Hepatocyte growth factor preserves beta cell mass and mitigates hyperglycemia in streptozotocin-induced diabetic mice.
Type I diabetes is an autoimmune disease that results in destructive depletion of the insulin-producing beta cells in the islets of Langerhans in pancreas. With the knowledge that hepatocyte growth factor (HGF) is a potent survival factor for a wide variety of cells, we hypothesized that supplementation of HGF may provide a novel strategy for protecting pancreatic beta cells from destructive death and for preserving insulin production. In this study, we demonstrate that expression of the exogenous HGF gene preserved insulin excretion and mitigated hyperglycemia of diabetic mice induced by streptozotocin. Blood glucose levels were significantly reduced in mice receiving a single intravenous injection of naked HGF gene at various time points after streptozotocin administration. Consistently, HGF concomitantly increased serum insulin levels in diabetic mice. Immunohistochemical staining revealed a marked preservation of insulin-producing beta cells by HGF in the pancreatic islets of the diabetic mice. This beneficial effect of HGF was apparently mediated by both protection of beta cells from death and promotion of their proliferation. Delivery of HGF gene in vivo induced pro-survival Akt kinase activation and Bcl-xL expression in the pancreatic islets of diabetic mice. These findings suggest that supplementation of HGF to prevent beta cells from destructive depletion and to promote their proliferation might be an effective strategy for ameliorating type I diabetes.
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Chunsun
C
Dai
Yingjian
Y
Li
Junwei
J
Yang
Youhua
Y
Liu
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt