Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Endocrinology. 2018 Sep 1;159(9):3235-3244. doi: 10.1210/en.2018-00451.
Glucose-stimulated insulin secretion (GSIS) is essential for blood glucose homeostasis and is impaired in type 2 diabetes mellitus. Understanding the regulatory components of GSIS has clinical implications for diabetes treatment. In this study, we found that olfactomedin 4 (OLFM4) is endogenously expressed in pancreatic islet β cells and further investigated its potential roles in glucose homeostasis and the pathogenesis of type 2 diabetes using mouse models. Olfm4-deficient mice showed significantly improved glucose tolerance and significantly increased insulin levels after glucose challenge compared with wild-type (WT) mice. GSIS, mitochondrial ATP production, and mitochondrial respiration were all significantly increased in islets isolated from Olfm4-deficient mice compared with those isolated from WT mice. In a high-fat diet (HFD)-induced diabetic mouse model, the increase in insulin levels after glucose challenge was significantly higher in Olfm4-deficient mice compared with WT mice. The impaired glucose tolerance and insulin resistance in HFD-fed mice were improved by loss of Olfm4. Olfm4 was found to be mainly localized in the mitochondria and interacts with GRIM-19 (a gene associated with retinoid-interferon mortality) in Min6 pancreatic β cells. Collectively, these studies suggest that Olfm4 negatively regulates GSIS. OLFM4 may represent a potential therapeutic target for impaired glucose tolerance and patients with type 2 diabetes.
葡萄糖刺激的胰岛素分泌（GSIS）对于血糖稳态至关重要，并且在 2 型糖尿病中受损。了解 GSIS 的调节成分对糖尿病的治疗具有临床意义。在这项研究中，我们发现嗅觉素 4（OLFM4）在胰岛β细胞中内源性表达，并使用小鼠模型进一步研究了其在葡萄糖稳态和 2 型糖尿病发病机制中的潜在作用。与野生型（WT）小鼠相比，Olfm4 缺陷型小鼠表现出明显改善的葡萄糖耐量和葡萄糖刺激后胰岛素水平显著升高。与 WT 小鼠分离的胰岛相比，Olfm4 缺陷型小鼠的 GSIS、线粒体 ATP 产生和线粒体呼吸均显著增加。在高脂肪饮食（HFD）诱导的糖尿病小鼠模型中，与 WT 小鼠相比，Olfm4 缺陷型小鼠葡萄糖刺激后胰岛素水平的升高更为明显。Olfm4 的缺失改善了 HFD 喂养小鼠的葡萄糖耐量受损和胰岛素抵抗。Olfm4 主要定位于线粒体，并与 Min6 胰岛β细胞中的 GRIM-19（与视黄醇干扰素死亡率相关的基因）相互作用。总之，这些研究表明 Olfm4 负调节 GSIS。OLFM4 可能代表改善葡萄糖耐量和 2 型糖尿病患者的潜在治疗靶标。
