Most of the time when people mention cannabis in the context of health its done in a tongue-in-cheek kind of way. By prejudice alone I usually listen with a light-hearted disbelief.
Yeah, I bet cannabis helps your glaucoma. It doesn't help that most people making the claims for cannabis' health benefits look like they were smoking it long before they started worrying about their health. And, yes, I realize how incredibly naive and immature of me it is to profile the way people look and their relationship with cannabis. Having grown up near Woodstock, NY, I've developed my own predispositions to "weed" and the crowd it attracts.
But it doesn't preclude me from actually acknowledging its numerous health benefits. Recently I was introduced to a group doing some very interesting work with the devil's lettuce.
Luke Bowman, of Cannabis for Diabetes, is leading a charge in bringing awareness to cannabis as a legitimate means of improving diabetes management. He's doing so through a substantial crumb trail of scientific literature looking at how the endocannabinoid system (ECS) impacts diabetes. And not just in a spacey "I like the way it makes me feel" kind of way. They are in the process of raising funds to conduct novel, patient initiated research in the world of cannabis. You can contribute to the funds here in the Call for Aid section.
I've spent the past few days looking at Luke's library of supporting research (check the livbrary tab). Here's what has my attention:
G-Coupled Receptor Activation
The endocannabinoid system (ECS) plays a pivotal role in regulating immune responses, inflammation, and metabolic processes, making it highly relevant for type 1 diabetes (T1D). Its receptors, CB1 and CB2, are G-protein-coupled receptors (GPCRs), belonging to the same superfamily as GLP-1 receptor agonists like semaglutide. This shared GPCR architecture means that cannabinoids, like those derived from cannabis, can influence cellular signaling in ways similar to modern diabetes medications—modulating pathways that impact beta-cell survival, insulin secretion, and immune balance. Unlike semaglutide, which directly targets glucose metabolism, cannabinoids uniquely address the inflammatory and autoimmune components of T1D, offering a promising avenue for holistic management. This fascinating overlap between pharmaceutical innovation and plant-derived therapy underscores the potential of the ECS in diabetes care.
The G-coupled receptor superfamily has gained a lot of attention in the world of diabetes because of its connections to GLP-1R Agonists (semaglutide AKA Ozempic, Trulicity, etc) . But did you know that cannabinoid receptors are also G-coupled receptors? And did you know that beta cells have receptors for both kinds of ECS receptors, CB1R and CB2R?
Much of the research states that the GCPR's impact on blood sugar regulation boils down to its ability to increase adenyl cyclase (AC) and its conversion to cAMP.
Influence of CB1R on Beta Cells
CB1R is primarily expressed in the central nervous system but is also found in peripheral tissues, including pancreatic islets.
Beta-Cell Function and Insulin Secretion:
CB1R activation generally inhibits insulin secretion from beta cells. This occurs via:
Modulation of calcium ion channels, reducing calcium influx required for insulin vesicle exocytosis.
Impairing glucose-stimulated insulin release, leading to reduced beta-cell responsiveness.
In conditions of metabolic stress, overactivation of CB1R exacerbates beta-cell dysfunction.
Beta-Cell Viability and Apoptosis:
Excessive CB1R activation is linked to increased beta-cell apoptosis due to:
Enhanced pro-inflammatory signaling.
Increased oxidative stress within beta cells.
Role in Obesity-Associated Insulin Resistance:
In obesity, CB1R expression is upregulated in pancreatic islets, contributing to impaired beta-cell function and insulin resistance.
Therapeutic Potential:
CB1R antagonism has been shown to:
Protect beta cells from apoptosis.
Improve glucose-stimulated insulin secretion.
Reduce inflammation in islets and peripheral tissues.
Examples: Rimonabant (a CB1R antagonist) demonstrated these benefits in preclinical studies, though side effects limited its clinical use.
CB1R and its impacts on insulin secretion
Influence of CB2R on Beta Cells
CB2R is primarily expressed in immune and peripheral tissues, including pancreatic islets, at lower levels than CB1R.
Anti-Inflammatory and Cytoprotective Role:
CB2R activation has anti-inflammatory effects that benefit beta cells by:
Reducing infiltration of immune cells into islets.
Modulating cytokine release to prevent immune-mediated beta-cell damage.
This is particularly relevant in autoimmune conditions like type 1 diabetes (T1D).
Beta-Cell Protection:
Activation of CB2R enhances beta-cell survival under conditions of oxidative and inflammatory stress.
Studies suggest that CB2R activation may improve beta-cell regeneration and preserve their function.
Insulin Secretion:
CB2R has less direct influence on insulin secretion compared to CB1R. However, its anti-inflammatory properties indirectly improve beta-cell function and insulin release.
Therapeutic Potential:
CB2R agonists are promising candidates for preserving beta-cell mass and function in T1D due to their ability to:
Suppress autoimmunity.
Protect beta cells from inflammatory damage.
CB1R vs. CB2R: Opposing Roles in Beta Cells
Aspect | CB1R | CB2R |
Expression in Islets | High in beta cells, especially in obesity. | Lower but present in islets. |
Effect on Insulin | Inhibits glucose-stimulated insulin release. | Indirectly supports insulin secretion. |
Inflammation | Promotes inflammation and oxidative stress. | Reduces inflammation and immune attack. |
Cell Viability | Increases beta-cell apoptosis. | Enhances beta-cell survival. |
Therapeutic Potential | Antagonists to reduce beta-cell dysfunction. | Agonists to protect and support beta cells. |
How this could look for T1D interventions
2CB1R (Cannabinoid Receptor Type 1) influences insulin secretion by interfering with the key steps needed for beta cells in the pancreas to release insulin:
Dynamic Nature of CB1R: CB1R is not static—it is continuously produced and broken down, with most receptors having a short lifespan of about 5 hours, but some lasting up to 24 hours.
