Alzheimer's disease (AD) is a growing public health concern in both the United States and the world. For Americans aged 65 or older, AD represents the fifth leading cause of death ("2020 Alzheimer's disease facts and figures," 2020), and it is estimated that over 80 million people worldwide will be living with some form of dementia by 2040 with AD comprising a majority of these (Ballard et al., 2011).AD is broadly characterized by an irreversible progressive loss of cognition and memory often accompanied by anxiety-like behavior

While glucagon has long been recognized as the primary counter hormone to insulin’s actions, it has recently gained recognition as a metabolic regulator with its effects extending beyond control of glycemia. Recently developed models of tissue-specific glucagon receptor knockouts have advanced our understanding of this hormone, providing novel insight into the role it plays within organs as well as its systemic effects. Studies where the pharmacological blockade of the glucagon receptor has been employed have proved similarly valuable in the study of organ-specific and systemic roles of glucagon signaling. Studies carried out employing these tools demonstrate that glucagon indeed plays a role in regulating glycemia, but also in amino acid and lipid metabolism, systemic endocrine, and paracrine function, and in the response to cardiovascular injury. Here, we briefly review recent progress in our understanding of glucagon’s role made through inhibition of glucagon receptor signaling utilizing glucagon receptor antagonists and tissue specific genetic knockout models.