PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance.
Diabetes is the most prevalent and serious metabolic disease, and the number of diabetic patients worldwide is increasing. The reduction of insulin biosynthesis in pancreatic beta-cells is closely associated with the onset and progression of diabetes, and thus it is important to search for ways to induce insulin-producing cells in non-beta-cells. In this study, we showed that a modified form of the pancreatic and duodenal homeobox factor 1 (PDX-1) carrying the VP16 transcriptional activation domain (PDX-1/VP16) markedly increases insulin biosynthesis and induces various pancreas-related factors in the liver, especially in the presence of NeuroD or neurogenin 3 (Ngn3). Furthermore, in streptozotocin-induced diabetic mice, PDX-1/VP16 overexpression, together with NeuroD or Ngn3, drastically ameliorated glucose tolerance. Thus PDX-1/VP16 expression, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. This approach warrants further investigation and may have utility in the treatment of diabetes.
Kaneto
Hideaki
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. kaneto@medone.med.osaka-u.ac.jp
Nakatani
Yoshihisa
Y
Miyatsuka
Takeshi
T
Matsuoka
Taka-aki
TA
Matsuhisa
Munehide
M
Hori
Masatsugu
M
Yamasaki
Yoshimitsu
Y
D000256:Adenoviridae; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D017405:Herpes Simplex Virus Protein Vmw65 / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D017405:Herpes Simplex Virus Protein Vmw65; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C093564:Neurogenic differentiation factor 1