Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cell

Juan-Picó, Pablo; Fuentes, Esther; Bermúdez‐Silva, Francisco Javier; Diaz-Molina, Francisco Javier; Ripoll, Cristina; Fonseca, Fernando Rodrı́guez de; Nadal, Ángel

doi:10.1016/j.ceca.2005.10.005

Cited by 245 publications

(219 citation statements)

References 33 publications

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“…76 These data generally support a model in which CB1R inverse agonists reduce the intake of all macronutrients with no selectivity related to palatability. Matias et al 60 increase GDIS block agonist effect Juan-Pico et al 61 decrease GDIS not determined Getty-Kaushik et al 63 not determined decrease GDIS Nakata et al 62 decrease GDIS not determined CB1R mechanism of action TM Fong and SB Heymsfield…”

Section: Do Cb1r Agents Produce Weight Loss-independent Effects?mentioning

confidence: 99%

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong

Heymsfield

2009

Int J Obes

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Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

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Section: Do Cb1r Agents Produce Weight Loss-independent Effects?mentioning

confidence: 99%

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong

Heymsfield

2009

Int J Obes

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“…Also, the CB contributes to the physiological regulation of energy balance, food intake and lipid and glucose metabolisms. Juan-Picó et al 30 have shown the existence of CB1 and CB2 receptors (both are seven domain transmembrane receptors coupled to G-proteins) in endocrine pancreas by PCR and immunocytochemistry studies, and their implication in Ca 2 þ signaling and insulin secretion. Endocannabinoids (EC), 2-acylglycerol and anandamide, regulate the Ca 2 þ channels inhibiting glucose-mediated intracellular calcium rise; these effects are mediated through CB1 and CB2 receptors, or through the TRVP receptors, a separate subgroup of non-selective cationic channels, transient receptor potential (TRP), belonging to the vanilloid receptor family present in the pancreatic islet.…”

Section: Endothelial Dysfunction In Erectile Dysfunction a Aversa Et Almentioning

confidence: 99%

Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users

et al. 2008

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Aim of the study was to evaluate whether endothelial dysfunction is a marker of erectile dysfunction (ED) in recreational drug abuse. Sixty-four non-consecutive men complaining of ED from at least 3 months were included. All patients underwent detailed history about recreational drug abuse and were then submitted to dynamic penile duplex ultrasound (PDU). According to pharmaco-stimulated peak systolic velocity (PSV) cutoff at 35 cm s À1 , patients were divided into two groups: organic (O; n ¼ 30) and non-organic (NO; n ¼ 34) ED. All subjects and 7 healthy age-matched subjects as controls, underwent veno-occlusive plethysmography (VOP) for the evaluation of endothelium-dependent dilatation of brachial arteries. Blood pressure, total and free testosterone, prolactin, estradiol, low-density lipoprotein and high-density lipoprotein cholesterol were also evaluated; patients were classified with regard to insulin resistance through the HOMA-IR index. Cannabis smoking was more frequent in O-ED vs NO-ED (78% vs 3%, Po0.001) in the absence of any concomitant risk factor or comorbidity for ED. VOP studies revealed impaired endotheliumdependent vasodilatation in O-ED but not in NO-ED and controls (12±6 vs 32±4 and 34 ± 5 ml min À1 , respectively; P ¼ 0.003). Overall patients showed a direct relationship between HOMA-IR and PSV (r 2 ¼ 0.47, Po0.0001), which was maintained in men with organic ED (r 2 ¼ 0.62, Po0.0001). In cannabis consumers, a direct relationship between HOMA-IR and VOP was also found (r 2 ¼ 0.74, Po0.0001). Receiver-operating characteristic (ROC) curve analysis revealed that VOP values below 17.22 ml min À1 were suggestive for vasculogenic ED. We conclude that early endothelial damage may be induced by chronic cannabis use (and endocannabinoid system activation); insulin resistance may be the hallmark of early endothelial dysfunction and may concur to determine vascular ED in the absence of obesity. Further studies are warranted to establish a direct relationship between cannabis abuse, onset of insulin resistance and development of vascular ED.

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“…31 Owing to the favourable metabolic and vascular effects recognized for adiponectin 32 , this may at least partially explain various effects such as improvement of insulin sensitivity and oxidation of fatty acids, and reduction in vascular inflammation. 31 These CB1 receptors are also found in the gut 33 , liver 34 , skeletal muscle 35 , and pancreas 36,37 , all organs playing a key role in the pathophysiology of type-2 diabetes (Figure 1) (see below).…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

“…31 Several findings indicate that the EC system participates locally in adipogenesis and fat accumulation, partially by accelerating the appearance and stimulating the activity of peroxisome proliferatoractivated receptor γ (PRAR-γ). 37 The precise roles of ECs and CB1 receptors in the skeletal muscle and in the pancreas 36,37 are less well known and deserve further research -especially in cells and tissues producing and responding to insulin -in order to better understand the role of the EC system in type-2 diabetes.…”

Section: Animal Datamentioning

confidence: 99%

Cannabinoid-1 receptor antagonists in type-2 diabetes

Scheen

2007

Best Practice & Research Clinical Endocrinology & Metab

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Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in HbA1c levels was observed in metformin-or sulphonylurea-treated patients with type-2 diabetes and in drugnaïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally welltolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration.Keywords: rimonabant ; obesity ; type-2 diabetes ; cardiovascular risk ; CB 1 receptor blocker ; endocannabinoid system. Type-2 diabetes frequently coexists with a cluster of other cardiovascular and metabolic risk factors -including abdominal obesity, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, elevated blood pressure and silent inflammation -and is considered to be a cardiovascular disease (CVD) risk equivalent. 1,2 Being overweight or obese -abdominally obese in particular -increases the risk of type-2 diabetes and CVD. [3][4][5] Yet individuals with type-2 diabetes often have more difficulty in losing weight and experience weight gain associated with most antidiabetic medications. 6,7 The treatment of multiple cardiovascular and metabolic riskfactors is central to the management of diabetic patients 1,2,5,8,9 , and the importance of weight management is well recognized in type-2 diabetes. 7,10,11 Over the last two decades a new biochemical/physiological system, known as the endocannabinoid (EC) system, was discovered. 12,13 There is considerable evidence that the EC system plays a significant role in appetite drive and associated behaviours, but also in endocrine and metabolic regulation and energy balance. 14 Indeed, cannabinoid (CB) receptors, especially CB1 receptors, participate in the physiological modulation of many central and peripheral functions. 14 The tremendous advances in the understanding of the molecular basis of CB activity 15 has encouraged many pharmaceutical companie...

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Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cell

Cited by 245 publications

References 33 publications

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users

Cannabinoid-1 receptor antagonists in type-2 diabetes

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