What Is GLP-1

GLP-1 (glucagon-like peptide – 1) is a hormone that is produced in the gut, brain, and tastebuds when you eat. It is almost immediately de-activated by an enzyme produced nearby called DPP-IV (dipeptidyl peptidase IV).

GLP-1 signals locally as a paracrine hormone, distally as an endocrine hormone, and (probably most significantly) synaptically as part of the intestinofugal system that transmits signals to the brain from the gut.

What Does GLP-1 Do

When you eat food, GLP-1 is immediately produced by the tastebuds in the mouth. The whole intestine has tastebuds called epitellium that continue tasting the food and producing GLP-1 as the food continues on its pathway. By the time food reaches the distal ileum and proximal colon the biggest burst of GLP-1 is released.

GLP-1 goes to the pancreas and stimulates insulin secretion so fuel can get into cells. GLP-1 also inhibits glucagon secretion in the pancreas so the liver won’t convert stored fuel to active fuel. While this is happening GLP-1 relaxes the stomach and makes the pyloris tight so food can’t get out of the stomach easily. Then GLP-1 slows the migrating motor complex (MMC) so peristalsis is decreased and it takes food a long time to move through the intestines. GLP-1 also activates the intestinofugal part of the nervous system in the gut that sends signals up to the brain so the brain tells you that you are full and that more food would be disgusting to eat. The intestinofugal system largely communicates via the sympathetic nervous system.

GLP-1 also makes the heart beat faster, makes the blood vessels more dilated, makes you pee more, and turns on the part of the immune system that is anti-inflammatory and promotes wound healing.

In The Wisdom of the Body

Where there is GLP-1 production, there is also DPP-IV production to ensure a short half-life. Even if we don’t understand why this is important, in natural medicine we want to honor that wisdom.

What Influences GLP-1 Production

GLP-1 production is increased by eating food. Sweet foods, fatty foods, bitter foods, and some proteins increase GLP-1 production.

GLP-1 production is also increased by some inflammatory health conditions like terminal ileal Crohn’s disease, ulcerative colitis, and diverticulitis.

Interestingly, GLP-1 production is decreased in other inflammatory health conditions like obesity, diabetes, and PCOS.

What’s the Difference between GLP-1 Produced by the Body and GLP-1 Receptor Agonists Like Ozempic

GLP-1 Receptor Agonists like Ozempic, Wegovy, Semaglutide and others have certain amino acids removed so DPP-IV cannot deactivate them. This means the drug will stay active during the whole time it is in your body; for a week or a day. That means the effects of GLP-1 will be persistent, whether they are on the heart, the kidney, the pancreas, the liver, the nervous system, or the immune system.

GLP-1 Receptor Agonists and Weight Loss

Some people lose weight on GLP-1 Receptor Agonists. Most of the lost weight is within the first 3-6 months of use, and the average loss for diabetics is .66 lb to 14 lb PMID: 3413773

Hemoglobin A1c is a blood marker for diabetes and inflammation. Across trials a decrease of 0.8-1.8% is reported PMID: 34137731 PMID: 34305810

Adverse Effects of GLP-1 Receptor Agonists like Semaglutide, Ozempic, and Wegovy

What Happens When You Stop Taking GLP-1 Receptor Agonists Like Semaglutide, Ozempic, Wegovy

One year after going off GLP-1 Receptor Agonists 2/3 of people return to prior weight and cardiometabolic function. This is true for placebo group, too.

Why Don’t People Maintain Weight Loss and Cardiometabolic Benefits after Stopping GLP-1 Receptor Agonists

Research suggests people do not maintain positive changes after cessation of the drug because

  • Hormones change in response to weight reduction making them more sensitive to increased calories
  • Central nervous system becomes incompetent at regulating weight without continual GLP-1 input
  • Pancreatic beta cells malfunction due to sustained exposure to GLP-1 receptor agonists
  • The microbiome is altered due to GLP-1 receptor agonists
  • PMID: 38765635

Could the Key to Permanent Weight Loss Be In the Immune System?

I am fascinated by the paradox that GLP-1 is an anti-inflammatory hormone,  and is high in some inflammatory conditions in the gut, but is low in other inflammatory conditions like obesity and diabetes. Why is this? I was not able to find direct research on this question, so I will propose one possible reason that lies in the nature of macrophages.

GLP-1 is part of the innate immune system. The innate immune system is the first line of defense and includes the barrier systems of the body like the skin, lining of the gut and brain and lungs. It also includes chemicals like enzymes, mucus, and acid. And finally it includes macrophages, neutrophils, and natural killer cells. When macrophages act as part of the innate immune system they phagocytize (i.e. eat up) bacteria and viruses that invade the body.

Polarization of Macrophages to M1 and M2

Macrophages are very intelligent. They are able to read the environment and know what is needed for protection, healing, and optimization. Once they read the environment they are polarized and changed into either M1 or M2. These are part of the adaptive immune system that has tailored responses to specific aspects of the immune environment.

