Hi Everyone! Welcome back to another Friday blog. The recent explosion of Ozempic (semaglutide), Rybelsus, Mounjaro, Wegovy, Trulicity and other GLP-1 (glucagon-like peptide-1) analogs on the market raises so many questions regarding long-term safety, side effects and benefits. These drugs are currently prescribed to treat obesity and T2D (type 2 diabetes) as a weekly injection for life. However, they are also being used off-label for weight-loss - with good results - but at a high cost of muscle loss as well. Some MDs are prescribing these drugs for children to take for the rest of their lives. These drugs can be > $1,000 per month and often insurance doesn't cover. Most of these drugs require a weekly injection. Let's delve in.

These drugs are peptides (linked amino acids) that are a synthetic version of GLP-1 receptor agonists. Okay, so they are trying to mimic what the body naturally does after eating. In the gut, intestinal cells (L-cells) literally "taste" and respond by secreting GLP-1. L-cells in the gut release GLP-1 that activates the GLP-1 receptors on the pancreatic beta cells (that release insulin) as well as send a message via the Vagus nerve to the appetite control center in the hypothalamus in the brain. This sends a message to shut down the hunger hormone and turn on the satiety hormone, leptin. These drugs significantly suppress appetite, but also suppress water intake. This can be a problem leading to dehydration. They significantly slow down digestion - even to the point of digestive paralysis - which contributes to the common side-effects of nausea and vomiting, constipation and/or diarrhea. Another worrisome side-effect is sarcopenia, or loss of skeletal muscle mass, quality and strength. So, you may lose a lot of weight relatively quickly on these drugs - most of that being fat - but a good portion of the weight lost - if you aren't actively working on prevention - is lean body mass (LBM) or muscle - "the proportion of LBM reduction ranged between 20% and 50% of total weight lost." Some studies show 40-60% of total weight loss was from lean body mass. You lose your metabolic lever when you lose muscle. 

This is not unlike muscle loss with bariatric surgery. Loss of muscle affects bone, so osteopenia or osteoporosis follows. Your risk of a fall goes up. To combat this, drug companies are rushing to develop medications to address this problem. Once again, they want to treat the side effect with an additional drug. More $ for them but will bankrupt us. If you are someone who got started on Ozempic but were abruptly taken off due to insurance, the weight gained back is strictly fat - not the muscle you just lost. 

Why not do this differently - change our diet to enhance our body's production of GLP-1 or, if you are severely obese and need a bigger boost to get started, a super tiny dose. Some naturopaths and functional medicine MDs are having success by microdosing in phases or cycles. This allows for a more controlled weight-loss, while resistance-training and modifying their diet and prioritizing protein so they can hang onto their muscle mass. Physicians that are paying attention should be requiring their patients to strength-train while taking GLP-1 drugs.

Most of us can modify what we are eating and begin implementing strategies to increase GLP-1 production naturally. Let's take a closer look at the sequence of events and what is required to produce GLP-1. It is a signaling peptide that is part of a feedback system to regulate hunger and feeding, while enhancing glucose uptake. Roughly 15 min after eating, intestinal L-cells sense nutrients and produce GLP-1, GLP-2 and PYY. These are hormones that help regulate feeding. These hormone levels peak at 40-90 minutes after eating a meal. Intestinal L-cells have taste receptors - similar to those on your tongue - that evoke a response. High levels of glucose shut down production of GLP-1, whereas low millimolar concentrations of glucose can activate release. This would be like eating a piece of fruit, vs a piece of cake. When L-cells taste bitter foods, PYY (peptide tyrosine tyrosine) evokes an aversive response to food, increasing release of GLP-1 and shutting down hunger. GLP-1 has several effects and works with PYY and other hormones to impact nutrient sensing and feeding behavior. 

