humulene and Insulin-Resistance

The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed.

Topics: Aged; Cannabinoid Receptor Agonists; Cannabinoids; Cannabis; Child; Diabetes Mellitus; Flavonoids; Humans; Insulin Resistance; Terpenes

Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of β-cell function and, ultimately, loss of β-cells. Insulin secretion by β-cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood-borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB1 receptor (CB1 R) system, as indicated by the therapeutic effects of CB1 R antagonists. Similar beneficial effects of CB1 R antagonists with limited brain penetrance indicate the important role of CB1 R in peripheral tissues, including the endocrine pancreas. Pancreatic β-cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose-induced insulin secretion and also affect β-cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance.

Topics: Animals; Blood Glucose; Cannabis; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Insulin Resistance; Insulin-Secreting Cells; Receptor, Cannabinoid, CB1

Nonalcoholic steatohepatitis (NASH) is defined histopathologically by the presence of macrovesicular steatosis, cellular ballooning, and inflammation. NASH represents a complex multifactorial disease that typically occurs within the context of the metabolic syndrome. NASH lacks homogeneity, and other forms of NASH can present atypically. Less than 50% of patients with NASH respond to pharmacologic treatment, which speaks to this heterogeneity. The authors discuss drugs, disease entities, and nutritional states that can cause or exacerbate underlying NASH indirectly through worsening insulin resistance or directly by interfering with lipid metabolism, promoting oxidative injury, or activating inflammatory pathways.

Topics: Amiodarone; Anti-Retroviral Agents; Bacterial Infections; Cannabis; Diet; Fatty Liver; Genetic Diseases, Inborn; Glucocorticoids; Humans; Hypothyroidism; Insulin Resistance; Intestinal Diseases; Lipid Metabolism; Metabolic Syndrome; Methotrexate; Non-alcoholic Fatty Liver Disease; Occupational Diseases; Perhexiline

Hemp seed and physical activity (PA) have many benefits for the metabolic and brain health of the body. This study investigated the effects of hemp seed alone and aerobic exercise on metabolic markers, oxidative stress, and neurotrophic factors in young sedentary men. This double-blind, placebo-controlled, randomized clinical trial was conducted on 48 sedentary young men in Tabriz, Iran, from April to August. The researcher in this study randomized all participants into four groups, including (1) hemp seed, (2) hemp seed + PA, (3) PA + placebo, and (4) placebo. Hemp seed supplement was administered in two 1-g capsules daily, and aerobic PA was performed a week thrice. Levels of anthropometric indices, dietary intake, antioxidant markers, lipid profile, fasting blood sugar (FBS), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI), brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), balance, reaction time, and sit-ups were evaluated for all participants at baseline and post-intervention. We used ANOVA and ANCOVA analysis to compare oxidative stress and neurotropic factors in all intervention groups. If the distribution of the response variable was not normal, the non-parametric equivalent of these tests was used (Wilcoxon and Kruskal-Wallis tests). We performed all statistical analyzes using SPSS software version 23, and the significance level was considered 0.05 in all the statistical tests. Aerobic PA with hemp seed consumption caused a significant difference in weight, body mass index, fat mass, high-density lipoprotein, catalase, and BDNF compared with baseline. Also, aerobic PA alone caused significant changes in body weight, fat mass, and triglyceride compared with baseline. Consumption of hemp seeds alone caused a significant increase in high-density lipoprotein levels compared with baseline. At the end of the study, fat mass, total cholesterol, low-density lipoproteins, and BDNF were significantly different between the groups. According to our results, aerobic PA combined with hemp seed consumption may improve anthropometric indices, lipid profile, and BDNF and improve health outcomes like cardiovascular comorbidities, oxidative stress, and insulin resistance. PRACTICAL APPLICATIONS: A sedentary lifestyle has numerous health-threatening consequences like cardiovascular comorbidities, oxidative stress, and insulin resistance. The importance of physical activity (PA

Topics: Brain-Derived Neurotrophic Factor; Cannabis; Exercise; Humans; Insulin; Insulin Resistance; Lipoproteins, HDL; Male; Oxidative Stress; Triglycerides

Obesity and nonalcoholic fatty liver disease (NAFLD) constitute global and growing epidemics that result in therapeutic dead ends. There is an urgent need for new and accessible treatments to improve and widen both preventive and curative approaches against NAFLD. The endocannabinoid system (ECS) is recognized as a complex signaling apparatus closely related to metabolic disorders and is a key target for treating NAFLD. Despite a lack of conclusive clinical trials, observational and pre-clinical studies highlight putative benefits of phytocannabinoids on liver steatosis through multiple pathways. Owing to both its safety profile and its diversity of active compounds acting primarily (although not exclusively) on the ECS-and its expanded version, the endocannabinoidome, the

