title: Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice.
abstract: OBJECTIVE
  The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.
  
  
  METHODS
  We analyzed the capacity of beta-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.
  
  
  RESULTS
  Young mice responded to high-fat diet by increasing beta-cell mass and beta-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in beta-cell mass or beta-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of beta-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas no changes in beta-cell proliferation were observed in older mice. The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of beta-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16(Ink4a)expression in the beta-cells. Young Bmi1(-/-) mice that prematurely upregulate p16(Ink4a)failed to expand beta-cell mass in response to exendin-4, indicating that p16(Ink4a)levels are a critical determinant of beta-cell mass expansion.
  
  
  CONCLUSIONS
  beta-Cell proliferation and the capacity of beta-cells to regenerate declines with age and is regulated by the Bmi1/p16(Ink4a)pathway.
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Shuen-Ing
authors.initials: SI
authors.lastname: Tschen
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Dhawan
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.forename: Anil
authors.initials: A
authors.lastname: Bhushan
mesh_terms: D000375:Aging; D000818:Animals; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004041:Dietary Fats / Q000494:pharmacology; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency; D010455:Peptides / Q000494:pharmacology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D012038:Regeneration; D012097:Repressor Proteins; D014688:Venoms / Q000494:pharmacology
chemical_list: C489421:Bmi1 protein, mouse; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D063150:Polycomb Repressive Complex 1