• Incretin effect - this is blood sugar lowering - GLP-1 binds to a receptor on Pancreatic B-cells. This results in increased intracellular calcium with subsequent exocytosis of insulin.
• Trophic effect - GLP-1 stimulates the proliferation of pancreatic β-cells (that produce insulin), while inhibiting apoptosis (programmed cell death). It upregulates insulin gene transcription and biosynthesis. GLP-1 also exerts a strong inhibition of glucagon secretion by interacting with pancreatic α-cells.
• Vagus nerve impact - GLP-1 binds to afferent vagal nerve fibers which sends a signal to the central hypothalamic nuclei that controls nutrient homeostasis - this slows gastric emptying and decreases nutrient absorption by decreasing intestinal contractions.
• Ileal brake - this braking system is activated by the sensing of unabsorbed dietary nutrient components in the ileum. This triggers a braking in the upper gastrointestinal tract to inhibit gastric acid secretion, decrease intestinal contraction, inhibit motilin by PYY to slow emptying and allow more time for digestion. Chronic exposure (as with GLP-1 agonist drugs) results in rapid tachyphylaxis - this is a rapidly diminishing response to successive doses of a drug, rendering it less effective.
• PYY induces hypophagia (decreased eating), satiety, nausea and even conditioned taste aversion.
• GLP-2 also contributes to satiety and is produced in response to proglucagon. It stimulates gut cell proliferation by increasing expression of IGF-1 (insulin like growth factor-1), inhibits apoptosis, increases blood flow to the intestines to enhance digestion and absorption and improve barrier function. It also slows gastric and intestinal speed and secretions following a meal.

Since the majority of us (93.6%) have some level of metabolic dysfunction and tend toward higher blood glucose and impaired insulin signaling, it makes sense that we are all somewhat GLP-1 - deficient. Why? What is causing this? We know GLP-1 is produced from intestinal L-cells. So, what is damaging our L-cells? Turns out that chronic exposure to inflammatory oils such as palmitate, results in lipotoxicity and is a major contributor to deregulation of L-cells. These intestinal cells rely on postbiotic products like butyrate, made by our gut microbiome. When we poison our microbiome with oxidized inflammatory oils, glyphosate sprayed highly processed foods that they don't recognize, they become sick and make inflammatory products. High glucose concentrations also damage our L-cells. When we eat the SAD (standard American diet) "non-foods" - void of fiber, vitamins, minerals and phytonutrients, sprayed with toxic chemicals like glyphosate - our microbiome and intestinal L-cells become injured, die or become dysfunctional.

Our intestinal cells rely on SCFA (short-chain fatty acids) and some amino acids like L-glutamine as fuel to remain healthy. They are not getting their needs met. We can't produce enough GLP-1. Blood glucose and insulin levels slowly and chronically rise, and insulin-resistance ensues. We march towards obesity and T2D (type 2 diabetes). If we keep going in this direction, the pancreas begins to fail. It can't keep up with insulin demands and we lose pancreatic β-cells. Eventually, we become T1D (type 1 diabetic) and require insulin injections.

So, if we support our L-cells in the gut by feeding our gut microbiome, consuming bitter greens, polyphenols and adequate protein we will increase their number and restore their function, thereby increasing GLP-1 levels. Let's look at strategies to correct L-cell function and stimulate increased production of GLP-1 to help us achieve ideal weight and nutrient uptake. 

