Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Division of Endocrinology, Department of Medicine, Duke Molecular Physiology Institute, Durham, North Carolina, USA.
J Clin Invest. 2022 Nov 1;132(21):e160097. doi: 10.1172/JCI160097.
The molecular mechanisms underlying obesity-induced increases in β cell mass and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet-induced (HFD-induced) obese mouse model. GPR92-KO mice exhibited glucose intolerance and reduced insulin levels - despite the enlarged pancreatic islets - as well as increased islet macrophage content and inflammation level compared with WT mice. These results indicate that the lack of GPR92 in islet macrophages can cause β cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, stimulation with the GPR92 agonist farnesyl pyrophosphate results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92-KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate β cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.
肥胖引起的β细胞质量增加和随之而来的β细胞功能障碍的分子机制需要进一步阐明。我们的研究表明，在代谢组织中，表达在胰岛巨噬细胞中的 GPR92 受到饮食干预的调节。因此，我们旨在使用高脂肪饮食诱导（HFD 诱导）肥胖小鼠模型来定义 GPR92 在胰岛炎症中的作用。与 WT 小鼠相比，GPR92-KO 小鼠表现出葡萄糖不耐受和胰岛素水平降低 - 尽管胰腺胰岛增大 - 以及胰岛巨噬细胞含量和炎症水平增加。这些结果表明，胰岛巨噬细胞中缺乏 GPR92 会导致β细胞功能障碍，导致葡萄糖稳态紊乱。或者，用 GPR92 激动剂法呢基焦磷酸刺激可抑制 WT 小鼠的 HFD 诱导的胰岛炎症和增加胰岛素分泌，但不能在 GPR92-KO 小鼠中进行。因此，我们的研究表明，GPR92 可以通过抑制与糖尿病进展相关的胰岛炎症来缓解β细胞功能障碍，成为一个潜在的治疗靶点。
