Optimize GLP-1 naturally
GLP-1 receptor agonist drugs have become so popular that Super Bowl LIX featured an ad for them. Practitioners today are likely to have patients taking these drugs or strongly interested in starting. These drugs are very expensive, are needed for a lifetime to maintain their effects and have other significant drawbacks. Nondrug approaches that enhance the natural production of GLP-1 are preferred, including natural methods, such as stimulation supplements and probiotics, as well as dietary changes and regular exercise, that offer promising, sustainable drug alternatives with fewer risks and costs.
What are GLP-1 drugs?
GLP-1 receptor agonists, such as semaglutide (Wegovy, Ozempic), are synthetic peptide drugs that mimic the hormone glucagon-like peptide-1 in the body. These drugs bind to GLP-1 receptors in the pancreas, brain, liver, kidneys and muscles. They trigger insulin release from the pancreas, delay gastric emptying and help with appetite reduction and increased satiety.
Side effects and drawbacks
While GLP-1 drugs are highly effective in improving blood sugar and triggering rapid weight loss, they have some significant drawbacks. Most importantly, stopping the drug stops the benefits, and almost all patients regain most or all of the lost weight. For many, the drugs cause unpleasant side effects, including nausea, vomiting, diarrhea and severe appetite loss.
The most worrisome effect of GLP-1 drugs is approximately 40% of the rapid weight loss comes from lean muscle mass.1 Although the studies vary considerably in the amount lost, any significant muscle loss is concerning, particularly in older adults. For them, stopping the drug and regaining the lost weight could lead to sarcopenic obesity—a high body fat percentage combined with sarcopenia, defined as low skeletal muscle mass accompanied by low muscle function.2 Sarcopenic obesity is associated with functional impairment, physical disability and frailty in older adults. Retaining muscle mass is the currency of longevity.
In addition to shrinking skeletal muscles, GLP-1 drugs may be associated with shrinking the heart. In a recent study, obese and normal-weight mice treated with semaglutide showed decreases in overall heart mass and the individual size of their heart muscle cells. Human heart cells showed a similar response, suggesting long-term use of GLP-1 drugs could cause cardiac damage.3
Despite the salutary effects of the GLP-1 drugs, most patients don’t stay on them for a long duration of time—more than 53% of adults who are prescribed a GLP-1 drug discontinued use within six months. At the one-year juncture, 68% have stopped using the drug. Unpleasant side effects are the most common reason for stopping.4
Another significant drawback to these drugs is their price, which can run well over $1,400 a month—a cost often not covered by health insurance. The cost of GLP-1 drugs outside the US is significantly less: $155 in Canada, $59 in Germany and $92 in the UK. Novo Nordisk, the manufacturer of Wegovy, could distribute the drug for $40 a month and still earn a 10% profit.5
Going deeper
GLP-1 is a hormone produced in the intestinal tract, primarily in the ileum (the distal end of the small intestine) and the colon by enteroendocrine L cells.6 The L cells play a key role in regulating appetite and blood sugar levels by sensing nutrients in the gut. They signal to the brain that food is present. Smaller amounts of GLP-1 are produced in the brainstem and by alpha cells in the pancreas. While GLP-1 is released in response to these triggers, it stimulates insulin release only when blood glucose levels are elevated.7
GLP-1 release triggers
Many factors trigger the release of GLP-1 by the L cells.
The primary trigger is the presence of nutrients from eating. The L cells respond to carbohydrates, lipids and amino acids in the gut. A high-protein, high-fiber meal with monounsaturated or omega-3 fatty acids is particularly effective in triggering GLP-1 release.
The hormones insulin and leptin also trigger the L cells. Insulin resistance can impair GLP-1 release.
Other triggers for GLP-1 release include physical activity and vagal nerve stimulation.
In the gut, GLP-1 is released in two waves. The early first release happens 15 to 30 minutes after eating. Another wave is released 90 to 120 minutes after eating. This wave occurs when digested nutrients stimulate the L cells. GLP-1 in the bloodstream increases two to three times after eating. The peptide has a very short half-life of only about two minutes before enzymes degrade it.
GLP-1 and the gut
In the colon, L cells release GLP-1 in response to microbial metabolites. Secondary bile acids, short-chain fatty acids and polysaccharides within the gut microbiota can trigger GLP-1 secretion.8 Some bacteria also produce metabolites, such as tryptophan and indole, that stimulate GLP-1 secretion.
The short-chain fatty acid (SCFA) butyric acid, produced when bacteria in the gut microbiome digest fiber and complex sugars, is particularly important for stimulating GLP-1 release. Butyric acid is essential for colon health in other ways: It helps maintain the integrity of the intestinal lining, reduces inflammation, provides about 70% of the energy for colon cells and regulates their growth. People with type 2 diabetes often have low amounts of butyric acid-producing bacteria in their gut.9
Current evidence suggests GLP-1 agonists may modulate the gut microbiome and vice versa.10 We know people with obesity have less diversity in their gut microbiome than people of normal weight. They have lower populations of bacteroidetes and an increased population of firmicutes. Their population of Akkermansia muciniphila is also decreased, and metabolites from this bacterium are known to increase GLP-1 production. This pattern of microbiome changes is linked to not only obesity but also insulin resistance and diabetes. It also impacts intestinal barrier integrity. In other words, the altered microbiome population can reduce SCFA production and contribute to leaky gut syndrome.11 In some patients, gut dysbiosis may be why they don’t produce enough GLP-1 naturally. This could also explain why they have stopped responding to their natural production of GLP-1.
