there is a reduced responsiveness of the beta cell to the insulinotropic action of GLP-1 as a consequence of the overexpression of the glucagon receptor. The experimental evidence for this is that the glucose lowering and insulin secretory effects of acute injection of GLP-1 during the IVGTT were severely diminished in RIP-Gcgr mice when compared to wild-type mice. Similarly, the reduced insulin response during the OGTT may be ascribed to impaired insulinotropic effect of GLP-1, since the release of GLP-1 was unaffected. Increased glucagon action on the beta cell has been suggested to contribute to the decreased insulinotropic effectiveness of endogenous GLP-1 in type 2 diabetes in humans [11]. In addition, the expression of the GLP-1 receptor is downregulated in the islets of hyperglycemic rats and humans with type 2 diabetes [12], [13], [14], [15]. This may explain why the insulinotropic effectiveness of endogenous GLP-1 is decreased in type 2 diabetic individuals, seemingly dependent on hyperglycemia, and can be improved by lowering circulating glucose levels [16], [17]. Whether or not glucagon action is involved in this reversible, glucose-dependent impairment of the insulinotropic action of GLP-1 is not known. Interestingly, in this study GLP-1 receptor expression was increased, not decreased in islets of RIP-Gcgr but despite this the insulinotropic action of GLP-1 was reduced. High overexpression of the GLP-1 receptor has been previously shown to result in receptor desensitization in vitro [18], however there is no previous evidence of this in vivo. The dissociated response between glucose and GLP-1 after glucagon receptor overexpression opened the broader question whether also other beta-cell secretagogues showed dissociated responses in these mice. We therefore examined also the amino Pazopanib receptor arginine and the muscarinic receptor agonist carbachol, both of which are known to be powerful insulin secretagogues through different signaling mechanisms [19]. We found that the insulin secretory responses to these non-glucose secretagogues were also dissociated in RIP-Gcgr mice. Arginine induced insulin secretion was in fact completely blunted in this mouse model whereas the acute response to carbachol was retained although the late phase insulin secretion in response to carbachol was however impaired in RIP-Gcgr mice. Arginine and carbachol have different mechanisms of action in regards to stimulating insulin secretion. Arginine transports across the membrane of the beta cell leading to membrane depolarization and the influx of extracellular calcium into the cell causing mobilization of insulin granules and insulin secretion [20]. Carbachol, on the other hand, is a cholinergic agent that activates muscarine receptors and activates the DAG-PLC pathway leading to mobilization of intracellular calcium stores [21]. Since there was an enhanced insulin secretion in response to glucose seen in RIP-Gcgr mice it may be concluded that the triggering phase of insulin secretion in response, at least to glucose, is not impaired. Therefore, the abolished acute insulin secretory response to arginine in RIP-Gcgr mice was unexpected since the majority of arginine’s stimulatory effect is through the depolarization of the membrane and the subsequent influx of calcium. However, for a full arginine effect an electrogenic transport across the membrane of the amino acid is also required to induce membrane depolarization [22]. It is thus possible that overexpression of the glucagon receptor impairs arginine transport into the beta cell and thus insulin secretion. In contrast, carbachol has a different signaling mechanism involving the DAG-PLC pathway leading to mobilization of intracellular calcium stores [21] rather than depolarization of the cells. The rather unaffected insulin secretory response to carbachol suggests therefore that this secretory pathway is largely unaffected by overexpression of the glucagon receptor.