title: Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice.
abstract: OBJECTIVE
  Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology.
  
  
  METHODS
  The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ.
  
  
  RESULTS
  In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice.
  
  
  CONCLUSIONS
  Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: Y
authors.initials: Y
authors.lastname: Fujita
authors.forename: J
authors.initials: J
authors.lastname: Honjo
authors.forename: T
authors.initials: T
authors.lastname: Yanagimachi
authors.forename: H
authors.initials: H
authors.lastname: Sakagami
authors.forename: Y
authors.initials: Y
authors.lastname: Takiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Makino
authors.forename: A
authors.initials: A
authors.lastname: Abiko
authors.forename: T J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: M
authors.initials: M
authors.lastname: Haneda
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000378:metabolism*; D018450:Disease Progression; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D005951:Glucose Tolerance Test; D006454:Hemoglobins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013311:Streptozocin / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006454:Hemoglobins; D054795:Incretins; D007328:Insulin; D013311:Streptozocin
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