Calcium and Insulin Secretion:
Insulin release depends on calcium entering beta cells.
CB1R reduces calcium influx into cells, which is crucial for insulin production and secretion.
Impact on Cellular Machinery:
CB1R activation slows down the process that moves insulin-filled granules to the cell surface for release.
It keeps potassium channels open (when they should close), reducing the cell’s ability to build up the electrical charge needed to allow calcium entry.
End Result:
Less calcium enters the beta cells, leading to reduced insulin secretion.
This disruption can worsen conditions like diabetes by impairing beta-cell function and insulin release.
In short, when CB1R is activated, it acts like a "brake" on insulin secretion, making it harder for the pancreas to release insulin effectively.
Identifying CB1R activity in those with T1D would be a meaningful step. Next would be to antagonize/regulate CB1R to prevent it from limiting insulin secretion. What are some natural ways to antagonize CBR?
Here's what a quick search produced:
Antioxidants: Polyphenols specifically (resveratrol, quercetin, ECGC, curcumin) Then, one would want to boost the pro-beta cell impacts of CB2R.
Omega-3 Fatty Acids: Fatty fish (salmon, mackerel), flaxseeds, chia seeds, and walnuts help produce endocannabinoids like DHEA and EPEA, which partially antagonize CB1R and balance the endocannabinoid system.
Terpenes: Pine needles, clove, black pepper, rosemary and basil act as CB2R agonists and may counterbalance CB1R activity while supporting anti-inflammatory pathways.
Medicinal Herbs: Ginseng and Magnolia Bark (magnolol) both impact the ECS and can help with CB1R overactivity.
Fiber-rich diet: The FOS, soluble fiber and resistant starch found in legumes, vegetables, and fruits promotes gut health and the production of short-chain fatty acids (SCFAs), like butyrate, which modulate the ECS and may reduce CB1R signaling.
Lifestyle Modifications: Regular exercise, intermittent fasting and healthy weight management impacts the ECS and down-regulates CB1R activity.
Reducing Dietary Fat: High-fat diets can upregulate CB1R in adipose tissue. Reducing fat intake helps normalize ECS activity and reduce CB1R overexpression.
Then we'd want to boost CB2R. Ironically theres a lot of overlap with the CB1R antagonism. Regular exercise, polyphenols, terpenes, omega-3s, fiber-rich foods and limiting dietary fat.
These things have given me a new outlook on how cannabis and its derivatives can make an important impact on diabetes health. Luckily, there is a lot of crossover in the methods we at Diabetics for Diabetics have been implementing. We are no strangers to the magic of quercetin and resveratrol, or the importance and regular exercise. I don't think its any coincidence these healthy foods and life habits have the reach they do win multiple body systems.
It reinforces the true significance of the seemingly over-simplified advice of eat whole foods and exercise regularly.
Food is they medicine, but maybe some cannabis can help.
Citations:
Endocannabinoid System and Islets of Langerhans
Forskolin and Adenylyl Cyclase Activation:
Seamon, K. B., et al. (1981). "Activation of adenylyl cyclase by forskolin directly in cell membranes." Proceedings of the National Academy of Sciences of the United States of America.
The Role of CB1R and CB2R in Beta-Cell Function:
Horvath, B., et al. (2012). "Cannabinoid signaling in pancreatic islets." Advances in Experimental Medicine and Biology.
Bermudez-Silva, F. J., et al. (2008). "Role of the endocannabinoid system in glucose metabolism." Pharmacological Research.
CB1R and Insulin Secretion:
Kim, W., et al. (2010). "Cannabinoid receptor signaling in β-cells." Diabetes/Metabolism Research and Reviews.
CB2R and Anti-Inflammatory Properties:
Pandey, R., et al. (2009). "Cannabinoids and immune modulation in diabetes." Journal of Endocrinology.
General Overview of ECS in Islets:
Pertwee, R. G. (2006). "Cannabinoid pharmacology: the first 66 years." British Journal of Pharmacology.
Natural Modulation of CB1R and CB2R
Polyphenols and ECS Modulation:
Rivera, L., et al. (2008). "Resveratrol ameliorates metabolic disturbances by acting on CB1 receptors." Journal of Clinical Investigation.
Terpenes as CB2R Agonists:
Gertsch, J., et al. (2008). "Beta-caryophyllene is a dietary cannabinoid." Proceedings of the National Academy of Sciences of the United States of America.
Omega-3 Fatty Acids and ECS:
Meijerink, J., et al. (2013). "Endocannabinoid biosynthesis and inflammation modulation by Omega-3 fatty acids." Biochimica et Biophysica Acta (BBA).
Diet and CB1R/CB2R Modulation:
Di Marzo, V., et al. (2004). "The endocannabinoid system: a general view of its potential in metabolic regulation." Trends in Endocrinology and Metabolism.
Probiotics and SCFAs Enhancing ECS:
Silva, Y. P., et al. (2020). "Gut microbiota as a regulator of the endocannabinoid system in metabolic disorders." Frontiers in Endocrinology.
Exercise and CB2R Upregulation:
Hill, M. N., et al. (2010). "Exercise effects on endocannabinoid signaling." Journal of Neuroscience.
Cannabinoid Receptors and G-Protein-Coupled Receptors (GPCRs)
Cannabinoid Receptors as GPCRs:
Howlett, A. C., et al. (2002). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors." Pharmacological Reviews.
GLP-1 Receptor Agonists and GPCR Overlap:
Drucker, D. J. (2006). "The biology of incretin hormones." Cell Metabolism.
Karaki, S. I., et al. (2008). "Role of G-protein-coupled receptors in gut peptide release." Biochemical Society Transactions.
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