cellular phenotype

• increased apoptosis
  • widespread pancreatic beta cell apoptosis is seen within 48 hours of doxycycline treatment of double-transgenic mice, but no apoptosis is observed in single transgenic littermates
  (MGI Ref ID J:127412)

homeostasis/metabolism phenotype

• improved glucose tolerance
  • after more than 8 months without doxycycline, glucose tolerance starts to recover
  (MGI Ref ID J:127412)
  • similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal
  (MGI Ref ID J:127412)
  • mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal
  (MGI Ref ID J:127412)

• hyperglycemia
  • blood glucose levels are elevated to 300-600 mg/dl; after doxycycline withdrawal, remission of hyperglycemia occurs such that fed and fasting glucose levels normalize
  (MGI Ref ID J:127412)
  • mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal
  (MGI Ref ID J:127412)

• increased circulating glucose level
  • mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal
  (MGI Ref ID J:127412)
  • blood glucose levels of treated mice are elevated to 300-600 mg/dl making the mice overtly diabetic; after withdrawal of doxycycline, blood glucose levels return to normal level
  (MGI Ref ID J:127412)

mammalian phenotype

• endocrine/exocrine gland phenotype
  • Normal - average size of regenerating beta cells is same as original cells
  (MGI Ref ID J:127412)

• homeostasis/metabolism phenotype
  • Normal - peripheral insulin sensitivity after beta cell regeneration is similar to controls after doxycycline withdrawal, beta cell mass in transgenic mice increases to levels comparable to wild-type
  (MGI Ref ID J:127412)

endocrine/exocrine gland phenotype

• abnormal pancreatic beta cell morphology
  • levels in treated mice fail to normalize as they do in controls treated with SirTac
  (MGI Ref ID J:127412)
  • permitting doxycycline-treated mice to recover in presence of immunosupressants Sirolimus and Tacrolimus (SirTac) significantly reduces beta cell proliferation and beta cell mass does not increase as it does in absence of immunosupressants; blood glucose levels in treated mice fail to normalize as they do in controls treated with SirTac
  (MGI Ref ID J:127412)
  • frequency of insulin-positive, glucagons-positive beta cells increases from 1:5500 in controls to 1:1000 beta cells in diabetic transgenic mice
  (MGI Ref ID J:127412)

• disorganized pancreatic islets
  • treatment of four-week old mice with doxycycline for 1 week results in severely disrupted islet architecture with non-beta cells at the core of shriveled islets rather than beta cells
  (MGI Ref ID J:127412)
  • after withdrawal of doxycycline, normalization of islet architecture occurs in ~90% of islets
  (MGI Ref ID J:127412)

• decreased pancreatic beta cell number
  • similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal
  (MGI Ref ID J:127412)
  • 70-80% of beta cells are lost in doxycycline-treated 5-week old double-transgenic mice relative to controls
  (MGI Ref ID J:127412)

• abnormal pancreas morphology
  • pancreatic insulin content is reduced by ~85%; after doxycycline withdrawal, pancreatic insulin level return to near control levels
  (MGI Ref ID J:127412)

• increased pancreatic beta cell number
  • rate of beta cell apoptosis in recovering mice is not different from controls, but beta cell proliferation is increased 2-3-fold within 48 hours of onset of beta cell ablation; this increased proliferation rate is maintained for several weeks
  (MGI Ref ID J:127412)