The Endocrines - Part 2

The Endocrines - Part 2: The Pancreatic-Enteroendocrine Axis

I will never be able to do this system justice. Our talk today could become dizzyingly difficult, and that would serve no one. This piece could also be called the Gut-Brain axis once we start discussing the enteroendocrine cells (EECs). Truly, I can’t express enough gratitude to you, the audience, for allowing me to try and convey the excitement that comes from my pursuit to help you comprehend the beauty of this system.

Adding to and refining our definitions from last week:

The Endocrines! Navigating Hormonal Balance Through The Eras

Endocrine: Refers to tissue that makes and releases hormones that travel in the bloodstream and control the actions of other cells or organs. There are polypeptide, peptide, and steroid hormones. Hormones previously called protein hormones are more appropriately called polypeptides.

Exocrine: A gland that makes substances such as sweat, tears, saliva, milk, bile, and digestive enzymes, and releases them through a duct or opening to a body surface.

Paracrine: Paracrine signaling is a type of cell communication where a cell releases signaling molecules (ligands) that affect nearby cells, but not the cell that released them. These signals travel a short distance and can trigger changes in the behavior of neighboring target cells, often coordinating local tissue activities or promoting coordinated responses.

Autocrine: a type of cell-to-cell communication where a cell releases signaling molecules that bind to receptors on its own surface, effectively signaling itself. This process allows a cell to regulate its own activity, influencing functions like growth, differentiation, and immune responses.

All of these signaling methods are involved in our current discussion. The beauty of EECs is that they also are electrically active (can “fire” on their own). As well they communicate with the nervous system, primarily through the Vagus Nerve (Cranial Nerve X), by both paracrine secretion and as Neuropod Cells with direct synaptic connections to the nervous system producing neuropeptides. This radically challenges us to rethink that which is endocrine and that which is neurologic! The EECs also talk directly to the intestinal lumen, “tasting our food” while also communicating with the 58 trillion cells we have there (compared to our own 50 trillion cells!).

This image comes from “Enteroendocrine cell regulation of the gut-brain axis”  This is an elegant article from Frontiers in Neuroscience 11/2023; to understand this you will need a good background in physiology. From this article:

• Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium.
• Our viscera are in constant conversation with our peripheral and central nervous system, a continuous two-way surveillance termed “interoception” (Maniscalco and Rinaman, 2018). This perception of our internal functions, while mostly unconscious, manifests itself in our behavior: influencing mood, activity level, and motivation (Büttiker et al., 2021). The concept of interoception has been discussed academically for over a century, notably championed by physiologist Carl Lange and psychologist William James, who wrote in Principles of Psychology (James, 1918):
• “If our hypothesis is true, it makes us realize more deeply than ever how much our mental life is knit up with our corporeal frame, in the strictest sense of the term. Rapture, love, ambition, indignation, and pride, considered as feelings, are fruits of the same soil with the grossest bodily sensations of pleasure and pain.”

I left these paragraphs intact as they beautifully represent medicine in a day where we didn’t live in reductionism. The importance of “you” exchanging information with our microbiome, food quality, and the parasympathetic system whereby we monitor the 32 square meters of contact with the “outside world” profoundly impacts all aspects of our lives.

Most of you know that 90% of serotonin is produced in the intestine by EECs known as enterochromaffin cells. At least 50% of lymphatic activity revolves around activity in the GI tract. This is why we always say “heal the gut first”, no matter what the disorder.

Gary, you haven’t even started talking about the pancreas yet!

This beauty of an article, “Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status”  published in Nature, Signal Transduction and Targeted Therapy, Feb 2025, challenges everyone to rethink what they consider to be pancreatic exocrine vs endocrine function. It is not a light read, but well worth it.

Pancreatic hormones:

Insulin: this beautiful polypeptide hormone, a linking of the 21 amino acid Alpha chain with the 30 amino acid Beta chain by two disulfide bonds secreted from the Beta cell in response to rising blood glucose. Signaling pathways with Insulin Receptors can not be understood without also understanding the polypeptide hormones Insulin-like Growth Factors 1 and 2 (IGF) produced by the liver and their Receptors, IGFR1 and IGFR2. The IGF family represents the primary mediator and feedback role with Growth Hormone(GH) regulation. These hormones and receptors play roles in inflammation, growth, cell repair, and function far past glucose metabolism.

Glucagon: Produced by the pancreatic alpha cell in response to hunger and dropping glucose levels to raise glucose levels. This hormone plays an important role also in amino acid and lipid metabolism

Somatostatin (SST): Produced by the pancreatic delta cell it inhibits insulin and glucagon release from the pancreas as well as gastrin from the stomach. The secretion of SST in response to rising glucose inhibits the entire anterior pituitary including GH, Thyroid Stimulating Hormone (TSH), Adrenocorticotropic Hormone (ACTH), Luteinizing Hormone (LJ), and Prolactin (PRL). Hopefully you are seeing the broad, profoundly negative influence of recurrent blood sugar swings related to carbohydrates and stress.

Other hormones such as Pancreatic Polypeptide (PP), Secretin, Cholecystokinin (CCK - produced in the duodenum) affect both pancreatic endocrine and exocrine (digestive enzymes) through both endocrine and paracrine mechanisms.

Let’s conclude here. The pancreatic-enteroendocrine axis must be balanced for us to ever balance the other endocrines, adrenal, thyroid, and gonads. Having some knowledge of how cool and complex the system is helps you understand why your doctor often can’t help you. Isolating one hormone, or hormone blocker so that you can do “real science” can’t work.

The way you access this symphony of hormones is through joy, laughter, the consumption of real foods, exercise and meditation. Don’t try to find answers in drugs as they will create chronic disease if taken chronically. Of course, the short term use of medicines can help restore balance, allowing you to self-regulate once the discomfort/disease has been improved.

Your Journey to Health and Healing,

Gary E. Foresman, MD