title: Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.
abstract: OBJECTIVE
  Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.
  
  
  METHODS
  In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.
  
  
  RESULTS
  Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.
  
  
  CONCLUSIONS
  These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.
authors.affiliation: Department of Surgery, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Misawa
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Grossman
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.forename: Piotr
authors.initials: P
authors.lastname: Witkowski
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
authors.forename: Anita S
authors.initials: AS
authors.lastname: Chong
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D000077205:Pioglitazone; D010880:Piperidines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012038:Regeneration / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013311:Streptozocin; D016559:Tacrolimus / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; C514817:Ins1 protein, mouse; D007328:Insulin; D010880:Piperidines; D045162:Thiazolidinediones; D014498:Uracil; D013311:Streptozocin; D008156:Luciferases; C520853:alogliptin; D020123:Sirolimus; D016559:Tacrolimus; D000077205:Pioglitazone