Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:29497784", "kind": "science-record", "revision": 8, "content_hash": "sha256:602df10000d8bf9c8dbe7e3589a601b451b8c8b496e3492b5c7c840c7cffe0fe", "created_at": "2026-11-01T15:40:32Z", "updated_at": "2026-11-01T22:43:17Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets.", "doi": "10.1007/s00125-018-4576-4", "pmid": "29497784", "authors": ["Isabel González-Mariscal", "Rodrigo A Montoro", "Máire E Doyle", "Qing-Rong Liu", "Michael Rouse", "Jennifer F O'Connell", "Sara Santa-Cruz Calvo", "Susan M Krzysik-Walker", "Soumita Ghosh", "Olga D Carlson", "Elin Lehrmann", "Yongqing Zhang", "Kevin G Becker", "Chee W Chia", "Paritosh Ghosh", "Josephine M Egan"], "journal": "Diabetologia", "year": 2018, "abstract": "AIMS/HYPOTHESIS: The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism.\nMETHODS: We generated a beta cell specific Cnr1 (CB1R) knockout mouse (β-CB1R-/-) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961.\nRESULTS: β-CB1R-/- mice had increased fasting (153 ± 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 ± 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high-fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from β-CB1R-/- mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells.\nCONCLUSIONS/INTERPRETATION: Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes.\nDATA AVAILABILITY: Microarray data have been deposited at GEO (GSE102027).", "claims": [{"id": "claim-method", "statement": "Differences between mean values for variables within individual experiments were compared statistically using Student’s t test or ANOVA, as appropriate.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29497784", "locator": "sections[11] \"Quantification and statistical analysis\" paragraph 2", "quote": "Differences between mean values for variables within individual experiments were compared statistically using Student’s t test or ANOVA, as appropriate."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Microarray data have been deposited at GEO (GSE102027). The data generated during the current study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29497784", "locator": "sections[25] \"notes\" paragraph 1", "quote": "Microarray data have been deposited at GEO (GSE102027). The data generated during the current study are available from the corresponding author on reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Headline result: CB1R is a negative regulator of beta cell function and a mediator of islet inflammation under metabolic stress. Statistical method: differences between means were compared using Student’s t test or ANOVA, as appropriate. 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