Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats
Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats
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DOI：
10.1073/pnas.1107163108
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发表时间：
2011-08-30
影响因子：
11.1
通讯作者：
Havel, Peter J.
中科院分区：
文献类型：
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作者：
Cummings, Bethany P.;Bettaieb, Ahmed;Havel, Peter J.
瘦素已被证明可以降低1型糖尿病啮齿动物模型的高血糖。我们研究了瘦素对加州大学戴维斯分校2型糖尿病(UCD-T2 DM)大鼠的影响，这些大鼠发展为成年型多基因肥胖症和2型糖尿病。对糖尿病2个月的动物给予皮下注射。每日两次注射生理盐水(对照组)或小鼠瘦素(0.5 mg/kg)，共1mo。对照组大鼠被配对喂养给瘦素治疗的动物。瘦素治疗使空腹血糖正常化，并伴随着糖化血红蛋白、血浆胰高血糖素和甘油三酯浓度和肝糖异生酶的表达低于对照组(P<；0.05)，与体重和食物摄入量无关。此外，与对照组相比，瘦素治疗的动物表现出显著的胰岛素敏感性和血糖稳态的改善，而胰腺胰岛素含量在瘦素治疗的动物中高出50%(P<；0.05)。这些效应与肝脏、骨骼肌和脂肪组织中瘦素和胰岛素信号通路的激活以及肝脏、骨骼肌和脂肪组织中ER应激的PKR样内质网(ER)激酶/真核翻译抑制因子2α(PERK-eIF2α)臂的下调以及下丘脑中前阿片黑素皮质素的增加和刺鼠相关肽的减少相一致。相反，在相同的组织中，瘦素治疗提高了炎症/免疫功能的几个标记物(P<；0.05)，这表明瘦素介导的胰岛素敏感性的增加并不是由于炎症的减少。因此，瘦素的应用改善了糖尿病UCD-T2 DM大鼠的胰岛素敏感性，并使空腹血糖正常化，不依赖能量摄入，通过外周和可能的中枢调节作用，部分通过减少循环中的胰高血糖素和内质网应激。
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 2 alpha (PERK-eIF2 alpha) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased proopiomelanocortin 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.