• beta cell mass almost 3X more than controls more than in wild-type controls

• cell size normal

• hyperplasia

• insulin content of Islets is almost 2X that of controls but plasma levels normal

• insulin content of Islets is almost 2X that of controls but plasma levels normal

• development of diabetes is accelerated compared to wild-type controls; all but one female develop diabetes between 7 and 15 weeks of age

• severe insulitis with primarily intraislet infiltrates

• both males and females have higher peak levels of insulin autoantibodies than wild-type

• severe insulitis with primarily intraislet infiltrates

• no beta cells are detected in the pancreas

• death in 48 hours after birth on average

• significant hyperplasia

• about 1.5X larger than in littermate controls

• ketoacidosis

• milky plasma

• severely diabetic (J:77595)

• glycosuria detectable after pups suckle

• mean body weight within a few hours of birth 22% less than littermate controls

• glycosuria detectable after pups suckle

• mice develop diabetes (blood glucose >250 ml/dl) more rapidly than transgenic Rag1-null, Ins2-sufficient mice

• at birth the relative reduction in body weight is 22%

• at E18.5, body weight is reduced by 15% compared to heterozygous pups

• there is decreased islet cell apoptosis in in all regions of the islets compared to controls

• at E18.5 there is increased islet cell proliferation compared to controls, with both alpha and beta cells proliferating

• total alpha cell mass is increased compared to wild-type and Ins1-null, Ins2-heterozygous controls (38 ug w.t. vs 45 ug vs 68 ug double nulls)

• total beta cell mass at E18.5, is 348 ug compared to 226 ug in Ins1-null, Ins2-heterozygous controls

• mean islet area is significantly increased compared with Ins1-null, Ins2-heterozygous controls at E18.5 and P1 but not at E17.5

• compared to wild-type controls, mice have more large islets and fewer small islets

• total alpha cell mass is increased compared to wild-type (68 ug vs 48 ug w.t.)

• male transgenic mice lacking both native insulin genes develop diabetes before 10 weeks of age (2 consecutive measurements of >250 mg/dl glucose)

• at 26 weeks of age, sialitis is observed but not insulitis

• female transgenic mice lacking both native insulin genes do not exhibit diabetes by 30 weeks of age

• at 26 weeks of age, sialitis is observed but not insulitis

• at 26 weeks of age, sialitis is observed but not insulitis

• at 26 weeks of age, sialitis is observed but not insulitis

• no female double knockout mice carrying the transgene on a NOD background develop diabetes over 30 weeks of observation

• females lacking both insulin genes do not produce insulin autoantibodies

• at 26 weeks of age, sialitis is observed but not insulitis

• at 26 weeks of age, sialitis is observed but not insulitis

• transgenic female mice lacking the Ins2 gene do not show increased resistance to diabetes development compared to nontransgenic NOD animals lacking the gene

• female mice having the insulin 1 gene but lacking the insulin 2 gene produce insulin autoantibodies