LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

Ruz‐Maldonado, Inmaculada; Pingitore, Attilio; Liu, Bo; Atanes, Patricio; Huang, Guo Cai; Baker, David; Alonso, Francisco; Bermúdez‐Silva, Francisco Javier; Persaud, Shanta J.

doi:10.1111/dom.13180

Cited by 22 publications

(31 citation statements)

References 62 publications

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“…Notwithstanding, immunohistological analysis of pancreas showed that treatment with Abn-CBD greatly lowered islet cell apoptosis while induced beta cell proliferation, thus promoting preservation of beta cell mass. These findings are in agreement with our previous work showing a proliferative and protective role of Abn-CBD against cytokine-induced apoptosis on isolated islets from lean mice and human (21). Similar observations were also obtained in STZ-induced diabetic mice by another group (15).…”

Section: Discussionsupporting

confidence: 93%

“…Indeed, Abn-CBD was found to improve glucose tolerance in streptozotocin-induced diabetic mice (15). In agreement with these findings we recently reported that Abn-CBD decreases cytokine-induced apoptosis in mouse and human isolated islets while promoting beta cell proliferation (21). However, the impact of Abn-CBD on obesity-related metainflammation and its relationship with prediabetes and NAFLD remains unstudied.…”

Section: Introductionsupporting

confidence: 60%

“…We and others have previously demonstrated that Abn-CBD can directly stimulate insulin secretion in vitro (21,23) as well as in vivo in a mouse model of mild type 1 diabetes (15). However, to the best of our knowledge it has not been assayed in a mouse model of obesity and prediabetes.…”

Section: Discussionmentioning

confidence: 95%

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The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

et al. 2020

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Results: Body weight and triglycerides profiles in blood and liver were comparable between vehicle-and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicletreated DIO mice. Romero-Zerbo et al. Abn-CBD in Prediabetes and NAFLD Conclusions: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionsupporting

confidence: 60%

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The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

et al. 2020

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“…Table S3. Images were visualized using a Nikon A1 Inverted Confocal microscope and analysed blindly before quantification using Fiji Image J software (https ://fiji.sc) [4]. For each experiment, the images were acquired with the same settings and histological quantifications were performed in paraffin sections that had been immunostained under the same conditions.…”

Section: Islet β-Cell Proliferationmentioning

confidence: 99%

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

Ruz‐Maldonado

Liu

Atanes

et al. 2020

Cell. Mol. Life Sci.

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Aims Endocannabinoids are lipid mediators involved in the regulation of glucose homeostasis. They interact with the canonical cannabinoid receptors CB 1 and CB 2 , and it is now apparent that some cannabinoid receptor ligands are also agonists at GPR55. Thus, CB 1 antagonists such as SR141716A, also known as rimonabant, and AM251 act as GPR55 agonists in some cell types. The complex pharmacological properties of cannabinoids make it difficult to fully identify the relative importance of CB 1 and GPR55 in the functional effects of SR141716A, and AM251. Here, we determine whether SR141716A and AM251 regulation of mouse and human islet function is through their action as GPR55 agonists. Methods Islets isolated from Gpr55 +/+ and Gpr55 −/− mice and human donors were incubated in the absence or presence of 10 µM SR141716A or AM251, concentrations that are known to activate GPR55. Insulin secretion, cAMP, IP 1 , apoptosis and β-cell proliferation were quantified by standard techniques. Results Our results provide the first evidence that SR141716A and AM251 are not GPR55 agonists in islets, as their effects are maintained in islets isolated from Gpr55 −/− mice. Their signalling through G q-coupled cascades to induce insulin secretion and human β-cell proliferation, and protect against apoptosis in vitro, indicate that they have direct beneficial effects on islet function. Conclusion These observations may be useful in directing development of peripherally restricted novel therapeutics that are structurally related to SR141716A and AM251, and which potentiate glucose-induced insulin secretion and stimulate β-cell proliferation.

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“…agonists like lysophosphatidylcholine (LPC) and abnormal Cannabidiol (abn-CBD) did not show any significant modulation in the cyclic AMP (Ruz-Maldonado et al, 2018, Drzazga, 2018; however, CB2 agonists have been shown to inhibit cyclic AMP (Herring et al, 1998). Additionally, literature shows, GPR55 heterodimerizes with CB2 to modulate downstream cell signaling (Balenga et al, 2014), further, GPR55 ligands also promote receptor coupling to multiple cell signaling pathways (Henstridge et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells

Parira¹

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LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

Abstract: This study showed that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55 mice suggests that designation of Abn-CBD and LH-21 as a GPR55 agonist and a CB1 antagonist, should be revised.

Cited by 22 publications

References 62 publications

The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells

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