Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys
Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys
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DOI：
10.1152/ajpendo.00699.2010
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发表时间：
2011-05-01
影响因子：
5.1
通讯作者：
Wagner, Janice D.
中科院分区：
文献类型：
--
作者：
Kavanagh, Kylie;Flynn, David M.;Wagner, Janice D.
修复HSP 70缺陷可改善糖尿病猴的葡萄糖耐量。Am J Physiol Endocrinol Metab 300：E894-E901，2011。首次发表于2011年2月15日; doi：10.1152/ajpendo.00699.2010.-我们评估了热休克蛋白70（HSP 70）的变化，糖尿病（DM）在非人灵长类动物模型。为此，在DM长尾猴中进行了两项研究。1)对正常对照和链脲佐菌素诱导的DM猴（Stz-DM）进行了评估，这些猴通过明智的胰岛素给药分化为中度或不良控制的DM。在链脲佐菌素后4、8、12、16和20周收集肝脏，暴露于42 ℃的离体热休克，并对热休克因子1（HSF 1）、HSP 70和磷酸化HSF 1进行免疫印迹。2)在HSP 70诱导药物香叶基香叶基丙酮（GGA）的交叉研究中，纳入了未诱导糖尿病的自发性糖尿病猴。GGA以20 mg/kg给药14天，洗脱期为6周。葡萄糖耐量测试以及血浆和肌肉HSP 70是主要结局测量值。在糖尿病患者中，高血糖以剂量依赖性方式降低肝脏HSP 70。与正常猴相比，在患有Stz-DM的猴的肝脏中HSF 1增加，但对离体热休克的反应受损。HSF 1的活化似乎很重要，因为热应激引起的磷酸化变化与HSP 70的增加几乎完全相关。慢性高血糖（> 12周）后，在Stz-DM中也观察到HSF 1活化受损。在自然发生的DM中，循环HSP 70的增加导致葡萄糖耐量的显著改善和其他胰岛素抵抗测量的显著积极趋势。肌肉HSP 70含量无明显变化。我们的结论是，增加HSP 70，潜在地通过靶向高血糖相关的缺陷在肝脏中的HSF 1诱导和激活，是一个有效的和可行的策略，以改善葡萄糖耐量。
Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys. Am J Physiol Endocrinol Metab 300: E894-E901, 2011. First published February 15, 2011; doi: 10.1152/ajpendo.00699.2010.-We evaluated heat shock protein 70 (HSP70) changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, two studies were conducted in DM vervet monkeys. 1) Normal control and streptozotocin-induced DM monkeys (Stz-DM) that were differentiated into moderately or poorly controlled DM by judicious insulin administration were evaluated. Liver was collected at 4, 8, 12, 16, and 20 wk after streptozotocin, exposed to ex vivo heat shock at 42 degrees C, and immunoblotted for heat shock factor 1 (HSF1), HSP70, and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced were included in a crossover study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-wk washout period. Glucose tolerance testing and plasma and muscle HSP70 were the primary outcome measurements. In Stz-DM, hyperglycemia reduced hepatic HSP70 in a dose-dependent fashion. HSF1 was increased in livers of monkeys with Stz-DM, but responses to ex vivo heat shock were impaired vs. normal monkeys. Activation of HSF1 appears to be important, because the phosphorylation change with heat stress was nearly perfectly correlated with HSP70 increases. Impaired HSF1 activation was also seen in Stz-DM after chronic hyperglycemia (> 12 wk). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant, positive trends in other measurements of insulin resistance. No change in muscle HSP70 content was observed. We conclude that increasing HSP70, potentially through targeting hyperglycemia-related deficits in HSF1 induction and activation in the liver, is a potent and viable strategy to improve glucose tolerance.