Topics: Cannabinoid Receptor Agonists; Cannabis; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity

The prevalence of obesity and insulin-resistance is on the rise, globally. Cannabis have been shown to have anti-diabetic/obesity properties, however, the effect mediated at various fat depots remains to be clarified. The aim of this study was to (1) investigate the anti-diabetic property of an oral cannabis administration in an obese and streptozotocin-induced diabetic rat model and (2) to determine and compare the effect mediated at the peritoneal and intramuscular fat level. Cannabis concentration of 1.25 mg/kg body weight (relative to THC content) was effective in reversing insulin-resistance in the rat model, unlike the other higher cannabinoid concentrations. At the peritoneal fat level, gene expression of fat beigeing markers, namely Cidea and UCP1, were significantly increased compared to the untreated control. At the intramuscular fat level, on the other hand, CE1.25 treatment did not promote fat beigeing but instead significantly increased mitochondrial activity, relative to the untreated control. Therefore, these findings indicate that the mechanism of action of oral cannabis administration, where glucose and lipid homeostasis is restored, is not only dependent on the dosage but also on the type of fat depot investigated.

Topics: Animals; Cannabis; Diabetes Mellitus, Experimental; Insulin Resistance; Insulins; Obesity; Rats; Streptozocin

The consumption of fatty acids has increased drastically, exceeding the nutritional requirements of an individual and leading to numerous metabolic disorders. Recent data indicate a growing interest in using cannabidiol (CBD) as an agent with beneficial effects in the treatment of obesity. Therefore, our aim was to investigate the influence of chronic CBD administration on the n-6/n-3 polyunsaturated fatty acids (PUFAs) ratio in different lipid fractions, inflammatory pathway and oxidative stress parameters in the white and red gastrocnemius muscle. All the designed experiments were performed on Wistar rats fed a high-fat diet (HFD) or a standard rodent diet for seven weeks and subsequently injected with CBD (10 mg/kg once daily for two weeks) or its vehicle. Lipid content and oxidative stress parameters were assessed using gas-liquid chromatography (GLC), colorimetric and/or immunoenzymatic methods, respectively. The total expression of proteins of an inflammatory pathway was measured by Western blotting. Our results revealed that fatty acids (FAs) oversupply is associated with an increasing oxidative stress and inflammatory response, which results in an excessive accumulation of FAs, especially of n-6 PUFAs, in skeletal muscles. We showed that CBD significantly improved the n-6/n-3 PUFA ratio and shifted the equilibrium towards anti-inflammatory n-3 PUFAs, particularly in the red gastrocnemius muscle. Additionally, CBD prevented generation of lipid peroxidation products and attenuated inflammatory response in both types of skeletal muscle. In summary, the results mentioned above indicate that CBD presents potential therapeutic properties with respect to the treatment of obesity and related disturbances.

Topics: Animals; Cannabidiol; Cannabis; Diet, High-Fat; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Inflammation; Insulin Resistance; Lipid Metabolism; Lipid Peroxidation; Lipids; Male; Muscle, Skeletal; Obesity; Oxidative Stress; Rats; Rats, Wistar

Topics: 3T3-L1 Cells; Animals; Cannabinoids; Cannabis; Energy Metabolism; Hydrogen-Ion Concentration; Insulin Resistance; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt

To ascertain the relationship between cannabis use, obesity, and insulin resistance.. Data on 786 Inuit adults from the Nunavik Inuit Health Survey (2004) were analyzed. Information on cannabis use was obtained from a self-completed, confidential questionnaire. Fasting blood glucose and insulin and homeostasis model assessment of insulin resistance (HOMA-IR) served as surrogate markers of insulin resistance. Analysis of covariance and multivariate logistic regression ascertained relationships between cannabis use and outcomes.. Cannabis use was highly prevalent in the study population (57.4%) and was statistically associated with lower body mass index (BMI) (P < 0.001), lower % fat mass (P < 0.001), lower fasting insulin (P = 0.04), and lower HOMA-IR (P = 0.01), after adjusting for numerous confounding variables. Further adjustment for BMI rendered fasting insulin and HOMA-IR differences statistically nonsignificant between past-year cannabis users and nonusers. Mediation analysis showed that the effect of cannabis use on insulin resistance was indirect, through BMI. In multivariate analysis, past-year cannabis use was associated with 0.56 lower likelihood of obesity (95% confidence interval 0.37-0.84).. Cannabis use was associated with lower BMI, and such an association did not occur through the glucose metabolic process or related inflammatory markers. The association between cannabis use and insulin resistance was mediated through its influence on weight.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; Cannabis; Drug Users; Female; Health Surveys; Humans; Insulin; Insulin Resistance; Inuit; Male; Middle Aged; Multivariate Analysis; Obesity; Prevalence; Surveys and Questionnaires; Young Adult

