title: Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice.
abstract: OBJECTIVE
  Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes. Here, we focused on a family of serine-threonine kinases known as homeodomain-interacting protein kinases (HIPKs). HIPKs are implicated in the modulation of Wnt signalling, which plays a crucial role in transcriptional activity, and in pancreas development and maintenance. The aim of the present study was to characterise the role of HIPKs in glucose metabolism.
  
  
  METHODS
  We used RNA interference to characterise the role of HIPKs in regulating insulin secretion and transcription activity. We conducted RT-PCR and western blot analyses to analyse the expression and abundance of HIPK genes and proteins in the islets of high-fat diet-fed mice. Glucose-induced insulin secretion and beta cell proliferation were measured in islets from Hipk3                   (                     -/-                   ) mice, which have impaired glucose tolerance owing to an insulin secretion deficiency. The abundance of pancreatic duodenal homeobox (PDX)-1 and glycogen synthase kinase (GSK)-3β phosphorylation in Hipk3                   (                     -/-                   ) islets was determined by immunohistology and western blot analyses.
  
  
  RESULTS
  We found that HIPKs regulate insulin secretion and transcription activity. Hipk3 expression was most significantly increased in the islets of high-fat diet-fed mice. Furthermore, glucose-induced insulin secretion and beta cell proliferation were decreased in the islets of Hipk3                   (                     -/-                   ) mice. Levels of PDX1 and GSK-3β phosphorylation were significantly decreased in Hipk3                   (                     -/-                   ) islets.
  
  
  CONCLUSIONS
  Depletion of HIPK3 impairs insulin secretion and glucose tolerance. Decreased levels of HIPK3 may play a substantial role in the pathogenesis of type 2 diabetes.
authors.affiliation: Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shojima
authors.forename: K
authors.initials: K
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Horikoshi
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: I
authors.initials: I
authors.lastname: Takamoto
authors.forename: M
authors.initials: M
authors.lastname: Ohsugi
authors.forename: H
authors.initials: H
authors.lastname: Aburatani
authors.forename: M
authors.initials: M
authors.lastname: Noda
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: K
authors.initials: K
authors.lastname: Ueki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D005260:Female; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism; D034622:RNA Interference
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin