Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14670-5. doi: 10.1073/pnas.1107163108. Epub 2011 Aug 22.
Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.
瘦素已被证明可降低 1 型糖尿病啮齿动物模型的高血糖。我们研究了瘦素给药对加利福尼亚大学戴维斯分校 2 型糖尿病（UCD-T2DM）大鼠的影响，这些大鼠患有成年发病的多基因肥胖和 2 型糖尿病。患有糖尿病 2 个月的动物接受皮下注射盐水（对照）或鼠瘦素（0.5mg/kg），每天两次，持续 1 个月。对照大鼠与瘦素治疗动物进行配对喂养。与载体相比，瘦素治疗使空腹血糖正常化，并伴有 HbA1c、血浆胰高血糖素和甘油三酯浓度以及肝糖异生酶表达降低（P<0.05），而与体重和食物摄入无关。此外，与对照组相比，瘦素治疗的动物表现出明显的胰岛素敏感性和葡萄糖稳态改善，而瘦素治疗的动物的胰腺胰岛素含量高 50%（P<0.05）。这些作用与肝、骨骼肌和脂肪组织中瘦素和胰岛素信号通路的激活以及内质网（ER）应激的 PKR 样内质网激酶/真核翻译抑制因子 2α（PERK-eIF2α）臂的下调以及下丘脑中促黑皮质素原和阿黑皮素原的增加有关。相比之下，瘦素治疗在相同组织中升高了几种炎症/免疫功能标志物（P<0.05），这表明瘦素介导的胰岛素敏感性增加不是由于炎症减少所致。因此，瘦素给药可改善 UCD-T2DM 糖尿病大鼠的胰岛素敏感性并使空腹血糖正常化，这与能量摄入无关，通过外周和可能的中枢介导作用，部分通过降低循环胰高血糖素和 ER 应激来实现。