Topics: Blood Glucose; Cannabis; Female; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Waist Circumference

Topics: Blood Glucose; Cannabis; Female; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Waist Circumference

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.

Topics: Adult; Blood Glucose; Cannabis; Cholesterol, HDL; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nutrition Surveys; Prevalence; Triglycerides; United States; Waist Circumference

It is recognized that the endocannabinoid system (ECS) plays a crucial role in the modulation of food intake and other aspects of energy metabolism. In this study, we aimed to investigate the effects of Δ(9)-tetrahydrocannabinol (THC) on adipocyte biology. 3T3-L1 cells were used to evaluate proliferation by sulforhodamine B (SRB) staining and methyl-(3)H-thymidine incorporation after 48 or 72 h of treatment with THC (1-500 nmol/l). Cells were differentiated in the presence or absence of the cannabinoid, and adipogenesis was determined by measuring lipid accumulation and peroxisome proliferator-activated receptor γ (PPARγ) transcription through reverse transcriptase-PCR (RT-PCR). Lipolysis was quantified under basal conditions or after isoproterenol (IP, 100 nmol/l) or insulin (INS, 100 nmol/l) treatment. Transforming growth factor β (TGFβ), diacylglycerol lipase α, and N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) transcriptions were determined by RT-PCR in preadipocytes and adipocytes and adiponectin only in adipocytes. THC treatment increased culture protein content and reduced methyl-(3)H-thymidine incorporation. Cells treated with THC underwent adipogenesis shown by the expression of PPARγ and had increased lipid accumulation. Basal and IP-stimulated lipolyses were inhibited by THC and there was no effect on lipolysis of INS-treated adipocytes. The effects on methyl-(3)H-thymidine incorporation and lipolysis seem to be mediated through CB1- and CB2-dependent pathways. THC decreased NAPE-PLD in preadipocytes and increased adiponectin and TGFβ transcription in adipocytes. These results show that the ECS interferes with adipocyte biology and may contribute to adipose tissue (AT) remodeling. Although these observations point toward increased AT deposition, the stimulation of adiponectin production and inhibition of lipolysis may be in favor of improved INS sensitivity under cannabinoid influence.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Cannabis; Dronabinol; Insulin; Insulin Resistance; Isoproterenol; Lipid Metabolism; Lipolysis; Lipoprotein Lipase; Mice; Phospholipase D; PPAR gamma; Proteins; Psychotropic Drugs; Receptors, Cannabinoid; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Type 2 diabetes, a chronic disease, affects about 150 million people world wide. It is characterized by insulin resistance of peripheral tissues such as liver, skeletal muscle, and fat. Insulin resistance is associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), which in turn inhibits insulin receptor tyrosine kinase autophosphorylation. It has been reported that cannabis is used in the treatment of diabetes. A few reports indicate that smoking cannabis can lower blood glucose in diabetics. Delta(9)-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. This study aimed to determine the effect of a lipophilic cannabis extract on adipogenesis, using 3T3-L1 cells, and to measure its effect on insulin sensitivity in insulin resistant adipocytes. Cells were cultured in Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS) and differentiated over a 3 day period for all studies. In the adipogenesis studies, differentiated cells were exposed to the extract in the presence and absence of insulin. Lipid content and glucose uptake was subsequently measured. Insulin-induced glucose uptake increased, while the rate of adipogenesis decreased with increasing THC concentration. Insulin-resistance was induced using TNF-alpha, exposed to the extract and insulin-induced glucose uptake measured. Insulin-induced glucose was increased in these cells after exposure to the extract. Semiquantitative real time polymerase chain reaction (RT-PCR) was performed after ribonucleic acid (RNA) extraction to evaluate the effects of the extract on glucose transporter isotype 4 (GLUT-4), insulin receptor substrate-1 (IRS-1) and IRS-2 gene expression.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Cannabis; Dronabinol; Glucose; Insulin; Insulin Resistance; Mice; Plant Extracts; Triglycerides