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Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes
• 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 endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass.
• The dysregulation of redox homeostasis has been linked with the development of various pathologies, including those associated with metabolic disorders such as type 2 diabetes and obesity, cardiovascular disease, as well as various neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis; figure 1) [6–11].
• There is evidence to suggest that stimulation of CB2R may also convey beneficial free radical scavenging effects. Indeed, in a study by Ribeiro et al. , and co-workers, the selective CB2R agonist AM1241 was shown to almost completely block ROS generation in response to lipopolysaccharide (LPS) in BV-2 cells. Consistent with this, CB2R activation has also been reported to attenuate oxidative stress damage in various tissue types, including brain , kidney , heart  and liver .
• Previous work using CB2R agonists and/or knockout mice indicates that activation of CB2R confers protection against hepatic ischaemia–reperfusion (I/R) injury, concomitant with its ability to alleviate tissue free radical damage [66–68]. Allied to this, further evidence supporting a protective role for the ECS was provided in a study by Cao et al. , who demonstrated that pharmacological inhibition of monoacylglycerol lipase, the enzyme which catalyses the hydrolysis of 2-AG, led to the suppression of oxidative stress and associated inflammation in liver tissue following hepatic I/R injury in mice .
• Adipose tissue influences many processes, including: energy metabolism, inflammation, and pathophysiological changes such as cancer and infectious disease
• Apart from the lipid-storage function, adipose cells produce and release several proteins that are involved in the regulation of energy metabolism at different levels. The most important members of these proteins, called adipokines, are leptin, tumour necrosis factor a (TNFa), resistin and adiponectin. Leptin inhibits food intake and stimulates energy expenditure; resistin and TNFa are involved in local inﬂammation and insulin resistance; and adiponectin improves insulin action and has anti-inﬂammatory action in liver and blood vessels.
• The endocannabinoid system is present in human adipose tissue. It promotes adipogenesis by complex and two-way interactions with the various isoforms of PPARs (c, a and d), and it is dysregulated in obesity in a depot-speciﬁc manner. Additionally, endocannabinoids are modulators of adipokines production, although evidence in humans is not fully demonstrated. Finally, endocannabinoids have an insulin-mimetic action on glucose uptake in human adipose cells that is mediated by activation of CB1 receptors, phosphatidylinositol 3-kinase, and an increase in intracellular calcium, and is relevant during adipogenesis (Fig. 3).
• Activation of CB1 receptor increases lipoprotein lipase activity in primary mouse adipocytes (9), and this would augment the ﬂux of free fatty acids to adipocytes for triglycerides synthesis. The role of endocannabinoids and CB1 receptors in the accumulation of neutral lipids in fat cells was conﬁrmed by Matias et al. (14), who reported that the treatment of 3T3-F442A cells with the potent CB1 receptor agonist, HU210 increases the accumulation of intracellular lipid droplets. It is noteworthy that adipose cell differentiation is preceded by a rise of 2-AG and anandamide production by adipocytes,thus further supporting the role of this system in driving adipose conversion of preadipocytes (14).
• Consistent with previous reports, our findings showed that insulin deficient diabetes induced by STZ exacerbated the accumulation of Aβ in APP/PS1 transgenic mice .
• The accumulating evidence that a lower expression of insulin and insulin receptors occurs in the brain of AD suggests a role of impaired insulin signaling pathway in the pathogenesis of AD [27, 28].
• In addition, insulin can be partially formed in the hippocampus, prefrontal cortex, entorhinal cortex, and the olfactory bulb . In the brain, insulin exerts its pleiotropic effects through binding to its receptors and forms the insulin/IR complex , and triggers the IR to undergo dimerization and autophosphorylation .
• The phosphorylated or active IR is involved in the activation of two major downstream signaling pathways, the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways [20, 40]. GSK3 is one of the key molecules downstream of the PI3K signaling pathway , and ERK and JNK are major components of two parallel cascades, respectively, in the MAPK pathways . Importantly, GSK3, ERK and JNK have all been shown to be involved in the formation of pathomorphological AD hallmarks, such as Aβ plaques [43–45], hyperphosphorylated tau [46–50], and cerebral neuronal death [51–53].
• In the present study we show that administration of CBD to 11–14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease.
• Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.
• The morphological structure of intact islets from CBD-treated NOD mice was similar to normal islets, in contrast to the abundant mononuclear cell invasion into islets in vehicle-treated and untreated mice. The number of intact islets in pancreata taken from untreated (6 out of 73, 8%) and vehicle treated mice (12 out of 94, 13%) decreased, compared to CBD-treated mice (108 out of 140, 77%).
• Treatment with Δ(9)-THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non-treatment diabetes group.
• The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic.
• We can suggest that Δ(9) -THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti-hyperglycaemic agents.
• Cannabis treatment reduced the deleterious effects of DIO by reducing weight gain, specifically fat depots, maintaining insulin levels, altering cytokine and gene expression levels that induce increased energy expenditure, while protecting pancreatic tissue from apoptosis by promoting proliferation.
• Our results show for the first time an insulin-like effect of CNR1 activation on human adipocytes.
• Our study is the first to demonstrate the effect of endocannabinoids on glucose uptake in human adipocytes, which was about 50% of the effect produced by insulin. Because adipocytes express the enzymatic pathways to produce endogenous cannabinoids, it appears that glucose uptake may be locally modulated by endocannabinoids.
• In conclusion, these studies demonstrate an insulin-mimetic action of endocannabinoids on glucose uptake that is mediated by activation of CNR1, PI3-kinase, and the increase of intracellular calcium. The metabolic effect of CNR1-mediated endocannabinoids, the reciprocal interaction with PPARγ, and the up-regulation of the endocannabinoid system in abdominal adipose tissue of obese subjects strengthen the role of local endocannabinoids in the regulation of adipose tissue in physiology and pathology.
We show that endocannabinoids (ω-6) via CB1 cannabinoid receptors and endovanilloid ligands via transient receptor potential cation channel subfamily V member 1, as well as dietary ω-3 polyunsaturated fatty acids, affect the cellular organization of pancreatic islets during organ development. Thus, lipid signaling emerges as a key determinant of tissue organization and can program hormone secretion for life.
Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration.
• The ECS plays an essential role in regulating metabolism and glucose homeostasis .
• Administration of SER601 ameliorated insulin resistance in HFD/STZ-induced diabetic mice
—As demonstrated in Figure 1 a&c, results from IPGTT tests showed no change on glucose tolerance in mice that have been treated with 2- or 4-week SER601 (closed circles) compared to controls (open circles). However, both 2- and 4-week exposure to SER601 resulted in significant improvement of insulin sensitivity, implicating a beneficial impact of CB2 receptor activation on overall insulin sensitivity in diabetic mice.
• Increased islet area, insulin content and more robust insulin secretory capacity in response to glucose were observed from islets obtained from the SER601-treated mice, implicating a beneficial impact of CB2 receptor activation on β-cell function, which is consistent with multiple previous studies reporting stimulatory impact of CB2 receptor activation on in vitro insulin secretion [1,5,6,7,8]. In addition, substantial elevation of fasting serum insulin level was also recorded from the SER601 animals, accompanied by normalised serum glucagon concentration, supporting a role of the CB2 receptor activation on maintaining islet hormone secretion.
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