• Fiber - prebiotic digestible and indigestible fiber feeds the microbiome and allows healthy populations of butyrate-producers to proliferate in the gut. Indigestible fiber is fermented by gut microbes producing a variety of SCFAs.
• Butyrate - temporarily supplement butyrate until you can grow enough producers
• Fermented and cultured foods - sauerkraut, kimchi, Greek yogurt, etc. provide some prebiotic fibers, probiotics (the live bacteria), as well as postbiotics in the liquid. Drink the sauerkraut liquid to get a good dose of butyrate for your intestinal L-cells.
• Probiotics - you can take a probiotic for a period of time to help restore the balance of your microbiome. The best one I've found is called "Seed" and has been shown to restore the microbiome in 3 months after antibiotic.
• Omit inflammatory oils - seed oils and soybean - these are widely used in restaurants. These damage every cell in the body. It's like putting gunked-up, thick, used oil in your car and expecting it to run well. Take a to-go bottle of HP-EVOO to the restaurant with you and ask for the salad dry. Avoid fried foods - these are all highly oxidized and inflammatory. 
• Eat bitter foods - arugula, kale, stinging nettle, turnip greens, mustard greens, collard greens, endive, watercress and radicchio are bitter greens that stimulate L-cell production of GLP-1 as well as multiple benefits for the liver.
• Allulose - tastes similar to sugar and has a glycemic index of ZERO! You can use in recipes in place of sugar - ex: add allulose to high-sugar fruits like mango, pineapple, peaches to decrease absorption of fructose and blunt the glucose spike. "Our results identify D-allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic D-allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders." 
• Protein - a potent stimulant of GLP-1. Protein is very satiating - a tell-tale sign that you are producing GLP-1. Getting adequate protein can be challenging. The RDA for protein is way low compared to what research is revealing. The current recommendation according to published literature is roughly 1G protein per pound of "ideal" body weight. Women have a harder time getting enough, but most men are not getting enough either. The older you are, the more protein it takes to get the "build muscle" signal to the body. Eat a few bites of high-fiber veggies, then focus on eating all your protein before working on the rest of the plate. You may find you are too full to finish the rest of the food.
• Fat - very satiating. Increases GLP-1
• Berberine - "Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptoms. Berberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell."
• Curcumin - "These findings demonstrate the biological function of curcumin as a GLP-1 secretagogue and the possible molecular target that mediates GLP-1 secretion."
• Bitter Melon – (Momordica charantia) stimulates bitter receptors that stimulate release of GLP-1 and has antidiabetic properties. 4.8G/day
• Yerba Mate – (Ilex paraguariensis) increases levels of GLP-1 as well as suppressing appetite through modulating leptin levels. 1,000mg/day.
• Ginseng – (panax ginseng) increases levels of GLP-1 and exerts antidiabetic effects. Modulates blood glucose levels by improving beta cell function and enhancing insulin sensitivity and increased beta cell proliferation and insulin secretion. Upregulates glucose transporters. Suppresses oxidative stress. Suppresses renal accumulation of AGEs and oxidative stress. 6-8G/day
• Sleep - adequate sleep allows your body to get rid of damaged proteins and cells, clear toxins and make repairs. When we don't get adequate sleep, we tend to crave carbohydrates the next day - our GLP-1 is suppressed.
• Exercise - the more muscle you have, the more insulin-sensitive you become. 
• HP-EVOO (high polyphenol extra virgin olive oil) not only do polyphenols in EVOO stimulate L-cells to secrete GLP-1, but they also inhibit the enzyme (DPP-4) that degrades it, increasing the half-life. Polyphenols in EVOO increase the peripheral response to insulin, improving insulin sensitivity. EVOO helps to heal and improve fluidity of cellular membranes, powerful anti-inflammatory, crucial in restoring the lining of the gut, reversing fatty liver, cardiovascular and all other chronic disease processes, including working epigenetically to suppress cancer genes and much more. 

So, until next time my friends…Drink, Drizzle, Digest HP-EVOO at least 4T raw daily, - use more for cooking and drizzling onto your food - eat the rainbow of organic or wild-sourced or organic veggies (7-9 C) and low-glycemic fruits (to get the rainbow of gut microbes!) - eat wild-caught, pasture-raised, grass-fed - get plenty of sunshine - supplement magnesium, zinc, vitamin D3 + K2 - get your trace minerals and electrolytes with good sea salt - Celtic is hand-harvested and Himalayan was formed before plastics - eat foods high in lutein - drink your body weight in oz of water - get a good pre/probiotic - consume digestible and indigestible fiber for your gut microbes - adaptogens (such as mushrooms) and methylation donors (kale, beets, spinach, cruciferous, lion’s mane…), marjoram, rosemary, oregano, parsley and other herbs to detox, enhance overall health and reverse aging and disease - exercise your body and mind - add a few minutes of mindful meditation and breathing exercises to your day to combat stress - take a hot Epsom salt bath and follow with a cold shower/ice plunge - practice “earthing” as an anti-inflammatory - remove EMF (electromagnetic frequency) devices and blue light - use IR (infrared) from incandescent lighting, non-toxic candle or light a fire to enhance sleep and...turn off the light!!   #HP-EVOO