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The ECS and Diabetes

The global burden of type 2 diabetes is rising and represents a major concern in healthcare worldwide. Global prevalence of type 2 diabetes is projected to increase from 6059 to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world.[1]  Consequently, urgent effective clinical preventive and supportive measures are warranted. In this context, pharmacological modulation of the endogenous cannabinoid system (ECS) is emerging as a promising therapeutic strategy in the pathogenesis of type 2 diabetes mellitus (T2DM) and its chronic complications.

The Endogenous Cannabinoid System

The endogenous cannabinoid system (ECS) comprises the endocannabinoids (ECs), the enzymes that regulate their production and degradation, and the receptors through which they signal.[2] ECs are bioactive lipid mediators produced from cell membrane phospholipids ‘on demand’ and the most studied ones are anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG).[3]

The actions of ECs are mediated primarily by the cannabinoid receptor 1 or 2 (CB1 receptor /CB2 receptor). AEA signals predominantly via CB1 receptors, while 2‐AG is a complete agonist at both CB1 and CB2 receptors.[4] Receptor activation triggers an array of biochemical responses such as inhibition of voltage‐gated Ca2+ channels and adenylate cyclase activity, leading to lower cAMP levels, as well as activation of K+ channels, phospholipases, and MAPK pathways.[5]

CB1 receptors are expressed highly in the CNS while CB2 receptors are found mostly in inflammatory, immune, and haematopoietic cells.[6] However, since these receptors are also present in different cell types, the ECS is increasingly implicated in various pathophysiological processes and its pharmacological modulation is emerging as a promising therapeutic strategy in a variety of pathological conditions, including the pathogenesis of T2DM and its chronic complications.[7]

The Role of the ECS in the Pathogenesis of T2DM

Insulin resistance in peripheral tissues and a relative deficiency in insulin secretion by islet beta cells are known hallmarks in the development of T2DM.[8] The central role of the ECS in the development of obesity and its consequence on glucose and lipid metabolism which can contribute to the development of insulin resistance and T2DM has also been studied.[9] Increasing evidence suggests that an overactive ECS may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, by exerting pro‐apoptotic effects in pancreatic beta cells and by facilitating inflammation in pancreatic islets.[10]

Novel Therapeutic Strategies

CB1 receptor blockade is beneficial in animal models of obesity and metabolic syndrome, and these findings have been confirmed in humans.[11] According to researchers, alternative strategies to counteract EC overactivity would consist in developing substances that modulates the biosynthesis and/or degradation of ECs or to elaborate dietary interventions that would reduce precursors.[12]

Palmitoylethanolamide and the ECS

Palmitoylethanolamide (PEA) is an endocannabinoid (eCB)-like bioactive lipid mediator belonging to the N-acyl-ethanolamine (NAE) fatty acid amide family and synthesized on demand within the lipid bilayer.[13] PEA acts locally and is found in all tissues including the brain.[14] PEA is also found in foods such as egg yolk, soy, and sunflower oils. Considered a cannabimimetic compound, PEA has been studied for its several health benefits for the past eighty years but has received more attention lately due to its crucial role in the endocannabinoid system (ECS).[15] The wonder molecule is produced locally by the cells, and it accumulates in tissues following an injury, physical stress, or pain. PEA exhibits direct and indirect mechanisms of action, and it has been shown to enhance the action of other endocannabinoids through its “entourage effect”.[16]

PEA and Diabetes

Animal models demonstrate that PEA improves insulin level, preserves Langerhans islet morphology reducing the development of insulitis in diabetic mice.[17] PEA was also shown to relieve mechanical allodynia and counteract nerve growth factor deficit. Based on these results, researchers concluded that PEA could be effective in controlling the development of type 1-diabetic patients and as a pain reliever.

PEA and Diabetic Neuropathy

A 2014 research published in Pain Research Treatment and involving 30 diabetic patients suffering from painful diabetic neuropathy treated with micronized PEA (PEA-m) (300 mg twice daily) revealed a highly significant reduction in pain severity (P < 0.0001) and related symptoms (P < 0.0001) evaluated by Michigan Neuropathy Screening instrument, Total Symptom Score, and Neuropathic Pain Symptoms Inventory.[18] The researchers concluded that PEA-m could be considered as a promising and well-tolerated new treatment to address the symptoms experienced by diabetic patients suffering from peripheral neuropathy.

Conclusion

Given the increasing burden caused by diabetes and the emergence of the modulation of the endogenous cannabinoid system as a promising therapeutic target strategy, lesser known yet widely studied substances such as palmitoylethanolamide deserve more attention as potential therapeutic agents.


[1] Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 2020 Mar;10(1):107-111. doi: 10.2991/jegh.k.191028.001. PMID: 32175717; PMCID: PMC7310804.

[2] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[3] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[4] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[5] Howlett AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17(14):1382-93. doi: 10.2174/092986710790980023. PMID: 20166926; PMCID: PMC3179980.

[6] Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease–successes and failures. FEBS J. 2013 May;280(9):1918-43. doi: 10.1111/febs.12260. Epub 2013 Apr 22. PMID: 23551849; PMCID: PMC3684164.

[7] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[8] Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013 Apr 2;17(4):475-90. doi: 10.1016/j.cmet.2013.03.001. PMID: 23562074.

[9] Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013 Apr 2;17(4):475-90. doi: 10.1016/j.cmet.2013.03.001. PMID: 23562074.

[10] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology, 173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[11] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology, 173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[12] Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the endocannabinoid system in diabetes and diabetic complications. British journal of pharmacology, 173(7), 1116–1127. https://doi.org/10.1111/bph.13226

[13] Clayton, P., Hill, M., Bogoda, N., Subah, S., & Venkatesh, R. (2021). Palmitoylethanolamide: A Natural Compound for Health Management. International journal of molecular sciences, 22(10), 5305. https://doi.org/10.3390/ijms22105305

[14] Esposito E, Cuzzocrea S. Palmitoylethanolamide in homeostatic and traumatic central nervous system injuries. CNS Neurol Disord Drug Targets. 2013 Feb 1;12(1):55-61. doi: 10.2174/1871527311312010010. PMID: 23394520.

[15] Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat. 2014;2014:849623. doi: 10.1155/2014/849623. Epub 2014 Apr 2. PMID: 24804094; PMCID: PMC3996286.

[16] Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH. Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain Physician. 2017;20(5):353-362. https://pubmed.ncbi.nlm.nih.gov/28727699/

[17] Donvito G, Bettoni I, Comelli F, Colombo A, Costa B. Palmitoylethanolamide relieves pain and preserves pancreatic islet cells in a murine model of diabetes. CNS Neurol Disord Drug Targets. 2015;14(4):452-62. doi: 10.2174/1871527314666150429111537. PMID: 25921749.

[18] Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat. 2014;2014:849623. doi: 10.1155/2014/849623. Epub 2014 Apr 2. PMID: 24804094; PMCID: PMC3996286.

About The Author

Chantal Ann Dumas, ND promotes an evidence-based approach while remaining faithful to the traditional principles of the different medical modalities she proposes to her patients. She undertook additional training including Licensed Birth Assistant, Healthy Breast Teacher, Licensed Homeopath and Mind-Body Therapist. She is currently completing her degree in Medical Anthropology at McGill University. Inspired by the Functional medicine paradigm, she has an inclination for functional laboratory testing and her recommendations encompass nutritional supplements, botanical and homeopathic remedies, aromatherapy, gemmotherapy as well as diet and lifestyle advice.

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