Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice.

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  • Additional Information
    • Source:
      Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
    • Publication Information:
      Original Publication: [München] : Elsevier GmbH, 2012-
    • Subject Terms:
      Diabetes Mellitus, Type 1*/metabolism ; Islets of Langerhans*/metabolism ; Diabetes Mellitus, Experimental*/metabolism ; Cannabinoids*/metabolism ; Hyperglycemia*/genetics ; Hyperglycemia*/metabolism; Mice ; Female ; Animals ; Mice, Inbred NOD
    • Abstract:
      Objective: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D.
      Methods: We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre +  Cnr1 fl/fl ) mice. We evaluated female NOD RIP Cre +  Cnr1 fl/fl mice and their NOD RIP Cre - Cnr1 fl/fl and NOD RIP Cre +  Cnr1 Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation.
      Results: Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre +  Cnr1 fl/fl mice compared to wild-type littermates. NOD RIP Cre +  Cnr1 fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node T reg cells were significantly higher in NOD RIP Cre +  Cnr1 fl/fl vs NOD RIP Cre - Cnr1 fl/fl .
      Conclusions: Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D.
      Competing Interests: Declaration of competing interest None.
      (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
    • Comments:
      Erratum in: Mol Metab. 2024 Mar 16;:101917. (PMID: 38499184)
    • Contributed Indexing:
      Keywords: Beta cell apoptosis; Beta cell proliferation; Cannabinoid 1 receptor; Insulitis; Islet of Langerhans; Type 1 diabetes
    • Accession Number:
      0 (Cannabinoids)
    • Publication Date:
      Date Created: 20240229 Date Completed: 20240402 Latest Revision: 20240402
    • Publication Date:
      20240402
    • Accession Number:
      PMC10940176
    • Accession Number:
      10.1016/j.molmet.2024.101906
    • Accession Number:
      38423253