Diabetes often presents with ocular surface complications including dry eye, keratopathy, and altered sensitivity, along with systemic disorders. A common theme associated with corneal surface defects is decreased cellular proliferation. The opioid growth factor (OGF)–OGF receptor (OGFr) regulatory axis maintains epithelial homeostasis and can be modulated by naltrexone, an opioid receptor antagonist, to block OGF–OGFr interaction and increase cellular replication. Complete blockade using naltrexone accelerates cell proliferation, increases the rate of re-epithelialization in corneal surface abrasions, reverses dry eye, and restores corneal surface sensitivity in animal models of type 1 and type 2 diabetes. Data on the efficacy of naltrexone in these models suggest that the OGF–OGFr axis is dysregulated in diabetes. In the present study, we investigated the OGF–OGFr axis by assessing serum and tissue levels of OGF and OGFr during the development of streptozotocin-induced hyperglycemia and postulated a mechanism of action. We correlated the dysregulation of the OGF–OGFr axis with the onset and magnitude of corneal surface complications (e.g. tear fluid production, corneal surface sensitivity) in type 1 diabetes (T1D). Serum levels of OGF increased in both uncontrolled T1D and insulin-controlled (T1D-INS) male rats within four weeks of streptozotocin injection. Serum OGFr levels were significantly reduced in diabetic rats on weeks 3 and 8 post streptozotocin. Tear production was significantly reduced, and corneal sensitivity measurements were abnormal in both T1D and T1D-INS animals within four weeks of streptozotocin. Corneal re-epithelialization was delayed in T1D rats, but not in T1D-INS animals; however, expression levels of the inhibitory growth factor OGF and its receptor, OGFr, were elevated in the corneal epithelium more than 2-fold in both diabetic groups. These data demonstrate for the first time that dysregulation of the OGF–OGFr axis in the diabetic cornea is associated with the onset and magnitude of ocular surface complications.

Impact statement

This research extends our knowledge about the presence and role of the OGF–OGFr regulatory axis in type 1 diabetes (T1D) and demonstrates specific targets within the pathway that are dysregulated. Serum levels of OGF, an inhibitory growth factor, are significantly elevated in male T1D rats, and OGFr serum values are increased in T1D. The onset of elevated OGF corresponds to the onset of ocular surface complications including dry eye, delayed corneal epithelial repair, and abnormal corneal surface sensitivity in T1D. Systemic insulin does not protect against elevated OGF levels or the onset of dry eye and sensitivity. These data are the first to associate some ocular surface defects in T1D with alterations in the OGF–OGFr pathway.

中文翻译：

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OGF-OGFr 通路的失调与糖尿病大鼠血清 OGF 升高和眼表并发症相关。

糖尿病通常会出现眼表并发症，包括干眼、角膜病变、敏感性改变以及全身性疾病。与角膜表面缺陷相关的一个常见主题是细胞增殖减少。阿片生长因子 (OGF)-OGF 受体 (OGFr) 调节轴维持上皮稳态，可以通过阿片受体拮抗剂纳曲酮进行调节，以阻断 OGF-OGFr 相互作用并增加细胞复制。在 1 型和 2 型糖尿病动物模型中，使用纳曲酮完全阻断可加速细胞增殖，增加角膜表面擦伤的再上皮化率，逆转干眼症并恢复角膜表面敏感性。纳曲酮在这些模型中的功效数据表明，OGF-OGFr 轴在糖尿病中失调。在本研究中，我们通过评估链脲佐菌素诱导的高血糖发生过程中 OGF 和 OGFr 的血清和组织水平来研究 OGF-OGFr 轴，并推测其作用机制。我们将 OGF-OGFr 轴的失调与 1 型糖尿病 (T1D) 角膜表面并发症（例如泪液产生、角膜表面敏感性）的发生和严重程度相关联。在注射链脲佐菌素 4 周内，不受控制的 T1D 和胰岛素控制 (T1D-INS) 雄性大鼠的 OGF 血清水平均升高。链脲佐菌素治疗后第 3 周和第 8 周，糖尿病大鼠的血清 OGFr 水平显着降低。在链脲佐菌素治疗 4 周内，T1D 和 T1D-INS 动物的泪液产生显着减少，角膜敏感性测量结果异常。T1D 大鼠的角膜再上皮化延迟，但 T1D-INS 动物则没有延迟；然而，在两个糖尿病组中，角膜上皮中抑制性生长因子 OGF 及其受体 OGFr 的表达水平均升高了 2 倍以上。这些数据首次证明糖尿病角膜中 OGF-OGFr 轴的失调与眼表并发症的发生和严重程度相关。

影响报告

这项研究扩展了我们对 OGF-OGFr 调节轴在 1 型糖尿病 (T1D) 中的存在和作用的认识，并展示了该通路中失调的特定目标。雄性 T1D 大鼠中 OGF（一种抑制性生长因子）的血清水平显着升高，并且 OGFr 血清值在 T1D 中升高。OGF 升高的发生与眼表并发症的发生相对应，包括干眼、角膜上皮修复延迟和 T1D 角膜表面敏感性异常。全身胰岛素不能预防 OGF 水平升高或干眼症和敏感症的发生。这些数据首次将 T1D 的一些眼表缺陷与 OGF-OGFr 通路的改变联系起来。