A Tale of Two GLP-1 Agonist Webinars - pharma vs hops; for Type 2 diabetes or weight loss & found helpful for Alzheimer's dementia prevention.
Medications versus phytonutrients - a showdown. "The meaning of SHOWDOWN is the placing of poker hands faceup on the table to determine the winner of a pot."
The take-home message from our showdown - mainstream dietitians are likely to support mainstream pharma - but can have excellent diet and health advice too. This post got quite long, first half is more GLP-1 agonist and weight loss focused, and then it takes a turn towards phytonutrients, bitter taste receptors, and Alzheimer’s risk. Hops is also helpful for sleep, anxiety, depression and stress. Pomegranate peel and tea catechins could provide similar benefits for preventing Alzheimer’s dementia and inflammation. Sumac and goji or wolf berries have similar catechins.
One webinar was a nice overview about GLP-1 agonist medications, and it covered common discomforts, but didn’t really address major complications that have been seen for some patients. It covered the history of developing the GLP-1 agonist medication semaglutide - brand names Ozempic and Wegovy. This group of medications were developed and are still used for Type 2 diabetes. The side effect of weight loss was noted in patients with Type 2 diabetes using the earlier drugs and research into use for weight loss led to the development of semaglutide. This drug group has increased in prescriptions by 2000% in recent years.
Semaglutide or other GLP-1 agonist meds are now being studied and recommended for use to prevent Alzheimer’s dementia amyloidosis too. I have qualms, but that info does point to the value of natural GLP-1 agonists for protecting our brains.
The second webinar shared research about a phytonutrient product using the beer making herb, hops, which is being developed as a GLP-1 promoter for the purpose of weight loss. That webinar did make the point that a natural herbal product would likely be safer than the pharmaceutical, synthetic substitutes.
Semaglutide is modified so our body enzymes can’t break it down - making it seem more effective and long lasting, only needing one weekly injection, BUT anything that our body can’t break down properly is likely to lead to some unwanted side effects.
Semaglutide is a synthetic chemical that our body enzymes can’t break down normally, so it is only needed as a weekly injection. However, that means too much could cause worse side effects. One case study example that was discussed in webinar 1, had a patient with discomforts at 30 mg who never advanced to the 40 mg typical dose, which is titrated up to over a few weeks or months. Weight regain is common after stopping use of GLP-1 agonist medications, but it might not be all of the weight that was lost. One patient example started use again after regaining a few pounds. Disordered eating or yo-yo dieting can be a risk with any type of dieting. Working on better sleep and exercise habits and daily sunshine are a better bet for improved weight and health - and long-term brain protection
Nutritional Considerations In the Era of GLP-1R Agonists, Presented by Jonathan Clinthorne, PhD, and Kristin Kirkpatrick, MS, RD.
Slideshow handout: (ln5.sync.com),
Reference List (ln5.sync.com/reference list),
Dietitians can get 1 CEU for free - register here: (ce.secondcenturyeducation.com).
The In vitro and In vivo Development of a GLP-1 Stimulating Neutraceutical: Taking a Full Pharmacological Approach, Presented by: Edward Walker, PhD.
Slideshow handout *The video was more complete, sharing some slide graphics must not have been allowed due to copyrights: (ln5.sync.com),
Reference list: (ln5.sync.com/reference list)
Dietitians can get 1.25 CEU for free - register here: (ce.todaysdietitian.com)
*The screenshots are a funny color because I added a blue blocking Iris app to my computer. Download for free, but they like a fee or referrals. I’m not really good at it yet - there is supposed to be a way to click it on or off if you want to watch a movie without blue blocking . . . or take a screenshot. Install yours here: (iristech.co). What I see is fairly normal looking compared to this screen shot. It is adaptive and gets dimmer during evening hours.
GLP-1 agonists/ligands activate the GLP-1 receptor. Nicotine is an agonist of that receptor in addition to being an agonist for the nicotinic Acetylcholine receptors (nAChRs). See this post.
GLP-1 receptors are found in the brain, on the tongue, and in the stomach and the small intestine.
Webinar 1. was by a doctor and a dietitian - it covered an overview of the research regarding use of GLP-1 agonists, and then the dietary support and common concerns with use of the medications was discussed for dietitians - the webinar was designed for dietitians. What wasn’t really discussed in depth or at all, was the more serious risks that have been seen with Ozempic use - gallbladder issues leading to surgical removal of the gallbladder for example. A risk of an eating disorder becoming worse was discussed and the dietitian cautioned that asking about a history of eating disorders would be a good screening question to ask a patient considering use of the medication.
