Gene Technology Center


研究発表を行った学会;IDF congress 2017
2017年 12月 4日〜8日(Abu Dhabi. UAE)
タイトル; The therapeutic potential of heat shock protein 72 in mice model of type 2 diabetes.
発表者;近藤 龍也氏
(熊本大学 医学部附属病院 糖尿病・代謝・内分泌内科)
Cell stresses, such as endoplasmic reticulum stress or oxidative stress is one of the key mediators in pathophysiology of type 2 diabetes. Molecular chaperone, which modulate protein folding and/or assembly and protect cells from those stresses, may be a favorable target for diabetic treatment. Heat shock protein (HSP) 72 is a major inducible heat shock protein against heat, ultraviolet, heavy metals or infection, and serves to protect cells from those cellular stress signals and works in protein quality control as well. Induction of HSP72 by pharmacologic agent or physical method, such as mild electrical stimulation with heat shock improves glucose intolerance in type 2 diabetic model mice.
In this study, we investigated glucose metabolism in whole body HSP72 deficient (KO) mice to explore the roles of HSP72 in diabetes. The effects of hepatic HSP72 induction in HSP72 KO mice were also investigated.
Male HSP72 KO mice or control mice were subjected to a high-fat diet (HFD) regimen for 16 weeks. Metabolic parameter and pathophysiological examination were performed. HSP72 was overexpressed in HSP72 whole body KO mice by lenti-virus system to investigate the role of HSP72 in liver.
KO mice showed significantly higher body weight after 10 weeks of HFD (HSP72 KO: 36.9 g v.s. control: 33.4 g). Fasting blood glucose was significantly elevated after 11 weeks of HFD (HSP72 KO: 143.3 mg/dL v.s. control: 115.5 mg/dL). Random fed blood glucose and food intake were comparable. Upon glucose challenge test, blood glucose levels at any time points measured were higher in HSP72 KO mice. On insulin tolerance test, HSP72 KO mice exhibited insulin resistant phenotype. Visceral fat mass was increased and hepatic steatosis was obvious in HSP72 KO mice with increased SREBP-1c mRNA expression. Upon insulin stimulation, phosphorylation of Akt was decreased by approximately 50% in HSP72 KO liver, with increased activation of c-jun N-terminal kinase. Inflammatory cytokiness activated by NF-B signal and oxidative stress were both increased. Hepatic gluconeogenesis was not suppressed in HSP72 KO mice accompanied by increased gluconeogenic enzyme mRNAs, such as PEPCK and G6Pase. When adding back to HSP72 protein expression in liver by lenti-viral system on HFD fed HSP72 KO mice, fasting blood glucose was reversed compared to control mice on HFD.
Deficiency of HSP72 leads to increased visceral adiposity, hepatic insulin resistance, glucose intolerance and hepatic steatosis. As induction of HSP72 in liver is beneficial to improve glucose homeostasis in HSP72 KO, our observations strongly indicate the abundance of HSP72 in liver is critical in diabetic pathophysiology, and appropriate HSP72 induction may serve as a target in the treatment of type 2 diabetes.

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