Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice
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The importance of pancreatic versus intestinal-derived GLP-1 for glucose homeostasis is controversial. We detected active GLP-1 in the mouse and human pancreas, albeit at extremely low levels relative to glucagon. Accordingly, to elucidate the metabolic importance of intestinal proglucagon-derived peptides (PGDPs), we generated mice with reduction of Gcg expression within the distal (Gcg DistalGut-/-) or entire (Gcg Gut-/-) gut. Substantial reduction of gut Gcg expression markedly reduced circulating levels of GLP-1, and impaired glucose homeostasis, associated with increased levels of GIP, and accelerated gastric emptying. Gcg DistalGut-/- mice similarly exhibited lower circulating GLP-1 and impaired oral glucose tolerance. Nevertheless, plasma levels of insulin remained normal following glucose administration in the absence of gut-derived GLP-1. Collectively, our findings identify the essential importance of gut-derived PGDPs for maintaining levels of circulating GLP-1, control of gastric emptying, and glucose homeostasis.
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The intestine is a primary site of endogenous GLP-1 production and likely responds to high local GLP-1 signaling in a paracrine manner, acting as both a sensor and a modulator of intestinal inflammation.
“The intestine is a primary site of endogenous GLP-1 production (81), and likely responds to high local GLP-1 signaling in a paracrine manner, acting as both a sensor and a modulator of intestinal inflammation.”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [81]
Mechanistic studies in rodents manipulating endogenous peripheral GLP-1 signaling show conflicting evidence, with reports of impaired glucose handling but no effect on cumulative food intake or body weight following deletion of the glucagon gene from L-cells.
“However, there is conflicting evidence from mechanistic studies manipulating endogenous peripheral GLP-1 signaling in rodents, with reports of impaired glucose handling, but no effect on cumulative food intake or body weight, following deletion of the glucagon gene from L-cells (28, 29).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [29]
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- Authors
- Song, Y., Koehler, J. A., Baggio, L. L., Powers, A. C., Sandoval, D. A., & Drucker, D. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Vanderbilt University (US)
- University of Michigan (US)
- Corresponding author
- Drucker, Daniel J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 30
- Issue
- 5
- Pages
- 976-986.e3
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC8140521
- OpenAlex
- W2972217240
- Cited by
- 140
- References
- 47
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 28 · 2023: 15 · 2022: 22 · 2021: 22 · 2020: 19 · 2019: 2
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (154321)
- Banting and Best Diabetes Centre, University of Toronto
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- proglucagon-derived peptides, glucagon-like peptide-1, glucose homeostasis, glucagon, glucose-dependent insulinotropic polypeptide, gastric emptying, oral glucose tolerance, insulin, intestinal endocrine cells
- MeSH terms
- Gastrointestinal Microbiome, Animals, Glucose, Homeostasis, Humans, Insulin, Peptides, Mice, Proglucagon
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