The endocannabinoid system in obesity and type 2 diabetes.
- Endocannabinoid Research Group at the Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078, Pozzuoli (NA), Italy. firstname.lastname@example.org
Endocannabinoids (ECs) are defined as endogenous agonists of cannabinoid receptors type 1 and 2 (CB1 and CB2). ECs, EC anabolic and catabolic enzymes and cannabinoid receptors constitute the EC signalling system. This system participates in the control of lipid and glucose metabolism at several levels, with the possible endpoint of the accumulation of energy as fat. Following unbalanced energy intake, however, the EC system becomes dysregulated, and in most cases overactive, in several organs participating in energy homeostasis, particularly, in intra-abdominal adipose tissue. This dysregulation might contribute to excessive visceral fat accumulation and reduced adiponectin release from this tissue, and to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes. This phenomenon might form the basis of the mechanism of action of CB1 antagonists/inverse agonists, recently developed by several pharmaceutical companies as adjuvants to lifestyle modification for weight reduction, glycaemic control and dyslipidaemia in obese and type 2 diabetes patients. It also helps to explain why some of the beneficial actions of these new therapeutics appear to be partly independent from weight loss.
New substances derived from cannabis are being used to tackle kidney failure caused by diabetes, as part of a new research project led by the University of Aberdeen.
Approximately 40% of people with diabetes develop kidney failure (diabetic nephropathy) as a result.
The project, funded by Diabetes UK, will explore whether these synthetic cannabinoid compounds can be used to make the kidneys respond better to insulin.
In 2013, 3.2 million people in the UK had diabetes. By 2025 it is estimated that number will rise to 5 million in the UK, and by 2040 there will be 640 million across the world living with the condition.
Active ingredients in the cannabis plant are already known to have beneficial effects for treatment of a number of conditions such as rheumatoid arthritis. They do this by acting on the body’s own endocannabinoid-system, which is made up of CB1 and CB2 receptors, with CB1 receptors found mainly in the brain, and the CB2 receptors in the other tissues of the body.
“CB1 and CB2 receptors are also found in the kidney cells with CB1 being increased in patients experiencing kidney failure due to diabetes (diabetic nephropathy) and CB2 being decreased in the same condition”, explains Dr Mirela Delibegovic.
“New evidence suggests that to combat diabetes and its complications, we want to block CB1 receptors and activate CB2, and we think these novel compounds could allow us to do this.”
“Diabetic nephropathy can lead to patients requiring dialysis or renal transplantation, therefore identifying if novel cannabinoid compounds can be used to ameliorate this disease is of upmost importance. There are already some cannabanoids used to treat inflammatory diseases like rheumatoid arthritis, so these compounds could be taken relatively fast from benchside to bedside.”
The research team at the University of Aberdeen led by Dr Delibegovic, together with Prof Roger Pertwee and Dr Maria Cascio are collaborating with Bristol University who have given access to human cells from patients with kidney disease. The new cannabinoids will be used to see if they improve insulin sensitivity in these cells. The ones that show improvement in human cell lines will be tested in mouse models of diabetes.
The study coincides with World Diabetes Day on November 14, as organised by the International Diabetes Federation.
To mark the day, landmarks across the world are lit up with blue lights, and this year the University of Aberdeen’s King’s College will take part in the awareness campaign. In past years iconic buildings to take part have included Sears Tower in Chicago, the London Eye and Brisbane City Hall.
Study: Cannabis Associated With Lower Diabetes Risk
- Adults with a history of marijuana use have a lower prevalence of type 2 diabetes and possess a lower risk of contracting the disease than those with no history of cannabis consumption, according to clinical trial datapublished in the British Medical Journal.Investigators at the University of California, Los Angeles assessed the association between diabetes mellitus (DM) and marijuana use among adults aged 20 to 59 in a nationally representative sample of the US population of 10,896 adults. The study included four groups: non-marijuana users (61.0%), past marijuana users (30.7%), light (one to four times/month) (5.0%) and heavy (more than five times/month) current marijuana users (3.3%). Diabetes was defined based on self-report or abnormal glycaemic parameters.Researchers hypothesized that the prevalence of type 2 diabetes would be reduced in marijuana users because of the presence of various cannabinoids that possess immunomodulatory and anti-inflammatory properties.Investigators reported that past and present cannabis consumers possessed a lower prevalence of adult onset diabetes, even after authors adjusted for social variables (ethnicity, level of physical activity, etc.), despite all groups possessing a similar family history of DM. Researchers did not find an association between cannabis use and other chronic diseases, including hypertension, stroke, myocradial infarction, or heart failure compared to nonusers.
Past and current cannabis users did report engaging in more frequent physical activity than nonusers, but also possessed higher overall levels of total cholesterol and triglycerides. By contrast, the highest prevalence of marijuana consumers were found among those with the lowest glucose levels.
Investigators concluded, “Our analysis of adults aged 20-59 years … Showed that participants who used marijuana had a lower prevalence of DM and lower odds of DM relative to non-marijuana users.” They caution, however: “Prospective studies in rodents and humans are needed to determine a potential causal relationship between cannabinoid receptor activation and DM. Until those studies are performed, we do not advocate the use of marijuana in patients at risk for DM.”
Previous studies in animals have indicated that certain cannabinoids possess anti-diabetic properties. In particular, a preclinical trial published in the journal Autoimmunity reported that injections of 5 mg per day of the non-psychoactive cannabinoid CBD significantly reduced the incidence of diabetes in mice compared to placebo. Investigators reported that control mice all developed adult onset diabetes at a median of 17 weeks (range 15-20 weeks), while a majority (60 percent) of CBD-treated mice remained diabetes-free at 26 weeks.
There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.
We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple linear regression, accounting for survey design and adjusting for potential confounders.
Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], −26, −6) and 17% lower HOMA-IR (95% CI, −27, −6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response.
We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference.