Phenotypes Associated with This Genotype

Genotype
MGI:3770688

• Allelic Composition: Tg(Ins2-rtTA)2Efr/0; Tg(tetO-DTA)1Gfi/0
• Genetic Background: involves: C57BL/6 * CBA

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:127412 )

N • average size of regenerating beta cells is same as original cells

abnormal pancreas morphology ( J:127412 )

• pancreatic insulin content is reduced by ~85%; after doxycycline withdrawal, pancreatic insulin level return to near control levels

abnormal pancreatic beta cell morphology ( 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

• 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

decreased pancreatic beta cell number ( J:127412 )

• 70-80% of beta cells are lost in doxycycline-treated 5-week old double-transgenic mice relative to controls

• 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

increased pancreatic beta cell number ( J:127412 )

• 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

disorganized pancreatic islets ( J:127412 )

• 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

• after withdrawal of doxycycline, normalization of islet architecture occurs in ~90% of islets

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:127412 )

N • 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

increased circulating glucose level ( 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

• 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

hyperglycemia ( J:127412 )

• 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

• 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

improved glucose tolerance ( J:127412 )

• after more than 8 months without doxycycline, glucose tolerance starts to recover

• 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

• 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

cellular

increased apoptosis ( J:127412 )

• 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