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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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Self-citationNew insights into the treatment of obesity
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“An alternative strategy is the creation of peptide combinations with complementary modes of action such as dual and triple co-agonists, with GLP-1 again emerging as an ideal partner.(121) Tirzepatide and mazdutide fall into this category.”
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“An account of these early developments was published recently (45).”
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“The incretin glucagon-like peptide 1 (Glp1) is produced primarily in intestinal L cells and a population of hindbrain neurons and is released post-prandially to facilitate glucose-dependent insulin secretion via Glp1r activation (Drucker et al., 2017).”
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“Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a kind of incretin analogs that can control blood glucose by increasing glucose-dependent insulin secretion, improving insulin resistance, slowing gastric empting, inhibiting glucagon release, and reducing appetite (1, 2).”
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“However, the same proglucagon gene is processed differently in the intestinal L-cells and neurons, producing GLP-1, GLP-2, and another peptide called glicentin.”
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“Observations in those treated with GLP-1RA subsequently confirmed weight loss in people with T2D, and later obesity (1).”
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“DISCUSSION GLP-1 exerts a broad range of metabolic activities, encompassing control of glycemia, reduction of food intake, and inhibition of gut motility, actions supporting the development of GLP-1R agonists for the treatment of type 2 diabetes and obesity (Drucker et al., 2017; Sandoval and D’Alessio, 2015).”
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“performed a seminal work on the sequencing and characterization of the second incretin hormone, GLP-1 [23].”
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“In animal studies, GLP-1 attenuates hypertension induced by angiotensin II, the main effector hormone of the renin–angiotensin system, by blockade of angiotensin II–induced superoxide formation (120, 121), and enhances glucose-stimulated insulin secretion from pancreatic β cells and inhibits glucagon release from α ce…”
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“This hormone derived from the posttranslational processing of proglucagon was discovered in the early 1980s (for a review of the history of GLP-1 therapeutics, see [40,122]).”
Leveraging the Gut to Treat Metabolic Disease
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“Comparison of the effects of glucagon-like peptide-1-(1-37) and -(7-37) and glucagon on islet hormone release from isolated perfused canine and rat pancreases.”
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“GLP-1 R A have proven to be useful agents for therapy of T2D, reducing University of Toronto, Toronto, ON M6B 3G3, Canada 80301. ber 9, 2022 Available online 14 November 2022 access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).”
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The Human Islet: Mini-Organ With Mega-Impact
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“The finding that native GLP-1 was rapidly cleared by the kidney and highly sensitive to enzymatic inactivation by dipeptidyl peptidase 4 (DPP-4) shifted the focus for clinical development away from native GLP-1 and toward longer-acting degradation-resistant GLP-1 receptor (GLP-1R) agonists (1).”
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What Is an L-Cell and How Do We Study the Secretory Mechanisms of the L-Cell?
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“Therefore, GLP-1 receptor (GLP-1R) targeting strategies are based on the use of either DPP-4 inhibitors to prolong the half-life of the endogenous GLP-1, or on GLP-1 receptor agonists (GLP-1RAs) that are DPP-4 resistant per se and/or become DPP-4 resistant when bound to a larger protein such as albumin (1, 13, 14).”
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“Initially developed to treat diabetes, GLP-1R agonists are a class of medications that augment glucose-dependent secretion of insulin to help with glycemic control and weight loss (102).”
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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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