Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic beta-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the beta-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.


METHODS
Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and beta-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.


RESULTS
Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, beta-cell mass, and insulin-positive cells in pancreatic ducts, and beta-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1- and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1 -and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-gamma to transforming growth factor-beta1, and beta-cells were protected from apoptosis.


CONCLUSIONS
Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic beta-cell mass and downregulating the autoimmune response.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Wilma L
WL
Suarez-Pinzon
Robert F
RF
Power
Yanhua
Y
Yan
Clive
C
Wasserfall
Mark
M
Atkinson
Alex
A
Rabinovitch
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004359:Drug Therapy, Combination; D005755:Gastrins / Q000008:administration & dosage / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007330:Insulin Antibodies / Q000097:blood; D050417:Insulin-Secreting Cells / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D012016:Reference Values
D001323:Autoantibodies; D001786:Blood Glucose; D005755:Gastrins; D007330:Insulin Antibodies; D052216:Glucagon-Like Peptide 1