Phloridzin improves hyperglycemia but not hepatic insulin resistance in a transgenic mouse model of type 2 diabetes
Phloridzin improves hyperglycemia but not hepatic insulin resistance in a transgenic mouse model of type 2 diabetes
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DOI：
10.2337/diabetes.53.11.2901
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发表时间：
2004-11-01
期刊：
影响因子：
7.7
通讯作者：
LeRoith, D
中科院分区：
文献类型：
--
作者：
Hong, Z;Yakar, S;LeRoith, D
2型糖尿病中发生的慢性高血糖可导致外周组织中β细胞功能和胰岛素抵抗的恶化。表达显性阴性IGF-1受体的小鼠，特别是在骨骼肌中表达的小鼠（MKR小鼠），表现出严重的胰岛素抵抗、高胰岛素血症、血脂异常和高血糖症。为了确定高血糖症在这些动物中糖尿病状态恶化中的作用，用根皮苷（PHZ）处理MKR小鼠，其抑制肠葡萄糖摄取和肾葡萄糖重吸收。在MKR小鼠中，响应于PHZ处理，血糖水平降低，尿糖水平升高。PHZ治疗也增加了MKR小鼠的摄食量;然而，脂肪量减少，瘦体重没有变化。MKR小鼠的血清胰岛素、脂肪酸和甘油三酯水平不受PHZ给药的影响。高胰岛素-正葡萄糖钳夹分析表明，白色脂肪组织中的葡萄糖摄取在PHZ处理后显著增加。尽管PHZ治疗后血糖降低，但MKR小鼠中胰岛素刺激的全身葡萄糖摄取没有改善，胰岛素也没有抑制内源性葡萄糖产生。这些结果表明，葡萄糖毒性在2型糖尿病的MKR小鼠模型中发生的胰岛素抵抗恶化中起很小或没有作用。
The chronic hyperglycemia that occurs in type 2 diabetes may cause deterioration of beta-cell function and insulin resistance in peripheral tissues. Mice that express a dominant-negative IGF-1 receptor, specifically in skeletal muscle (MKR mice), exhibit severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperglycemia. To determine the role of hyperglycemia in the worsening of the diabetes state in these animals, MKR mice were treated with phloridzin (PHZ), which inhibits intestinal glucose uptake and renal glucose reabsorption. Blood glucose levels were decreased and urine glucose levels were increased in response to PHZ treatment in MKR mice. PHZ treatment also increased food intake in MKR mice; however, the fat mass was decreased and lean body mass did not change. Serum insulin, fatty acid, and triglyceride levels were not affected by PHZ treatment in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated that glucose uptake in white adipose tissue was significantly increased in response to PHZ treatment. Despite the reduction in blood glucose following PHZ treatment, there was no improvement in insulin-stimulated whole-body glucose uptake in MKR mice and neither was there suppression of endogenous glucose production by insulin. These results suggest that glucotoxicity plays little or no role in the worsening of insulin resistance that occurs in the MKR mouse model of type 2 diabetes.