What was covered quite well, is that just taking the drug isn’t an automatic weight loss win - a dietitian’s help may really be very helpful. Ozempic/semaglutide/Wegovy seems to help only a percentage of people, like 25%, to lose much weight. People starting out with a lot to lose are more likely to see larger numbers come off - BUT, lean muscle mass is part of the weight loss and that is bad - up to 40% loss of lean mass. We want to build muscle as it burns more energy even as we sleep. More muscle is protective of a healthy weight and supports us during an illness. Dieting that leads to loss of muscle can lead to a lower metabolic rate and more risk of weight regain later - yo-yo dieting, with a weight that tends to increase with each cycle rather than normalizing.
As a counselor, tips included - Protein adequacy, Exercise, Water and Fiber, Nutrient dense food choices, and a lower carbohydrate ratio in the diet - to help promote better weight loss results with use of a GLP-1 agonist medication. Those tips would be helpful in general too, as better habits which might help prevent weight regain when use is stopped. Most patients are paying out of pocket for these medications when used for weight loss reasons, and the cost is roughly $400/month. Nicotine lozenges are only about $40. Pomegranate are about $3 each, when in season.
Recommend or instruct on the importance of muscle building exercise and adequate protein intake to reduce risk of lean muscle loss. The best route to weight loss is generally a combination of better diet and an increase in aerobic and weight bearing exercise. Circuit training with more intense shorter workouts with rest in between can also be helpful.
And common discomforts with use of semaglutide seem to include for many people loose stools or constipation or both - recommend good water and fiber intake - but a lower carbohydrate diet ratio may support weight loss better than the standard ratio of ~ 50% carb / 20% protein / 30% fat.
General good advice was to teach about nutrient density - anyone who is eating a smaller amount of food, needs to choose foods that have a lot of good nutrients rather than empty calories - a bag of Gummy Bears was the example for not being nutrient dense food - however tapioca or pectin starches would be helping to feed good species of the microbiome and that can help prevent negative digestive symptoms.
*I recommend ~ 30% carb / 20% protein / 50% fat - with only 10% from saturated fats as an excess of that can inhibit methylation cycles.
GLP-1 Agonist medications for preventing Alzheimer’s dementia?
Worries I see … use of GLP-1 agonist medications may reduce amyloidosis and so it is being studied or recommended for Alzheimer’s prevention too.
This finding suggests that more natural GLP-1 agonist would also be protective . . . but maybe safer for the gallbladder. If bitter tasting phytonutrients are GLP-1 promoters, then the simple solution here is to have more bitter tasting foods and herbs/spices with your meals and snacks.
Brave AI sees no direct research link (yet) between bitter taste receptors, GLP-1 agonists, and Alzheimer’s dementia prevention/treatment. (Brave AI summary/GLP-1 Phytonutrients and Alzheimer's) <- did include a lot of research links regarding GLP-1 medications and Alz.
There is research showing that berberine, a bitter tasting phytonutrient, stimulates GLP-1 production. (Brave AI summary/Bitter Taste Receptors and GLP-1)
The logic follows that if bitter taste receptors promote GLP-1, and if GLP-1 agonist medications seem to be protective against Alzheimer’s dementia, then bitter tasting phytonutrients would also be protective against Alzheimer’s dementia - and that research does exist, but has looked at other mechanisms of action.
See this thorough review article: Phytochemicals: A Promising Alternative for the Prevention of Alzheimer’s Disease. (Koul, et al., 2023) An excerpt from the paper on RAGEs and Alzheimer’s is included later in this post.
Genetic studies on Single Nucleotide Polymorphisms (SNPs) in an population with African ancestry, have identified three SNPs associated with increased risk for Alzheimer’s dementia risk and which caused down regulation of two bitter taste receptors. Two of the SNPs also increased production of two other proteins (“EPHB6 and ADGRB3”)
“In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis.”
Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer's disease. (Joseph, et al., 2024)
TAS2R41 is a bitter taste receptor. (Thalmann, et al., 2013) TAS2R60 is also a bitter taste receptor. (Gene/338398) EphB6 is a pseudokinase - an inactive chemical similar to kinase enzymes. (Strozen, et al., 2021) ADGRB3 is a brain signaling protein involved with G protein receptors - which is a larger descriptive group that includes taste receptors and cannabinoid receptors. (genecards.org/ADGRB3) More on that tangent is a different rabbit hole.
“RAGE is a receptor tyrosine kinase (RTK) and that its activation leads to downstream signaling events involving protein tyrosine phosphorylation, rather than G protein activation.” (Brave AI summary/Are RAGE receptors G protein coupled receptors? - No, but they may interact/effect each other indirectly.)
I am detecting that health inequities might be involved in elevated Ephb6 - better to have active kinases in the ERK pathway maybe?
In a study considering Major Depressive Disorder, Guo, et al., used a Chronic Social Defeat Stress mouse model and a control group of mice, and compared the protein levels in the brains of the mice. The key proteins identified at differing levels, were “proteins of the ephrin receptor signaling pathway, ephrin type-B receptor 6 (EphB6) and the ERK pathway.” (Guo, et al., 2017)
‘iTRAQ-Based Proteomics Suggests Ephb6 as a Potential Regulator of the ERK Pathway in the Prefrontal Cortex of Chronic Social Defeat Stress Model Mice’ (Guo, et al., 2017)
What do we know about pomegranate peel extract??
. . . That pomegranate/peel is a MAPK, kinase/ERK pathway inhibitor. (Du, et al., 2018) Search results provide tea polyphenols as inhibitors of EphB6. (Noberini, et al., 2012)
Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. (Noberini, et al., 2012)
Catechins in tea are similar to catechins in pomegranate/peel, Goji berries or Sumac spice. Pomegranate peel, Sumac and Goji berries can be used for hot beverages or Structured water style Suntea. (Brave AI summary/Goji Berry drinks)
RAGE receptors & Alzheimer’s risk revisited,
…see this post: Pomegranate peel extract or citrus peel inhibits RAGE receptors . . . isn't that nice? . . . polyphenols help calm RAGE receptors - which tend to be elevated in patients with Alzheimer’s dementia.
“2.3.3. Food and Malnutrition
Studies on how diet affects AD have been more prevalent in recent years. Antioxidants, vitamins, polyphenols etc. are a few dietary supplements that have been shown to reduce the risk of AD, although high-calorie foods and saturated fats exacerbate the risk of AD [45].
As a consequence of the nonenzymatic glycation of free amino groups in proteins, lipids, and nucleic acids, heat-sensitive micronutrients such as vitamin C and folates degrade, a significant quantity of water is lost, and hazardous secondary products (advanced glycation end products: AGEs) are formed [46,47]. The harmful impact of AGEs is their capacity to cause oxidative stress and inflammation by altering the structure and function of the body’s proteins and cell surface receptors.
Several investigations have shown that a raised AGEs serum level is linked to cognitive deterioration and the development of AD [48].
The AGE receptor (RAGE), which is present in the microglia and astrocytes among other body tissues, has been shown to be overexpressed in the brains of AD patients where it serves as a cell surface receptor and a transporter for Aβ [49].
An additional AD risk factor is malnutrition, as low levels of minerals, including vitamin D, vitamin B12, and folate, may impair cognitive performance. Patients with AD also face difficulties swallowing and eating, which raises the chances of malnutrition [50].”
- Phytochemicals: A Promising Alternative for the Prevention of Alzheimer’s Disease. (Koul, et al., 2023)
*Excellent resource - lengthy list of functional foods and phytonutrients with research showing benefits against Alzheimer’s - acetylcholinesterase inhibition is a common mechanism of action, but doesn’t mention GLP-1 agonist as a mechanism of action.
The In vitro and In vivo Development of a GLP-1 Stimulating Neutraceutical: Taking a Full Pharmacological Approach, Presented by: Edward Walker, PhD.
Slideshow handout *The video was more complete, sharing some slide graphics must not have been allowed due to copyrights: (ln5.sync.com),
Reference list: (ln5.sync.com/reference list)
Dietitians can get 1.25 CEU for free - register here: (ce.todaysdietitian.com)
Webinar two, was about the development of an alternative herbal product for GLP-1 promotion. The beer making herb hops was found to be most effective out of a number of tested herbs or bitter foods. Bitter taste receptors are the key point - they are in our stomach and our intestines and they help regulate appetite. Bitter tastes in the stomach can increase appetite, but then when they enter the small intestine, they promote GLP-1 which inhibits appetite.
The research team developed a delayed release hops product that helped suppress appetite for up to four hours - longer than hops in a capsule that dissolves in the stomach. Both capsule products did promote GLP-1 more than seen in the control/placebo group (100-500 mg doses were effective).
Beer drinkers are thin right? ;-) Drumroll … beer does not act the same way. The hops phytonutrients are modified too much during the production of beer to promote GLP-1 production in the same way.
