Hong Eun-Gyoung, Jung Dae Young, Ko Hwi Jin, Zhang Zhiyou, Ma Zhexi, Jun John Y, Kim Jae Hyeong, Sumner Andrew D, Vary Thomas C, Gardner Thomas W, Bronson Sarah K, Kim Jason K
Dept. of Cellular and Molecular Physiology, Penn State Univ. College of Medicine, 500 University Dr. (H166 C4600D, Hershey, PA 17033, USA.
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1687-96. doi: 10.1152/ajpendo.00256.2007. Epub 2007 Oct 2.
Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects.
虽然胰岛素抵抗传统上与2型糖尿病相关，但最近在人类和动物模型中的证据表明，1型糖尿病也可能出现胰岛素抵抗。Ins2(Akita)小鼠的胰岛素2基因突变导致胰腺β细胞凋亡和高血糖，这些小鼠常用于研究1型糖尿病及其并发症。由于胰岛素抵抗在糖尿病并发症中起重要作用，我们对清醒的Ins2(Akita)小鼠和野生型小鼠进行了高胰岛素-正葡萄糖钳夹试验，以测量体内胰岛素作用和葡萄糖代谢。非肥胖的Ins2(Akita)小鼠出现了胰岛素抵抗，钳夹期间葡萄糖输注速率降低约80%表明了这一点。胰岛素抵抗是由于骨骼肌、棕色脂肪组织中的葡萄糖摄取以及肝脏胰岛素作用降低了约50%。Ins2(Akita)小鼠骨骼肌胰岛素抵抗与总GLUT4减少40%以及PKCepsilon水平增加三倍有关。慢性根皮苷治疗降低了Ins2(Akita)小鼠的全身血糖水平，并使肌肉胰岛素作用、GLUT4和PKCepsilon水平恢复正常，表明高血糖在胰岛素抵抗中起作用。超声心动图显示Ins2(Akita)小鼠存在显著的心脏重塑伴心室肥厚，慢性根皮苷治疗后改善。总体而言，我们首次报告非肥胖、胰岛素缺乏的Ins2(Akita)小鼠出现了2型糖尿病表型，包括外周和肝脏胰岛素抵抗以及心脏重塑。我们的研究结果为影响1型糖尿病和瘦型2型糖尿病患者的代谢异常和并发症的发病机制提供了重要见解。
