Mouse Genome Informatics
ht
    Pdx1tm1Ted/Pdx1+
involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
endocrine/exocrine glands
• islet isolation procedures generate very few islets (always <100) from heterozygotes compared with wild-type mice (almost always >200 islets)
• isolated heterozygous islets appear fragmented and slightly smaller than wild-type
• in vivo, heterozygotes show a striking disruption of islet architecture and expansion of islet microvasculature at 3 months; however, even at 12 months, some heterozygous islets show no signs of damage or apoptosis
• in heterozygotes, islet number fails to increase with age and is ~50% less than wild-type by 12 months
• in heterozygotes, beta cell mass fails to increase with age and is ~50% less than wild-type by 12 months
• reduced beta cell mass is mirrored by a lower pancreatic insulin content in older mice and can be explained by a reduced number of functional islets, rather than a reduction in insulin stored in single beta cells
• heterozygotes display normal depolarization-evoked single-cell exocytosis and voltage-gated Ca2+ currents in beta cells
• however, isolated heterozygous islets and dispersed beta cells are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets; no significant differences are noted at high glucose (25 mM) or Ca2+ stress
• perfused pancreata from heterozygous males display attenuated first-phase insulin secretion in response to a stepwise increase in glucose concentration from 5 mM to 20 mM glucose
• also, mutant pancreata show a reduced insulin release in response to 20 mM KCl; in the continued presence of 26 mM glucose, the large response to 20 mM arginine is also reduced
• notably, insulin secretion in perifusion or static incubation experiments in response to glucose and other secretagogues is similar in islets isolated from heterozygous mutants compared with wild-type littermates
• glucose sensing and islet Ca2+ responses are also normal in large, intact heterozygous mutant islets
• at 12 months, older heterozygotes exhibit infiltration of lymphocytes (some TUNEL-positive) within or around islets
• immunofluorescent localization of Ki67 nuclear antigen indicates proliferation of lymphocytes within these islets

homeostasis/metabolism
• perfused pancreata from heterozygous males display attenuated first-phase insulin secretion in response to a stepwise increase in glucose concentration from 5 mM to 20 mM glucose
• also, mutant pancreata show a reduced insulin release in response to 20 mM KCl; in the continued presence of 26 mM glucose, the large response to 20 mM arginine is also reduced
• notably, insulin secretion in perifusion or static incubation experiments in response to glucose and other secretagogues is similar in islets isolated from heterozygous mutants compared with wild-type littermates
• glucose sensing and islet Ca2+ responses are also normal in large, intact heterozygous mutant islets
• heterozygous mutant males exhibit significantly elevated blood glucose concentrations relative to wild-type males
• notably, heterozygous females display an attenuated increase in blood glucose levels relative to wild-type
• heterozygotes exhibit a decline in glucose tolerance with increasing age (J:82969)

immune system
• at 12 months, older heterozygotes exhibit infiltration of lymphocytes (some TUNEL-positive) within or around islets
• immunofluorescent localization of Ki67 nuclear antigen indicates proliferation of lymphocytes within these islets

Mouse Models of Human Disease
OMIM IDRef(s)
Maturity-Onset Diabetes of the Young, Type 4; MODY4 606392 J:82969
Maturity-Onset Diabetes of the Young; MODY 606391 J:48516 , J:82969