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Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and \u03b1-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in \u03b1-cells (\u03b1TSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of \u03b1-cell proliferation, cell size, and mass expansion. Hyperglucagonemia in \u03b1TSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in \u03b1TSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), PEPCK, and genes involved in amino acid metabolism and urea production. Glucagon resistance in \u03b1TSC2KO mice was associated with improved glucose levels in streptozotocin-induced \u03b2-cell destruction and high-fat diet\u2013induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.<\/jats:p>","DOI":"10.2337\/db20-0440","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T20:55:25Z","timestamp":1606337725000},"page":"477-491","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":28,"title":["Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia"],"prefix":"10.2337","volume":"70","author":[{"given":"Nadejda","family":"Bozadjieva Kramer","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI"},{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI"},{"name":"Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, 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