Disruption of glucagon receptor induces single α-cell hypersecretion through upregulation of VGF

Abstract

Abstract Antagonism of the glucagon receptor (GCGR) improves glycemic control both in rodent diabetes models and humans with diabetes. However, GCGR antagonism, as well as GCGR-deficiency in animal models, cause side effects of α-cell hyperplasia and hyperglucagonemia, which limit its clinical applications. The cause of these side effects has been unclear. In this study, we performed single-cell transcriptomic sequencing of α cells from glucagon receptor knockout (GCGR-KO) mice. We confirmed that α cells increased proliferation, and increased the expression of Glucagon and Slc38a5. We also found that the interaction of α cells with other endocrine cells increased, and insulin- and somatostatin-mediated inhibition of glucagon secretion was blunted. Importantly, we demonstrated that the GCGR-KO mouse not only had induced α-cell hyperplasia but also increased glucagon secretion at the single-cell level. Interestingly, GCGR-KO mouse dramatically and specifically increased VGF in α cells. Suppression of VGF reduced the α cell hypersecretion both ex vivo and in vivo. Moreover, inhibition of VGF impaired the formation of immature proglucagon secretory granules in the trans‑Golgi network, and reduced glucagon peptide maturation. These results demonstrated the basis for hyperglucagonemia in the GCGR-deficient animal, and will be beneficial for optimization of clinical application of GCGR antagonism for diabetes treatment.