Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice.
Pancreatic islet transplantation as a treatment for type 1 diabetes is limited by human donor tissue availability. We investigated whether the beta-cell mass in human isolated islets could be expanded by treatments with glucagon-like peptide-1 (GLP-1) and gastrin, peptides reported to stimulate beta-cell growth in mice and rats with deficits in beta-cell mass. Human islets with low endocrine cell purity (7% beta-cells, 4% alpha-cells) and abundant exocrine cells (29% duct cells and 25% acinar cells) were implanted under the renal capsule of nonobese diabetic-severe combined immune deficiency (NOD-scid) mice made diabetic with streptozotocin. The mice were treated with GLP-1 and gastrin, separately and together, daily for 5 weeks. Blood glucose was significantly reduced only in mice implanted with human pancreatic cells and treated with GLP-1 plus gastrin. Correction of hyperglycemia was accompanied by increased insulin content in the human pancreatic cell grafts as well as by increased plasma levels of human C-peptide in the mice. Immunocytochemical examination revealed a fourfold increase in insulin-positive cells in the human pancreatic cell grafts in GLP-1 plus gastrin-treated mice, and most of this increase was accounted for by the appearance of cytokeratin 19-positive pancreatic duct cells expressing insulin. We conclude that combination therapy with GLP-1 and gastrin expands the beta-cell mass in human islets implanted in immunodeficient diabetic mice, largely from pancreatic duct cells associated with the islets, and this is sufficient to ameliorate hyperglycemia in the mice.
Suarez-Pinzon
Wilma L
WL
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Lakey
Jonathan R T
JR
Rabinovitch
Alex
A
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005755:Gastrins / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010183:Pancreatic Ducts / Q000166:cytology / Q000187:drug effects; D051381:Rats; D014183:Transplantation, Heterologous
D001786:Blood Glucose; D002096:C-Peptide; D005755:Gastrins; D007328:Insulin; D052216:Glucagon-Like Peptide 1