(Walker, et al., 2022) Edward G Walker, Kim R Lo, Malcolm C Pahl, Hyun Sang Shin, Claudia Lang, Mark W Wohlers, Sally D Poppitt, Kevin H Sutton, John R Ingram, An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy weight men: a randomised, cross-over clinical trial, The American Journal of Clinical Nutrition, Vol 115, Issue 3, 2022, pp 925-940, ISSN 0002-9165, https://doi.org/10.1093/ajcn/nqab418. https://www.sciencedirect.com/science/article/pii/S0002916522002088?via%3Dihub
Gastrointestinal Bitter Taste Receptor Expression exhibits inter-regional, inter-individual and cytogenetic variation. Edward Walker, Russell Walmsley, Kate Richards, Ann-Thea McGill,, Sally D Poppitt , and John Ingram (Manuscript in prep) ← may be why the video had graphics that weren’t available for the pdf handout.
A question from the live audience asked about “prescribing” this delayed release hops supplement . . . and the answer was that the delayed release hops supplement would be over the counter - an unregulated herbal product. Doctor recommendations and guidance would be preferred therapeutically (*this is a doctor talking), but it would not be a requirement for an herbal product.
Just go buy some hops… it is inexpensive as a dried herb to put in your own capsules.
Delayed release, empty capsules are available for sale. (varied products, Amazon)
Hops flowers have a very strong odor - I have used it as a dried arrangement flowering vine in the past. Hops flowers are used at weddings, for their distinctive aroma. And I found that it is an outdoor decoration… (essentiallyhops.co.uk/product/hops/hops-for-decoration/hop-garland-dried-vintage/)
Mountain Rose Herbs offers an extract of hops: (mountainroseherbs.com/hops-extract); or bulk dried flowers - more expensive than I expected: (mountainroseherbs.com/hops-flowers). And Hops flower essential oil, ~ “used for calming blends… no known precautions, dilute for use, not intended for edible use,” (mountainroseherbs.com/hops-flower-essential-oil).
The use of hops for young adults with negative mood symptoms for four weeks helped reduce stress, anxiety and/or depression. “(Melcalin hops or placebo; two 0.2 gr capsules once daily)”, a 0.2 gr dose was used which is equal to 200 milligrams. It was found beneficial for reducing their levels of anxiety, depression and stress (n=36, crossover study design). Weight loss was not observed. (Kyrou, et al., 2017)
Melcalin hops is a specific research-tested brand. Mood or sleep or anti-inflammatory benefits are suggested as reasons for use of Melcalin Hops. A product of Italy, 16.24 Euro for a bottle: (melcalin.com/en/food-supplement-melcalin-hops/).
Myricetin content would be a sleep promoting phytonutrient found in hops.
“Using the ORAC assay, cinnamic, caffeic, and ferulic acids; gallocatechin, xanthohumol; and myricetin were described as the most active in hydroxyl and peroxyl radical-scavenging [32, *evaluated brewery waste rather than plain hops]. The effect of phenolic compounds was related with vitamin C, using ABTS and DPPH-scavenging assays. Antioxidant activities are expressed as vitamin C equivalent antioxidant capacity (VCEAC). VCEAC results for phenolic compounds were gallic acid > quercetin > epicatechin > catechin > vitamin C > rutin.” (Knez Hrnčič, et al., 2019)
Pomegranate peel would work on bitter taste receptor pathways too.
Or go buy some pomegranate while it is in season - the peel has similar bitter tasting polyphenols and catechins as hops - “cinnamic, caffeic, and ferulic acids; gallocatechin”. (Knez Hrnčič, et al., 2019)
Coffee, tea, or nicotine too.
Or moderate use of coffee and tea (1-2 cups/day rather than a pot a day habit) have shown protective benefits against Alzheimer’s dementia (AD) too. (Eskelinen and Kivipelto, 2010; Brave AI summary/Coffee and Alzheimer's Prevention) Caffeine is an Acetylcholinesterase inhibitor, which is a mechanism of action for medications that are used for AD. See this post: (substack.denutrients)
Caffeic acid sourced from used coffee grounds has been studied for preventing Alzheimer’s dementia and Parkinson’s Disease.
Could coffee grounds be the key to preventing Alzheimer’s and Parkinson’s?, (medicalnewstoday.com).
Coffee - with a side of baicalin (skullcap herb) and pomegranate peel.
I’m still enjoying my coffee (3-4 tablespoons) made with pomegranate peel (1 inch piece) and skullcap herb (1 teaspoon) for 8-10 cups of water. I tend to make a couple more weaker cups with the same grounds later in the day or next morning. The herbals add a tangy flavor in addition to the coffee flavor. I’ve always been more of a pot a day coffee drinker. It helps my ADHD.
Nicotine lozenges or gum - nicotine is a GLP-1 receptor agonist.
Smoking is a health negative, I have been using nicotine lozenges and would recommend that or nicotine gum, rather than smoking or vaping. Vape ingredients are bad for the lungs. The nicotine patches may use hydrogel, so I would avoid those too. I tried them first, but had to stop as it became a fairly immediate skin irritant.
Disclaimer: This information is being shared for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.
Reference List
(Du, et al., 2018) Lin Du, Jianke Li, Xitong Zhang, Lifang Wang, Weimin Zhang, Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of MAPKs activation, Journal of Functional Foods, Vol 43, 2018, pp 62-69, ISSN 1756-4646, https://doi.org/10.1016/j.jff.2018.01.028. https://www.sciencedirect.com/science/article/pii/S1756464618300355
(Eskelinen and Kivipelto, 2010) Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer's disease. J Alzheimers Dis. 2010;20 Suppl 1:S167-74. doi: 10.3233/JAD-2010-1404. PMID: 20182054. https://pubmed.ncbi.nlm.nih.gov/20182054/
(Guo, et al., 2017) Guo H, Huang ZL, Wang W, Zhang SX, Li J, Cheng K, Xu K, He Y, Gui SW, Li PF, Wang HY, Dong ZF, Xie P. iTRAQ-Based Proteomics Suggests Ephb6 as a Potential Regulator of the ERK Pathway in the Prefrontal Cortex of Chronic Social Defeat Stress Model Mice. Proteomics Clin Appl. 2017 Dec;11(11-12). doi: 10.1002/prca.201700115. Epub 2017 Nov 9. PMID: 28967185. https://onlinelibrary.wiley.com/doi/10.1002/prca.201700115
(Joseph, et al., 2024) Joseph PV, Abbas M, Goodney G, Diallo A, Gaye A. Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer's disease. Sci Rep. 2024 Sep 16;14(1):21560. doi: 10.1038/s41598-024-71669-9. PMID: 39284855; PMCID: PMC11405524. https://pmc.ncbi.nlm.nih.gov/articles/PMC11405524/
(Knez Hrnčič, et al., 2019) Knez Hrnčič M, Španinger E, Košir IJ, Knez Ž, Bren U. Hop Compounds: Extraction Techniques, Chemical Analyses, Antioxidative, Antimicrobial, and Anticarcinogenic Effects. Nutrients. 2019 Jan 24;11(2):257. doi: 10.3390/nu11020257. PMID: 30678345; PMCID: PMC6412513. https://pmc.ncbi.nlm.nih.gov/articles/PMC6412513/#B32-nutrients-11-00257
(Koul, et al., 2023) Koul B, Farooq U, Yadav D, Song M. Phytochemicals: A Promising Alternative for the Prevention of Alzheimer’s Disease. Life. 2023; 13(4):999. https://doi.org/10.3390/life13040999 https://www.mdpi.com/2075-1729/13/4/999
(Kyrou, et al., 2017) Kyrou I, Christou A, Panagiotakos D, Stefanaki C, Skenderi K, Katsana K, Tsigos C. Effects of a hops (Humulus lupulus L.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: a randomized, placebo-controlled, double-blind, crossover pilot study. Hormones (Athens). 2017 Apr;16(2):171-180. doi: 10.14310/horm.2002.1738. PMID: 28742505. https://link.springer.com/article/10.14310/horm.2002.1738
(Noberini, et al., 2012) Noberini R, Koolpe M, Lamberto I, Pasquale EB. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012 Oct;66(4):363-73. doi: 10.1016/j.phrs.2012.05.010. Epub 2012 Jun 28. PMID: 22750215; PMCID: PMC3677025. https://pmc.ncbi.nlm.nih.gov/articles/PMC3677025/
(Strozen, et al., 2021) Strozen TG, Sharpe JC, Harris ED, Uppalapati M, Toosi BM. The EphB6 Receptor: Kinase-Dead but Very Much Alive. Int J Mol Sci. 2021 Jul 30;22(15):8211. doi: 10.3390/ijms22158211. PMID: 34360976; PMCID: PMC8347583. https://pmc.ncbi.nlm.nih.gov/articles/PMC8347583/
(Thalmann, et al., 2013) Sophie Thalmann, Maik Behrens, Wolfgang Meyerhof, Major haplotypes of the human bitter taste receptor TAS2R41 encode functional receptors for chloramphenicol, Biochemical and Biophysical Research Communications, Vol 435, Issue 2, 2013, pp 267-273, ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2013.04.066. https://www.sciencedirect.com/science/article/pii/S0006291X13007055