title: Effect of alogliptin, pioglitazone and glargine on pancreatic β-cells in diabetic db/db mice.
abstract: OBJECTIVE
  Progressive β-cell dysfunction and loss of β-cell mass are fundamental pathogenic features of type 2 diabetes. To examine if anti-diabetic reagents, such as insulin, pioglitazone (pio), and alogliptin (alo), have protective effects on β-cell mass and function in vivo, we treated obese diabetic db/db mice with these reagents.
  
  
  METHODS
  Male db/db mice were treated with a chow including pio, alo, or both of them from 8 to 16 weeks of age. Insulin glargine (gla) was daily injected subcutaneously during the same period.
  
  
  RESULTS
  At 16 weeks of age, untreated db/db mice revealed marked increase of HbA1c level, whereas those treated with pio, pio+alo, or insulin revealed the almost same HbA1c levels as non-diabetic db/m mice. Islet mass evaluated by direct counting in the whole pancreas and insulin content in isolated islets were preserved in pio, pio+alo and gla groups compared with untreated or alo groups, and there was no difference among pio, pio+alo and gla groups. To precisely evaluate islet β-cell functions, islet perifusion analysis was performed. In pio, pio+alo and gla groups, biphasic insulin secretion was preserved compared with untreated or alo groups. In particular, pio+alo as well as gla therapy preserved almost normal insulin secretion, although pio therapy improved partially. To examine the mechanism how these reagents exerted beneficial effects on β-cells, we evaluated expression levels of various factors which are potentially important for β-cell functions by real-time RT-PCR and immunohistochemistry. The results showed that expression levels of MafA and GLP-1 receptor were markedly decreased in untreated and alo groups, but not in pio, pio+alo and gla groups.
  
  
  CONCLUSIONS
  Combination therapy with pio and alo almost completely normalized β-cell functions in vivo, which was comparable with gla treatment.
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawashima
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Matsuoka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tochino
authors.forename: Ken
authors.initials: K
authors.lastname: Kato
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Munehide
authors.initials: M
authors.lastname: Matsuhisa
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000032:analysis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D000069036:Insulin Glargine; D007333:Insulin Resistance; D000078790:Insulin Secretion; D049528:Insulin, Long-Acting; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000077205:Pioglitazone; D010880:Piperidines / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D001786:Blood Glucose; D003849:Deoxyguanosine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D051473:Maf Transcription Factors, Large; D000077205:Pioglitazone; D010880:Piperidines; D018027:Receptors, Glucagon; D045162:Thiazolidinediones; D014280:Triglycerides; D014498:Uracil; C000593834:Glp1r protein, mouse; C485160:Mafa protein, mouse; C520853:alogliptin