Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Mol Metab. 2024 Apr;82:101906. doi: 10.1016/j.molmet.2024.101906. Epub 2024 Feb 28.
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.
We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre Cnr1) mice. We evaluated female NOD RIP Cre Cnr1 mice and their NOD RIP CreCnr1 and NOD RIP Cre Cnr1 littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation.
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 mice compared to wild-type littermates. NOD RIP Cre Cnr1 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 cells were significantly higher in NOD RIP Cre Cnr1vs NOD RIP CreCnr1.
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.
1 型糖尿病（T1D）是由于自身反应性免疫细胞浸润胰岛导致β细胞破坏引起的，目前显然β细胞功能障碍也参与了这一过程。我们之前的研究报道，在小鼠中，通过基因敲除和药理学拮抗大麻素 1 型受体（CB1），可以改善胰岛素的合成和分泌，上调葡萄糖感应机制，通过减少细胞凋亡来促进β细胞的存活，并增强β细胞的增殖。此外，β细胞特异性敲除 CB1 可保护高脂高糖饮食喂养的小鼠免受胰岛炎症和β细胞功能障碍的影响。因此，我们假设它可以减轻导致 T1D 的早期事件中β细胞的功能障碍。
我们特异性地从非肥胖型糖尿病（NOD；NOD RIP Cre Cnr1）小鼠的β细胞中敲除 CB1。我们评估了雌性 NOD RIP Cre Cnr1 小鼠及其 NOD RIP Cre Cnr1 和 NOD RIP Cre Cnr1 同窝仔鼠 26 周内发生高血糖的情况。我们还检查了胰岛形态、免疫细胞浸润和β细胞功能和增殖。
与野生型同窝仔鼠相比，NOD 小鼠中 CB1 的β细胞特异性敲除显著降低了高血糖的发生率，从而维持了β细胞的功能和质量。与野生型同窝仔鼠相比，敲除还可防止 NOD RIP Cre Cnr1 小鼠的β细胞凋亡和侵袭性胰岛炎。NOD RIP Cre Cnr1 胰岛保持正常形态，没有β细胞去分化或胰岛外β细胞出现的证据，表明从自身免疫中保护β细胞是 CB1 基因敲除所固有的。与 NOD RIP Cre Cnr1 相比，NOD RIP CreCnr1 胰腺淋巴结 T 细胞明显升高。
这些数据共同表明，在 T1D 的活跃期保护β细胞免受代谢应激可以改善破坏性胰岛炎，并为 CB1 作为 T1D 的潜在药物靶点提供了证据。