M2 Macrophages are associated with GLP-1, Terminal Ileal Crohn’s Disease, Ulcerative Colitis, Diverticulitis

M2 macrophages are known as the pro-resolution, or anti-inflammatory, macrophages. They promote

  • Vascular endothelial growth factor (VEGF)
  • Transforming growth factor (TGF)-beta 1
  • Modulation of reactive oxygen species (ROS)
  • Iron homeostasis
  • Tumor growth

M2 macrophages are polarized via glutamine–UDP-N-acetylglucosamine pathway and α-ketoglutarate produced via glutaminolysis

This means M2 macrophages use fatty acid oxidation and oxidative phosphorylation for slow energy production. PMID: 31998297

M1 Macrophages are associated with Obesity, Diabetes, and PCOS

M1 macrophages are known as pro-inflammatory. They promote

  • Proinflammatory cytokines
  • Gobbling up microbes
  • Immune response
  • Production of nitric oxide
  • Production of reactive oxygen intermediates (ROI)

M1 macrophages are polarized via succinate synthesized via glutamine-dependent anerplerosis or the γ-aminobutyric acid shunt

This means M1 uses glycolysis for fast energy production. PMID: 31998297

A Dutch study suggests that lower GLP-1 production precedes a diagnosis of diabetes or obesity PubMed: 25677912

And basic science research suggests that an alteration in glutamine metabolism shifts persons into an M1 polarization, which is the type of macrophage polarization found in obesity or diabetes PMID: 30753258

Why Would Chronic Conditions Like Diabetes and Obesity Use the Acute Macrophage M1?

Glutamine Pathway, Environmental Toxins, and Inflammation

The glutamine pathway is down-regulated by environmental toxins. This pushes polarization of macrophages down the M1 pathway that is associated with obesity and diabetes and low GLP-1 production. PMID: 37586651

Recall that M2 macrophages (anti-inflammatory, pro-resolution) use fatty acid oxidation to activate.

What Inhibits Fatty Acid Oxidation (and thus prevents activation of M2 macrophages)

What if the Problems Is Not That You Are Pigging Out Because You Are Low on GLP-1

***

What if the Problem Is That You Are Low on GLP-1 Because of the Environment in Which We Live Has Created an Internal Inflammatory State That Cannot Produce Adequate GLP-1

Fortunately, Mosaic Lab has a test to determine if you have an overload of environmental toxins that could be pushing you into an M1 inflammatory state that is related to low GLP-1 production and the development of obesity and diabetes. That test is called EnviroTOX Complete + Metals.

If you are loaded with environmental toxins, a good idea is to detox first before trying any GLP-1 receptor agonist like Semaglutide, Ozempic, or Wegovy.

Once you have detoxed, the next step is to re-activate GLP-1 production in your body using natural means.

How To Increase GLP-1 Production Naturally

Many herbs increase the production of GLP-1 like

The amino acid glycine supports secretion of GLP-1 PMID: 37510995

Short Chain Fatty Acids are bacterial metabolites that come from foods such as whole grains, legumes, vegetables, nuts, seeds, and mushrooms. These metabolites stimulate GLP-1 secretion PMID: 38055342 PMID: 30862015

The prebiotic oligofructose increases GLP-1. It is found in foods like dandelion greens, broccoli, kale, cabbage,onions, garlic, legumes, and rye.

Secondary bile acids increase GLP-1. They are formed when primary bile acids (produced in the liver from cholesterol) are broken down in the colon by the microbiome PMID: 38055342 PMID: 30862015

GLP-1 is increased by cruciferous vegetables like kale, bok choy, and turnips (which all have indole), and also is increased by foods high in 2-oleoyl glycerol including sunflower lecithin, olive oil, and cacao butter PMID: 38055342 PMID: 34048925

Bitter foods increase GLP-1 production, as do sweet and umami flavors PMID: 34674725

Brown Adipose Tissue & GLP-1

GLP-1 and brown adipose tissue (BAT) have a special relationship. GLP-1 activates brown adipose tissue. In turn, BAT promotes energy expenditure, suppresses weight-gain, and protects against hyperglycemia and insulin resistance PMID: 29601492

You can promote beiging or browning of white adipose tissue by doing the following

  • Cold exposure like cold plunge or sleep in a cool room
  • Regular physical exercise
  • Eat foods high in ursolic acid like cranberries, apple peels, papaya, prunes, peppermint, rosemary, oregano, and thyme
  • Eat spices like chili peppers and turmeric
  • Drink green tea and take fish oil PMID: 26050667 PMID: 32373072

Unknowns About GLP-1 Receptor Agonists like Semaglutide, Ozempic, Wegovy

  • How will long-term use affect metabolic status?
  • How will microglia respond to persistent priming by GLP-1RA?
  • What is the long-term effect of continual stimulation of the sympatho-gastro-spinal-reticular-hypothalamic pathway?
  • How will long-term stimulation of M2 macrophages affect cancer development?

Conclusion

  • Little long-term information exists about GLP-1RA
  • GLP-1RA works differently from the body’s design
  • Benefits of being on GLP-1RA are lost soon after cessation, and other problems due to GLP-1RA are retained
  • There are alternative ways to support the body’s natural design by working with foods, the environment, and behavioral patterns
  • Environmental toxins could be playing a role in polarizing macrophages to inflammatory M1 which is associated with low GLP-1, diabetes, and obesity