There’s been a lot of hype about GLP-1 peptides over the past few years due to their measurable success at helping people lose significant weight and reduce the biomarkers related to type-2 diabetes.
This blog is a sneak peek from my new book, The Quantum Power of GLP-1 Peptides.
The body naturally produces glucagon-like peptides, which are made up of 30 amino acids, to aid in the digestion and absorption of the foods we eat, regulate appetite, manage blood sugar levels, and contribute to overall metabolic homeostasis. Considered to be both peptides and hormones, these powerful agents also exert control over cognitive functions, anxiety, and neurogenesis.
Most GLP-1 peptides are produced by the ileum; they are produced in smaller amounts by the intestines and neurons in the brain. GLP-1s are released in response to eating to stimulate insulin secretion, slow digestion, reduce appetite, and make sure blood sugar levels are balanced. Together, these activities comprise the incretin system.
Different forms of GLP-1s are produced in the body:
- GLP-1(7–36)-amide: A truncated form of GLP-1 that is secreted in response to eating
- GLP-1(7–37): A truncated form of GLP-1 that is the biological precursor to GLP-1(7–36)-amide
- GLP-1(1–37): A form of GLP-1 that has a lower insulinotropic efficacy than the truncated forms
As I’ve been discussing in Masterminds, courses, and other SSRP gatherings, people with chronic inflammation along with insulin resistance and/or type 2 diabetes have reduced metabolic functioning – they also suffer from an insufficiency in their incretin system and low levels of GLP-1 peptide production, which in turn triggers difficulty in managing blood sugar levels.
And as we know, type 2 diabetes is closely associated with obesity, heart disease, cancer, and other metabolic disorders that compromise quality of life.
How GLP-1s Work
GLP-1s work on several different molecular pathways, all of which support metabolism and redox homeostasis. Consider the figure below.
Signaling pathways activated by GLP-1 to promote beta cell mass expansion that supports overall cellular metabolism and redox balance
The Role of the Human Ileum in Gut Peptide Release
Before researchers identified GLP-1 receptor agonists and other gut peptides to address type-2 diabetes and weight loss, they were looking at the function of GLP-1 release in the body and its role in managing metabolism. Specifically, researchers discovered that the L cells found in the ileum, the final and longest part of the small intestine, release two important gut peptides: GLP-1 and peptide tyrosine tyrosine (PYY), both of which contribute to satiety and the regulation of appetite and food intake.
It is the job of the L cells to secrete GLP-1s and PYY to stimulate insulin secretion from the pancreatic beta cells, inhibit glucagon release, and slow gastric emptying after a meal; we call this the ileal brake system, and it is at the heart of managing blood sugar, appetite, and metabolic efficiency.
The L cells are stimulated by a range of metabolites, including dietary, microbial, and endogenous molecules to produce short-chain fatty acids (SCFAs). The ileum’s L cells also serve as sensing mechanisms; depending on the nature and degree of nutrients absorbed from food by the ileum, the L cells will release the gut peptides PYY and GLP-1.
Interestingly, in a study published in 2024, researchers examined the dynamic, wide-ranging molecular environment in the intact human ileum and found that when plant-based foods with intact cellular structures are consumed, they can increase the delivery of nutrients to the ileum, which subsequently can lead to an increased release of satiety peptides (in particular, PYY).
Of note, the researchers of this study discovered that the structure of the food sources did not impact the delivery of nutrients or the release of gut peptides. In other words, whether we ingest whole foods or break down our food into a liquid structure (as you’d do in a smoothie, for instance), the positive impact on the ileum and satiety is the same. The key player? Fiber.
A Closer Look at the Role of L Cells
So, why this focus on L cells and the ileum?
Under normal conditions (i.e., in the absence of insulin resistance, type 2 diabetes, or obesity), L cells have special protein and fatty acid receptors that help raise intracellular calcium levels, which in turn promote the release of GLP-1s.
In addition, the binding of fatty acids to specific receptors also raises intracellular calcium levels. The now-elevated calcium levels promote exocytosis of GLP-1–containing vesicles, releasing GLP-1 into the circulation. (Note that proteins also promote GLP-1 release, but the mechanics are not yet fully understood.)
Specifically, in the presence of sodium, L cells promote calcium influx by inducing depolarization; glucose also induces calcium influx by raising adenosine triphosphate (ATP) levels as a result of its catabolism.
L cells have also been shown to express receptors for metabolic hormones, including insulin, leptin, and gastric inhibitory polypeptide (GIP). The degree to which leptin and insulin stimulate overall GLP-1 secretion is still unclear, but GIP-mediated GLP-1 release has been shown to occur in rodents via acetylcholine release by the enteric nervous system. Supraphysiological concentrations of GIP can also activate GIP receptors on L cells, potentially enhancing GLP-1 secretion.
The figure below is a visual depiction of the importance of L cells.
Keep in mind how and why L cells produce GLP-1s
The L cell mechanism related to GLP-1 release underscores the different factors related to metabolic homeostasis. In particular, L cells help coordinate glucose metabolism, appetite regulation, and insulin secretion. Once released, GLP-1 enhances insulin secretion from pancreatic beta cells (in a glucose-dependent manner) and improves postprandial glucose control while suppressing glucagon release to prevent unnecessary glucose production. Additionally, GLP-1 slows gastric emptying, reducing the rate of nutrient absorption and promoting satiety, which helps regulate energy balance and prevent overeating. Beyond these immediate metabolic effects, GLP-1 also influences lipid metabolism, inflammation, and cardiovascular health, contributing to overall metabolic stability.
In Part X, when we dig into the specific GLP-1 RA peptides, keep in mind how the body’s innate GLP-1 release begins as a response to both the foods we eat and the state of our microbiome. In the next section, we will look at how the health of our microbiome can contribute to metabolic flexibility . . . or its degradation.
Taken from The Quantum Power of GLP-1 Peptides.