Improving the bacteroidetes to firmicutes ratio and increasing the population of A. muciniphila could increase the natural production of GLP-1 in the gut. In addition, a higher bacteroidetes to firmicutes ratio can improve fiber fermentation in the colon, which increases the amount of butyrate and other SCFAs available to the L cells.12 This increases their release of GLP-1 while also improving gut permeability. Improving the gut microbiome composition may also impact the gut’s internal environment by delaying gastric emptying and changing nutrient availability.
Probiotic supplements that are known to increase bacteroidetes and decrease firmicutes can improve secretion from the L cells by improving butyrate production. Supplements of A. muciniphila could directly stimulate greater secretion from the L cells. Increasing A. muciniphila may also improve leaky gut syndrome because these bacteria help maintain tight junctions in the gut barrier.13
Mitochondrial function and GLP-1
Leaky gut syndrome directly affects the energy-producing mitochondria in cells through inflammation, increased oxidative stress and disruption of the bidirectional communication between the gut microbiome and mitochondria.
When mitochondrial function is impaired, one result is decreased sensitivity to the actions of GLP-1. Activating GLP-1 can positively affect mitochondrial function by enhancing oxygen consumption and increasing ATP production.14 GLP-1 also reduces the production of ROS and oxidative stress, which helps maintain efficient ATP production.
GLP-1 has a beneficial effect on the mitochondria of the insulin-producing beta cells in the pancreas. It increases their mass, improves efficiency, reduces free radical production and prevents apoptosis.15 In the heart, GLP-1 protects cardiomyocytes by improving mitochondrial function and reducing oxidative stress. It can also help prevent ischemic injury following a cardiac event.16
Appetite control
GLP-1 is essential in suppressing appetite and creating a feeling of fullness and satiety in the brain. The peptide probably activates receptors in the brain that are responsible for regulating hunger and reducing cravings.
Another likely reason GLP-1 affects satiety, appetite and cravings is its role along the gut-brain axis. This axis is disrupted in people with obesity, prediabetes and diabetes. While GLP-1 doesn’t seem to cross the blood-brain barrier significantly, it acts on brain regions outside the barrier and relays signals to areas responsible for appetite regulation.17 GLP-1 also acts on the vagus nerve. Vagal sensory neurons have GLP-1 receptors, which allows them to receive signals directly from intestinal L cells. The GLP-1 secreted in the gut increases the activity of vagal afferent nerves. This increases the transmission of signals from the gut to the brain, modulates food intake, improves satiety and slows gastric emptying. The vagus nerve is also involved in GLP-1 signaling to regulate blood sugar levels and insulin secretion. Interestingly, vagal neurons responsive to GLP-1 extend into the brainstem, particularly the nucleus tractus solitarius, an area of the brain important for regulating digestion.
Activate GLP-1 naturally
GLP-1 is released in response to dietary and bacterial metabolite triggers, but its effects on insulin secretion are glucose-dependent. The hormone will only stimulate insulin release when blood glucose levels are elevated, as they are after a meal and most or all of the time in people with prediabetes and diabetes.
The natural production of GLP-1 can be increased in the gut through dietary changes and supplements.
A high-fiber, plant-forward diet will support GLP-1 production by stimulating release from the L cells in the colon. Specific foods that have been shown to support GLP-1 levels include eggs, tofu, nuts (almonds, pistachios, peanuts), high-fiber grains, avocados, olive oil, fruits (apples, berries, pomegranates) and vegetables (Brussels sprouts, broccoli, carrots).18 Dark chocolate, green tea and coffee (including decaf) may also support GLP-1 production. Foods high in resistant starch (complex carbohydrates that reach the colon largely undigested), such as beans and whole grains, are fermented in the colon and become a good source of SCFAs to stimulate GLP-1 release. Fiber supplements such as psyllium have a similar effect.
The impact on GLP-1 comes from the fiber in these foods and their high polyphenol content, which acts as a prebiotic. Interestingly, cinnamon, a standard treatment for diabetes in traditional Ayurvedic medicine, has been shown to increase GLP-1 production.19 Cinnamon is very high in polyphenols, including procyanidins, catechins, epicatechins and phenolic acids.
Probiotics containing strains of Akkermansia muciniphila, Clostridium butyricum and Bifidobacterium infantis can help alter the bacterial balance in the gut microbiome toward bacteria that stimulate GLP-1 production.
Supplements that support colon health and GLP-1 production include berberine, ginseng, green tea extract, magnesium, glutamine and fish oil.
Exercise is an excellent way to improve the production of GLP-1. Studies show roughly equal increased post-exercise concentrations after high-intensity interval training, sprint interval training and moderate-intensity continuous training. No matter which type of exercise, the increased level effect lasts about 90 minutes.20
Final thoughts
While GLP-1 receptor agonist drugs offer benefits in managing blood sugar and promoting weight loss, their high cost, potential side effects and possibility of long-term dependency make them less than ideal for many individuals. Fortunately, there are natural methods to enhance GLP-1 production, such as stimulation supplements and probiotics, as well as dietary changes and regular exercise, that offer promising, sustainable drug alternatives with fewer risks and costs.
Robert G. Silverman, DC, DACBN, DCBCN, MS, CCN, CNS, CSCS, CIISN, CKTP, CES, HKC, FAKTR, is a doctor of chiropractic, clinical nutritionist, national/international speaker, author of Amazon’s best-sellers “Immune Reboot” and “Inside-Out Health” and founder and CEO of Westchester Integrative Health Center. He graduated magna cum laude from the University of Bridgeport College of Chiropractic and has a master’s degree in human nutrition. The American Chiropractic Association Sports Council named Silverman Sports Chiropractor of the Year in 2015, and he is on the advisory board for Functional Medicine University. A thought leader and seasoned health and wellness speaker, he is frequently published in peer-reviewed journals and other mainstream publications and was the principal investigator in two Level 1 FDA laser studies. For more information, visit drrobertsilverman.com.
References
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