title: Constitutively active heat shock factor 1 enhances glucose-driven insulin secretion.
abstract: Weak pancreatic β-cell function is a cause of type 2 diabetes mellitus. Glucokinase regulates insulin secretion via phosphorylation of glucose. The present study focused on a system for the self-protection of pancreatic cell by expressing heat shock factor (HSF) and heat shock protein (HSP) to improve insulin secretion without inducing hypoglycemia. We previously generated a constitutively active form of human HSF1 (CA-hHSF1). An adenovirus expressing CA-hHSF1 using the cytomegalovirus promoter was generated to infect mouse insulinoma cells (MIN6 cells). An adenovirus expressing CA-hHSF1 using a human insulin promoter (Ins-CA-hHSF1) was also generated to infect rats. We investigated whether CA-hHSF1 induces insulin secretion in MIN6 cells and whether Ins-CA-hHSF1 can improve blood glucose and serum insulin levels in healthy Wister rats and type 2 diabetes mellitus model rats. CA-hHSF1 expression increased insulin secretion 1.27-fold compared with the overexpression of wild-type hHSF1 in MIN6 cells via induction of HSP90 expression and subsequent activation of glucokinase. This mechanism is associated with activation of both glucokinase and neuronal nitric oxide synthase. Ins-CA-hHSF1 improved blood glucose levels in neonatal streptozotocin-induced diabetic rats. Furthermore, Ins-CA-hHSF1 reduced oral glucose tolerance testing results in healthy Wister rats because of an insulin spike at 15 minutes; however, it did not induce hypoglycemia. CA-hHSF1 induced insulin secretion both in vitro and in vivo. These findings suggest that gene therapy with Ins-CA-hHSF1 will be able to be used to treat patients with type 2 diabetes mellitus and impaired glucose tolerance without causing hypoglycemia at fasting.
authors.affiliation: Laboratory of Signal Transduction and Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan. uchiyat@med.gunma-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Shoichi
authors.initials: S
authors.lastname: Tomono
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Utsugi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ohyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawazu
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism; D005822:Genetic Vectors; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D047468:Immunoprecipitation; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D020799:Pancrelipase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D007328:Insulin; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020799:Pancrelipase; D052248:Nitric Oxide Synthase Type I; D005941:Glucokinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose