GLP-1 Peptides: Natural Regulators of Metabolism and Appetite

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid incretin hormone primarily produced by L-cells in the ileum, with minor contributions from brain neurons and other intestinal sites. GLP-1 promotes insulin secretion, slows gastric emptying, suppresses glucagon, regulates appetite, and supports metabolic homeostasis, cognitive function, and neurogenesis (1,2).

Key Forms of GLP-1

Postprandial processing of proglucagon yields:

• GLP-1(7–36)amide: Predominant bioactive form (~80% of circulating GLP-1), highly insulinotropic (3).
• GLP-1(7–37): Minor glycine-extended form (~20%), equipotent (3).
• GLP-1(1–37): Full-length precursor with reduced potency (4).

These forms are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) (3).

Role in Metabolic Health

In type 2 diabetes, obesity, and chronic inflammation, GLP-1 secretion is impaired, exacerbating insulin resistance and hyperglycemia, which link to cardiovascular disease and other comorbidities (1). GLP-1 acts glucose-dependently on pancreatic beta cells while activating the ileal brake to enhance satiety via co-released peptide YY (PYY) (5).

L Cells and Ileal Brake

Ileal L-cells sense nutrients (glucose via ATP, fatty acids/proteins via calcium influx), short-chain fatty acids, and metabolites to release GLP-1 and PYY (5,6). Glucose catabolism depolarizes cells, promoting calcium-dependent exocytosis; GIP potentiates this via enteric acetylcholine in rodents (7). Receptors for insulin, leptin, and GIP modulate output (6).

Diet’s Impact on Ileal GLP-1/PYY

High-fiber, plant-based diets increase ileal nutrient delivery (e.g., stachyose, amino acids), boosting PYY release independently of food structure (whole vs. blended smoothies) (8). Fiber is key, enhancing L-cell stimulation without structural dependence (8).

Broader Effects

GLP-1 supports redox balance, autophagy, inflammation reduction, lipid metabolism, and cardiovascular health, coordinating glucose control, energy balance, and microbiome-influenced flexibility (1,6).

References

1. Holst JJ. Incretin hormones and the satiation signal. Int J Obes (Lond). 2013;37(9):1161-1168.
2. Müller TD, et al. GLP-1 receptor agonists: Beyond glycemic control. Nat Rev Endocrinol. 2023;19(4):207-222.
3. Deacon CF. Physiology of the incretin hormones. Rev Diabet Stud. 2004;1(1):18-28.
4. Orskov C, et al. Production and secretion of proglucagon-derived peptides. J Biol Chem. 1994;269(20):16326-16332.
5. Maljaars PW, et al. Ileal brake: A feedback mechanism of the small intestine. World J Gastroenterol. 2008;14(6):909-917.
6. Gribble FM, Reimann F. Enteroendocrine L cells sense nutrients. Annu Rev Physiol. 2022;84:487-509.
7. Rochman NM, et al. GIP potentiates GLP-1 secretion via vagal afferents. Biochem Biophys Res Commun. 2002;297(4):1011-1014.
8. Lockie J, et al. Diet shapes metabolite profile in intact human ileum, affecting PYY release. Gut. 2024;73(12):1987-1996. doi:10.1136/gutjnl-2024-332345.