Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of insulin-dependent diabetes mellitus (IDDM). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of IDDM was investigated using PTP1B deficient (KO) mice and a PTP1B inhibitor. IDDM wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared to non-IDDM WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-IDDM WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in IDDM WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in IDDM WT mice improved glucose metabolism to the same level as non-IDDM WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle via the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of IDDM with leptin, PTP1B deficiency or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for IDDM.

中文翻译：

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蛋白酪氨酸磷酸酶 1B 缺乏可改善瘦素治疗的胰岛素依赖型糖尿病患者的葡萄糖稳态

瘦素是一种由脂肪细胞分泌的激素，具有治疗胰岛素依赖型糖尿病 (IDDM) 的治疗潜力。蛋白酪氨酸磷酸酶 1B (PTP1B) 是负调节瘦素受体信号传导的关键酶。在这里，使用 PTP1B 缺陷 (KO) 小鼠和 PTP1B 抑制剂研究了 PTP1B 在 IDDM 治疗中的作用。与非 IDDM WT 小鼠相比，由链脲佐菌素诱导的 IDDM 野生型 (WT) 小鼠显示出明显的高血糖症。KO 小鼠显示出与非 IDDM WT 小鼠相当的葡萄糖代谢显着改善，而瘦素的外周或中枢给药部分改善了 IDDM WT 小鼠的葡萄糖代谢。在 IDDM WT 小鼠中使用瘦素和 PTP1B 抑制剂进行外周联合治疗可将葡萄糖代谢改善至与非 IDDM WT 小鼠相同的水平。瘦素被证明作用于下丘脑的弓状核，以抑制肝脏中的糖异生，并通过交感神经系统增强棕色脂肪组织和比目鱼肌中的葡萄糖摄取。这些影响因 PTP1B 缺乏而增强。因此，用瘦素、PTP1B 缺乏症或 PTP1B 抑制剂治疗 IDDM 可增强下丘脑中的瘦素活性，从而改善葡萄糖代谢。这些发现提示了 IDDM 的潜在替代疗法。PTP1B 缺乏症或 PTP1B 抑制剂显示可增强下丘脑中的瘦素活性，从而改善葡萄糖代谢。这些发现提示了 IDDM 的潜在替代疗法。PTP1B 缺乏症或 PTP1B 抑制剂显示可增强下丘脑中的瘦素活性，从而改善葡萄糖代谢。这些发现提示了 IDDM 的潜在替代疗法。