Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys
Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys
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DOI：
10.1007/s12192-008-0084-7
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发表时间：
2009-05-01
影响因子：
3.8
通讯作者：
Wagner, Janice D.
中科院分区：
文献类型：
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作者：
Kavanagh, K.;Zhang, Li;Wagner, Janice D.
伴侣蛋白热休克蛋白（HSP）70已被证明可以防止肥胖相关的胰岛素抵抗。因此，热休克蛋白的诱导被认为是一个令人兴奋的糖尿病（DM）的治疗策略。本研究的目的是（1）确定2型糖尿病灵长类动物血浆、肝脏和胰腺组织中的HSP水平和（2）评估HSP家族伴侣蛋白与细胞保护之间的关系。我们从24只2型糖尿病和25只血糖正常对照（CTL）食蟹猴中收集血浆。DM猴的一个子集具有可用的肝脏和胰腺样品，其与第二组CTL猴进行比较。我们发现，DM猴循环中的HSP 70降低了32%，即使在调整了这些猴的较大年龄和体重后仍显着降低（p < 0.001）。肝脏表现出类似的HSP 70和90的减少，这与转录因子热休克因子1（HSF 1; p = 0.03）的水平降低50%有关。胰腺组织具有相反的表达模式，具有显著更高的HSF 1（p = 0.004）和相应更高的HSP 70和90。糖尿病猴胰腺亚硝化氧化作用较少（p = 0.03），这与超氧化物歧化酶无关，与HSP水平呈负相关（r =-0.57，p = 0.009）。糖尿病肝脏存在HSF 1/HSP缺陷，可能与肝脏胰岛素抵抗有关，这种缺陷反映在较低的循环浓度。尽管高血糖，胰腺仍维持HSP水平，可能是试图保护脆弱的β细胞免受胰腺外分泌损伤和与胰岛素分泌过多相关的应激。
The chaperone protein heat shock protein (HSP) 70 has been shown to protect against obesity-associated insulin resistance. Induction of HSPs is thus considered an exciting therapeutic strategy for diabetes (DM). The aims of this study were to (1) determine HSP levels in plasma, hepatic, and pancreatic tissues of type 2 DM primates and (2) assess the relationship between chaperone proteins of the HSP family and cellular protection. We collected plasma from 24 type 2 DM and 25 normoglycemic control (CTL) cynomolgus macaques. A subset of DM monkeys had liver and pancreas samples available which were compared to a second group of CTL monkeys. We found that DM monkeys had 32% lower HSP70 in circulation which remained significant even after adjustment for the greater age and bodyweight of these monkeys (p < 0.001). The liver demonstrated a similar reductions in both HSP70 and 90 that was related to 50% lower levels of the transcription factor, heat shock factor 1 (HSF1; p = 0.03). Pancreatic tissue had the opposite expression pattern with significantly higher HSF1 (p = 0.004) and accordingly higher HSP70 and 90. Pancreas from DM monkeys had less nitrosative oxidation (p = 0.03) which was unaccounted for by superoxide dismutases and was negatively associated with HSP levels (r = -0.57, p = 0.009). HSF1/HSP deficiency exists in DM liver which may contribute to hepatic insulin resistance and this deficiency was reflected in lower circulating concentrations. Pancreas maintains HSP levels despite hyperglycemia, likely in an attempt to protect vulnerable beta cells from exocrine pancreatic damage and from stress associated with insulin hypersecretion.