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Discovery, characterization, and clinical development of the glucagon-like peptides
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The discovery, characterization, and clinical development of glucagon-like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.
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“Circulating levels of GLP-1 are low in the fasting or inter-prandial state but spike quickly following oral nutrient loads, thus stimulating insulin secretion from the pancreatic β-cells, inhibiting glucagon secretion from the α-cells and slowing gastric emptying, thereby reducing hyperglycemia in T2D (Figure 1).13,14”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [13]
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Drucker, D. J. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3449 · Cited by 63
Self-citationHoist, J. J. (2009) · Digestion · doi:10.1159/000198107 · Cited by 55
Drucker, D. J., Lee, Y. C., Asa, S. L., & Brubaker, P. L. (1992) · Molecular Endocrinology · doi:10.1210/mend.6.12.1491697 · Cited by 43
Self-citationHow glucagon-like is glucagon-like peptide-1?
Ghiglione, M., UTTENTHAL, L. O., George, S. K., & Bloom, S. R. (1984) · Diabetologia · doi:10.1007/bf00276976 · Cited by 42
Philippé, J., Drucker, D. J., Knepel, W., et al. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.11.4877-4888.1988 · Cited by 41
Self-citationInhibition of pancreatic proglucagon gene expression in mice bearing subcutaneous endocrine tumors
Ehrlich, P. F., Tucker, D., Asa, S. L., BRUBAKER, P. L., & Drucker, D. J. (1994) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1994.267.5.e662 · Cited by 26
Self-citationThe major proglucagon fragment: An abundant islet protein and secretory product
Patzelt, C., & Schug, G. (1981) · FEBS Letters · doi:10.1016/0014-5793(81)80772-7 · Cited by 24
GUT GLUCAGON AND REACTIVE HYPOGLYCÆMIA
Holst, J. J., Hedïng, L. G., & Rehfeld, J. F. (1973) · The Lancet · doi:10.1016/s0140-6736(73)91659-0 · Cited by 3
Self-citation
Flagged first, then by citations
4 of the 105 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1
Drucker, D. J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.001 · Cited by 2,170
“…potentiate glucose-dependent insulin secretion and inhibit glucagon secretion in islet cells while minimizing hypoglycemia supported the development of multiple structurally distinct GLP-1R agonists for the treatment of T2D (Drucker et al., 2017; Drucker and Nauck, 2006; Ussher and Drucker, 2014).”
BackgroundInfluentialSelf-citationTan, Y., Zhang, Z., Zheng, C., Wintergerst, K. A., Keller, B. B., & Cai, L. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-0339-2 · Cited by 862
Advances in oral peptide therapeutics
Drucker, D. J. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0053-0 · Cited by 686
Self-citationGLP-1 physiology informs the pharmacotherapy of obesity
Drucker, D. J. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101351 · Cited by 510
“Overall, the bench to bedside GLP-1 story [131] illuminates the importance of how understanding mechanisms of peptide hormone action enabled the development of multiple new classes of therapies for people living with metabolic disorders, providing new effective options for individuals with obesity.”
BackgroundSelf-citationThe cell biology of systemic insulin function
Tokarz, V. L., MacDonald, P. E., & Klip, A. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201802095 · Cited by 471
“HID-1 is required for homotypic fusion of immature secretory granules during maturation. eLife.”
Background
Metadata
- Authors
- Drucker, D. J., Habener, J. F., & Holst, J. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Harvard University (US)
- University of Copenhagen (DK)
- Corresponding author
- Drucker, Daniel J.
- Venue
- Journal of Clinical Investigation
- Published
- 2017-12-01
- Volume
- 127
- Issue
- 12
- Pages
- 4217-4227
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5707151
- OpenAlex
- W2772059359
- Cited by
- 418
- References
- 105
- Citations by year
- 2026: 46 · 2025: 62 · 2024: 58 · 2023: 41 · 2022: 52 · 2021: 49 · 2020: 38 · 2019: 42 · 2018: 29
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Funders
- Canada Research Chairs, Canadian Institutes for Health Research (MOP123391)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- glucagon-like peptide-1, glucagon-like peptide-2, enteroendocrine hormones, insulin secretion, glucoregulation, intestinal mucosal growth, short bowel syndrome
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Diabetes Mellitus, Type 2, Humans, Short Bowel Syndrome, Structure-Activity Relationship, Glucagon-Like Peptide 1, Glucagon-Like Peptide 2, Drug Discovery
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