Key Points
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Perturbation of normal homeostatic control of proglucagon processing can occur, which gives rise to production of glucagon-like peptide 1 in the inflamed or injured pancreas
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The plasticity and interconversion of α cells and β cells provides opportunities for cell replacement and differentiation strategies for the treatment of diabetes mellitus
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The central role of glucagon in maintenance of euglycaemia underscores the rationale for clinical strategies for simultaneous glucagon and insulin administration for therapy of type 1 diabetes mellitus (T1DM)
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Glucagon agonists reduce food intake and increase energy expenditure, which highlights pathways that could be targeted in the treatment of obesity
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Dysregulated glucagon secretion and increased hepatic glucose production in patients with T1DM or type 2 diabetes mellitus forms the basis of attempts to reduce glucagon action to treat these individuals
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Mechanism-based adverse events, such as cardiovascular effects, are mediated by glucagon receptor signalling and should be considered when developing therapeutic strategies directed at enhancing or attenuating glucagon action
Abstract
Glucagon is secreted from islet α cells and controls blood levels of glucose in the fasting state. Impaired glucagon secretion predisposes some patients with type 1 diabetes mellitus (T1DM) to hypoglycaemia; whereas hyperglycaemia in patients with T1DM or type 2 diabetes mellitus (T2DM) is often associated with hyperglucagonaemia. Hence, therapeutic strategies to safely achieve euglycaemia in patients with diabetes mellitus now encompass bihormonal approaches to simultaneously deliver insulin and glucagon (in patients with T1DM) or reduce excess glucagon action (in patients with T1DM or T2DM). Glucagon also reduces food intake and increases energy expenditure through central and peripheral mechanisms, which suggests that activation of signalling through the glucagon receptor might be useful for controlling body weight. Here, we review new data that is relevant to understanding α-cell biology and glucagon action in the brain, liver, adipose tissue and heart, with attention to normal physiology, as well as conditions associated with dysregulated glucagon action. The feasibility and safety of current and emerging glucagon-based therapies that encompass both gain-of-function and loss-of-function approaches for the treatment of T1DM, T2DM and obesity is discussed in addition to developments, challenges and critical gaps in our knowledge that require additional investigation.
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J.E.C. and D.J.D. researched data for the article, provided substantial contributions to discussions of the content, contributed equally to writing the article, and to reviewing and/or editing of the manuscript before submission.
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D.J.D. has served as a consultant for companies developing incretin-based therapies for the treatment of diabetes mellitus, including Arisaph Pharmaceuticals, Intarcia Therapeutics, MedImmune, Merck Research Laboratories, Novo Nordisk, NPS Pharmaceuticals and Receptos. Neither D.J.D. nor his family members hold stock directly or indirectly in any of these companies. Preclinical studies in D.J.D.'s laboratory are supported, in part, by grants to Mount Sinai Hospital from Merck, Novo Nordisk and Sanofi. J.E.C. declares no competing interests.
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Campbell, J., Drucker, D. Islet α cells and glucagon—critical regulators of energy homeostasis. Nat Rev Endocrinol 11, 329–338 (2015). https://doi.org/10.1038/nrendo.2015.51
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DOI: https://doi.org/10.1038/nrendo.2015.51
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