The GLP-1 journey: from discovery science to therapeutic impact Daniel J. Drucker Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Over several decades, the JCI has published key advances in our understanding of glucagon-like peptide 1 (GLP-1) biology. The first incretin peptide characterized in the 1970s, glucose-dependent insulinotropic polypeptide (GIP), was isolated from porcine gastric extracts. Subsequently, the sequence of GLP-1 was identified following the cloning of the glucagon cDNAs and genes, soon followed by the demonstration that GLP-1 potentiated glucose-dependent insulin secretion in cells, animals, and humans. The findings that the acute insulinotropic actions of GLP-1, but not GIP, were relatively preserved in people with type 2 diabetes (T2D) focused greater attention on the therapeutic potential of GLP-1, ultimately supporting multiple clinical development programs for GLP-1 receptor (GLP-1R) agonists (GLP-1RA). Physiologically, the essential roles of incretin receptors for glucose homeostasis have been demonstrated in single and double incretin receptor knockout mice. Glp1r^-/- mice, and to a greater extent, Glp1r^-/-:Gipr^-/- mice, exhibit defective glucose-stimulated insulin secretion, subnormal upregulation of insulin gene expression in response to high-fat diet (HFD) feeding, and impaired glucose tolerance. In contrast, Gipr^-/- mice exhibit greater resistance to diet-induced obesity. The physiological importance of GLP-1R signaling has also been revealed in humans treated with GLP-1 receptor agonists such as exendin(9-39). Among the holy grails of human islet research is the identification of methods to safely and effectively stimulate replication of human islet β cells. Dai and colleagues studied the uncoupling of GLP-1 responses linked to cell proliferation from those that potentiate glucose-dependent insulin secretion in juvenile versus adult human islets. Exendin-4 stimulated glucose-dependent insulin secretion in both juvenile and older adult human islets. However, examination of the proliferative response identified age-associated impairments in components of the calcineurin/NFAT signaling pathway that were responsive to exendin-4 in juvenile, but not in adult, human islets. As GIP and GLP-1 exert their actions through structurally similar G protein coupled receptors, the differential mechanisms underlying preserved GLP-1, but not GIP, insulin stimulatory responses in diabetic β cells have remained enigmatic. Oduori and colleagues probed this anomaly in studies of mice and both murine and human islets exposed to hyperglycemia, and determined that a Gs/GqThe GLP-1 journey: from discovery science to therapeutic impact Daniel J. Drucker Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Over several decades, the JCI has published key advances in our understanding of glucagon-like peptide 1 (GLP-1) biology. The first incretin peptide characterized in the 1970s, glucose-dependent insulinotropic polypeptide (GIP), was isolated from porcine gastric extracts. Subsequently, the sequence of GLP-1 was identified following the cloning of the glucagon cDNAs and genes, soon followed by the demonstration that GLP-1 potentiated glucose-dependent insulin secretion in cells, animals, and humans. The findings that the acute insulinotropic actions of GLP-1, but not GIP, were relatively preserved in people with type 2 diabetes (T2D) focused greater attention on the therapeutic potential of GLP-1, ultimately supporting multiple clinical development programs for GLP-1 receptor (GLP-1R) agonists (GLP-1RA). Physiologically, the essential roles of incretin receptors for glucose homeostasis have been demonstrated in single and double incretin receptor knockout mice. Glp1r^-/- mice, and to a greater extent, Glp1r^-/-:Gipr^-/- mice, exhibit defective glucose-stimulated insulin secretion, subnormal upregulation of insulin gene expression in response to high-fat diet (HFD) feeding, and impaired glucose tolerance. In contrast, Gipr^-/- mice exhibit greater resistance to diet-induced obesity. The physiological importance of GLP-1R signaling has also been revealed in humans treated with GLP-1 receptor agonists such as exendin(9-39). Among the holy grails of human islet research is the identification of methods to safely and effectively stimulate replication of human islet β cells. Dai and colleagues studied the uncoupling of GLP-1 responses linked to cell proliferation from those that potentiate glucose-dependent insulin secretion in juvenile versus adult human islets. Exendin-4 stimulated glucose-dependent insulin secretion in both juvenile and older adult human islets. However, examination of the proliferative response identified age-associated impairments in components of the calcineurin/NFAT signaling pathway that were responsive to exendin-4 in juvenile, but not in adult, human islets. As GIP and GLP-1 exert their actions through structurally similar G protein coupled receptors, the differential mechanisms underlying preserved GLP-1, but not GIP, insulin stimulatory responses in diabetic β cells have remained enigmatic. Oduori and colleagues probed this anomaly in studies of mice and both murine and human islets exposed to hyperglycemia, and determined that a Gs/Gq