title: Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD-scid IL-2rg(null) RIP-DTR mice engrafted with human islets.
abstract: OBJECTIVE
  Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo.
  
  
  METHODS
  Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis.
  
  
  RESULTS
  Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice.
  
  
  CONCLUSIONS
  Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Chaoxing
authors: C
authors: Yang
authors: Sanofi-Aventis, Diabetes Division, Frankfurt, Germany.
authors: Matthias
authors: M
authors: Loehn
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Agata
authors: A
authors: Jurczyk
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Natalia
authors: N
authors: Przewozniak
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Linda
authors: L
authors: Leehy
authors: University of Geneva, Geneva, Switzerland.
authors: Pedro L
authors: PL
authors: Herrera
authors: The Jackson Laboratory, Bar Harbor, ME, USA.
authors: Leonard D
authors: LD
authors: Shultz
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Dale L
authors: DL
authors: Greiner
authors: Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: David M
authors: DM
authors: Harlan
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Rita
authors: R
authors: Bortell
keywords: GLP-1 receptor agonist; beta cells; glucose tolerance tests; human islet transplant; lixisenatide; plasma insulin