title: Therapeutic effects of a non-β cell bioartificial pancreas in diabetic mice.
abstract: BACKGROUND
  Cell-based insulin therapies can potentially improve glycemic regulation in insulin-dependent diabetic patients. Enteroendocrine cells engineered to secrete recombinant insulin have exhibited glycemic efficacy, but have been primarily studied as uncontrollable growth systems in immune incompetent mice. Furthermore, reports suggest that suboptimal insulin secretion remains a barrier to expanded application.
  
  
  METHODS
  Genetic and tissue engineering strategies were applied to improve recombinant insulin secretion from intestinal L-cells on both a per-cell and per-graft basis. Transduction of insulin-expressing GLUTag L-cells with lentivirus carrying an additional human insulin gene-enhanced secretion twofold. We infected cells with lentivirus expressing a luciferase reporter gene to track cell survival in vivo. To provide a growth-controlled and immune protective environment without affecting secretory capacity, cells were microencapsulated in barium alginate. Approximately 9×10(7) microencapsulated cells were injected intraperitoneally in immune competent streptozotocin-induced diabetic mice for therapeutic efficacy evaluation.
  
  
  RESULTS
  Graft insulin secretion was increased to 16 to 24 mU insulin per day. Transient normoglycemia was achieved in treated mice two days after transplantation, and endogenous insulin was sufficient to sustain body weights of treated mice receiving minimal supplementation.
  
  
  CONCLUSIONS
  Glycemic efficacy of a bioartificial pancreas based on insulin-secreting enteroendocrine cells is insufficient as a standalone therapy, despite enhancement of graft insulin secretion capacity. Supplemental strategies to alleviate secretion limitations should be pursued.
authors.affiliation: 1 School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA. 2 Section Endocrinology & Metabolism, Atlanta VA Medical Center, Division of Endocrinology, Lipids, & Diabetes, Emory University School of Medicine, Atlanta, GA. 3 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA. 4 Address correspondence to: Athanassios Sambanis, Ph.D., School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 315 Ferst Dr. NW, IBB Building, Room 1306, Atlanta, GA 30332.
authors.forename: Aubrey R
authors.initials: AR
authors.lastname: Tiernan
authors.forename: Peter M
authors.initials: PM
authors.lastname: Thulé
authors.forename: Athanassios
authors.initials: A
authors.lastname: Sambanis
mesh_terms: D000818:Animals; D021522:Bioartificial Organs; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D019858:Enteroendocrine Cells / Q000378:metabolism / Q000637:transplantation*; D005818:Genetic Engineering; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000378:metabolism*; D013311:Streptozocin; D023822:Tissue Engineering; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007328:Insulin; D013311:Streptozocin