anandamide and Diabetes-Mellitus--Type-2

Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels. Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression. These cannabinoid receptors are part of a large family of G protein coupled receptors (GPCRs). GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal, and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus. Obesity is considered a state of chronic low-grade inflammation elicited by an immunological response. Interestingly, the newly deorphanized GPCR (GPR18), which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function. In this review, the current scientific knowledge on GPR18 is explored including its localization, signaling pathways, and pharmacology. Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described. Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.

Topics: Animals; Arachidonic Acids; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Endocannabinoids; Energy Intake; Genetic Therapy; Glycerides; Humans; Obesity; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Signal Transduction

Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders.

Topics: Adipose Tissue; Animals; Arachidonic Acids; Body Weight; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Humans; Insulin Resistance; Obesity; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Signal Transduction

The endogenous cannabinoid system participates in the regulation of energy homeostasis, and this fact led to the identification of a new group of therapeutic agents for complicated obesity and diabetes. Cannabinoid receptor antagonists are now realities in clinical practice. The use of such antagonists for reducing body weight gain, lowering cholesterol and improving glucose homeostasis is based on the ability of the endocannabinoids to coordinately regulate energy homeostasis by interacting with central and peripheral targets, including adipose tissue, muscle, liver and endocrine pancreas. In this review we will analyse the presence of this system in the main cell types of the islets of Langerhans, as well as the physiological relevance of the endocannabinoids and parent acylethanolamides in hormone secretion and glucose homeostasis. We will also analyse the impact that these findings may have in clinical practice and the potential outcome of new therapeutic strategies for modulating glucose homeostasis and insulin/glucagon secretion.

Topics: Amides; Animals; Arachidonic Acids; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Ethanolamines; Glucagon; Glucose; Glycerides; Homeostasis; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to "fix" the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.

Topics: Adipocytes; Adiponectin; Animals; Appetite Regulation; Arachidonic Acids; Cannabinoid Receptor Modulators; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Dronabinol; Eating; Endocannabinoids; Energy Metabolism; Humans; Lipid Metabolism; Obesity; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

Endothelial dysfunction is considered as a major risk factor of cardiovascular complications of type I and types II diabetes. Impaired endothelium-dependent vasodilatation can be directly linked to a decreased synthesis of the endothelium-derived nitric oxide (NO) and/or an increase in the production of reactive oxygen species such as superoxide. Administration of tetrahydrobiopterin, an important co-factor for the enzyme nitric oxide synthase (NOS), has been demonstrated to enhance NO production in prehypertensive rats, restore endothelium-dependent vasodilatation in coronary arteries following reperfusion injury, aortae from streptozotocin-induced diabetic rats and in patients with hypercholesterolemia. Tetrahydrobiopterin supplementation has been shown to improve endothelium-dependent relaxation in normal individuals, patients with type II diabetes and in smokers. These findings from different animal models as well as in clinical trials lead to the hypothesis that tetrahydrobiopterin, or a precursor thereof, could be a new and an effective therapeutic approach for the improvement of endothelium function in pathophysiological conditions. In addition to NO, the endothelium also produces a variety of other vasoactive factors and a key question is: Is there also a link to changes in the synthesis/action of these other endothelium-derived factors to the cardiovascular complications associated with diabetes? Endothelium-derived hyperpolarizing factor, or EDHF, is thought to be an extremely important vasodilator substance notably in the resistance vasculature. Unfortunately, the nature and, indeed, the very existence of EDHF remains obscure. Potentially there are multiple EDHFs demonstrating vessel selectivity in their actions. However, until now, identity and properties of EDHF that determine the therapeutic potential of manipulating EDHF remains unknown. Here we briefly review the current status of EDHF and the link between EDHF and endothelial dysfunction associated with diabetes.

Topics: Animals; Arachidonic Acids; Biological Factors; Diabetes Mellitus, Type 2; Endocannabinoids; Endothelium, Vascular; Fatty Acids, Unsaturated; Gap Junctions; Humans; Hydrogen Peroxide; Isoprostanes; Models, Biological; Nitric Oxide; Polyunsaturated Alkamides; Potassium

Endocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac function is still unknown. Therefore, our aim was to investigate this relationship in obese T2D patients with coronary artery disease (CAD).. In a prospective intervention study, obese T2D patients with CAD (n = 27) followed a 16 week very low calorie diet (VLCD; 450-1000 kcal/day). Cardiac function and fat accumulation were assessed with MRI and spectroscopy. Plasma levels of lipid species, including ECs, were measured using liquid chromatography-mass spectrometry.. Caloric restriction in T2D patients with CAD decreases AEA levels, but not 2-AG levels, which is paralleled by decreased lipid accumulation in adipose tissue, liver and heart, and improved cardiovascular function. Interestingly, baseline AEA levels strongly correlated with SAT volume. We anticipate that dietary interventions are worthwhile strategies in advanced T2D, and that reduction in AEA may contribute to the improved cardiometabolic phenotype induced by weight loss.

Topics: Adipose Tissue; Aged; Arachidonic Acids; Body Fat Distribution; Caloric Restriction; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diet, Reducing; Endocannabinoids; Energy Intake; Ethanolamines; Female; Glycerides; Heart; Humans; Lipid Metabolism; Liver; Male; Middle Aged; Myocardium; Obesity; Polyunsaturated Alkamides; Prospective Studies; Ventricular Function, Left; Weight Loss

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.

Topics: Animals; Apoptosis; Arachidonic Acids; Cannabinoid Receptor Agonists; Carrier Proteins; Cell Line; Cell Survival; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Hyperglycemia; Inflammasomes; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Polyunsaturated Alkamides; Rats; RNA Interference; RNA, Small Interfering

Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cell Line; Diabetes Mellitus, Type 2; Endocannabinoids; Enzyme Activation; Exocytosis; Focal Adhesion Kinase 1; Glycerides; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Knockout; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Receptor, Cannabinoid, CB1; Secretory Vesicles

Circulating levels of anandamide are increased in diabetes, and cannabidiol ameliorates a number of pathologies associated with diabetes. The aim of the present study was to examine how exposure to anandamide or cannabidiol might affect endothelial dysfunction associated with Zucker Diabetic Fatty rats. Age-matched Zucker Diabetic Fatty and Zucker lean rats were killed by cervical dislocation and their arteries mounted on a myograph at 37 °C. Arteries were incubated for 2h with anandamide, cannabidiol or vehicle, contracted, and cumulative concentration-response curves to acetylcholine were constructed. Anandamide (10 µM, 2h) significantly improved the vasorelaxant responses to acetylcholine in aortae and femoral arteries from Zucker Diabetic Fatty rats but not Zucker lean rats. By contrast, anandamide (1 µM, 2h) significantly blunted acetylcholine-induced vasorelaxation in third-order mesenteric arteries (G3) from Zucker Diabetic Fatty rats. Cannabidiol incubation (10 µM, 2h) improved acetylcholine responses in the arteries of Zucker Diabetic Fatty rats (aorta and femoral) and Zucker lean (aorta, femoral and G3 mesenteric), and this effect was greater in the Zucker Diabetic Fatty rat. These studies suggest that increased circulating endocannabinoids may alter vascular function both positively and negatively in type 2 diabetes, and that part of the beneficial effect of cannabidiol in diabetes may be due to improved endothelium-dependent vasorelaxation.

Topics: Animals; Aorta, Thoracic; Arachidonic Acids; Cannabidiol; Diabetes Mellitus, Type 2; Disease Models, Animal; Endocannabinoids; Endothelium, Vascular; Femoral Artery; Male; Mesenteric Arteries; Polyunsaturated Alkamides; Rats; Rats, Zucker; Vasodilation

Obstructive sleep apnea chronically increases blood pressure through sympathetic nervous system activation. In animals, hypertension and sympathetic activity are restrained by cannabinoid receptor activation. Therefore, we hypothesized that increased blood pressure in patients with obstructive sleep apnea is associated with increased circulating endocannabinoid concentrations.. Arterial oxygen saturation and apnea/hypopnea episodes were recorded in 29 patients with normal glucose tolerance, 26 patients with type 2 diabetes mellitus, and 21 patients obese subjects without sleep apnea. We determined seated blood pressure, insulin, glucose, and high-sensitive C-reactive protein in the morning, and insulin sensitivity by euglycemic-hyperinsulinemic clamp the next day. Anandamide, the sum of 1-arachidonoylglycerol and 2-arachidonoylglycerol, and oleoylethanolamide were measured in plasma by liquid chromatography-tandem mass spectrometry.. Endocannabinoid concentrations in sleep apnea patients were increased compared to obese individuals without disordered nocturnal breathing. Correction for variables of obesity and insulin resistance almost completely abrogated this difference in endocannabinoids. Anandamide strongly correlated with blood pressure in sleep apnea patients (r = 0.60 for SBP and r = 0.58 for DBP, P < 0.001). In multivariate regression analysis, anandamide was a stronger determinant of blood pressure than sleep apnea severity, obesity, insulin resistance, and inflammation.. Obstructive sleep apnea patients show positive correlations between blood pressure and venous anandamide concentrations independent of confounding factors. Our data suggest a previously not recognized role of the endocannabinoid system for blood pressure regulation in patients with high risk for hypertension and cardiovascular disease.

Topics: Aged; Arachidonic Acids; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endocannabinoids; Female; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Obesity; Polyunsaturated Alkamides; Risk Factors; Sleep Apnea, Obstructive

The endocannabinoids, anandamide and 2-AG, are produced by adipocytes, where they stimulate lipogenesis via cannabinoid CB1 receptors and are under the negative control of leptin and insulin. Endocannabinoid levels are elevated in the blood of obese individuals and nonobese type 2 diabetes patients. To date, no study has evaluated endocannabinoid levels in subcutaneous adipose tissue (SAT) of subjects with both obesity and type 2 diabetes (OBT2D), characterised by similar adiposity and whole body insulin resistance and lower plasma leptin levels as compared to non-diabetic obese subjects (OB).. The levels of anandamide and 2-AG, and of the anandamide-related PPARalpha ligands, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), in the SAT obtained by abdominal needle biopsy in 10 OBT2D, 11 OB, and 8 non-diabetic normal-weight (NW) subjects, were measured by liquid chromatography-mass spectrometry. All subjects underwent a hyperinsulinaemic euglycaemic clamp.. As compared to NW, anandamide, OEA and PEA levels in the SAT were 2-4.4-fold elevated (p < 0.05), and 2-AG levels 2.3-fold reduced (p < .05), in OBT2D but not in OB subjects. Anandamide, OEA and PEA correlated positively (p < .05) with SAT leptin mRNA and free fatty acid during hyperinsulinaemic clamp, and negatively with SAT LPL activity and plasma HDL-cholesterol, which were all specifically altered in OBT2D subjects.. The observed alterations emphasize, for the first time in humans, the potential different role and regulation of adipose tissue anandamide (and its congeners) and 2-AG in obesity and type 2 diabetes.

Topics: Adiposity; Adult; Amides; Arachidonic Acids; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Ethanolamines; Female; Humans; Lipids; Male; Middle Aged; Obesity; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Subcutaneous Fat

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.

Topics: 3T3 Cells; Adipocytes; Adult; Aged; Amides; Animals; Arachidonic Acids; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Ethanolamines; Female; Humans; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Models, Biological; Obesity; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; PPAR gamma; Review Literature as Topic; Structure-Activity Relationship