Phenotypes Associated with This Genotype

Genotype
MGI:5637560

• Allelic Composition: Gadd45gip1^tm2Kong/Gadd45gip1^tm2Kong; Tg(Ins2-cre)25Mgn/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA

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

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:220742 )

• islet area is normal at 4 weeks of age but is decreased by 45% at 11 weeks of age

abnormal pancreatic beta cell morphology ( J:220742 )

• beta cells exhibit an increased number of mitochondria

• endoplasmic reticulum in beta cells is distended around swollen mitochondria

decreased pancreatic beta cell mass ( J:220742 )

• progressive loss of beta cell mass associated with autophagy

• treatment with the glucagon-like peptide 1 agonist, exenatide, does not increase beta cell proliferation or mass in mutants as in wild-type mice

decreased pancreatic beta cell number ( J:220742 )

• mice show extensive loss of insulin-positive beta cells at 11 weeks of age

abnormal pancreatic beta cell physiology ( J:220742 )

• pancreatic insulin content is reduced in mice by 20% at 4 weeks and by 68% at 11 weeks of age

• beta cells exhibit an increase in autophagosomes, indicating increased autophagy

decreased pancreatic beta cell proliferation ( J:220742 )

• mice show a decrease in cell proliferation of beta cells at 4 and 11 weeks of age

• however, level of apoptosis in islets is similar to wild-type levels

decreased insulin secretion ( J:220742 )

• insulin secretion from islets upon either glucose or KCl stimulation in reduced in 4 and 11 week old mutants

cellular

abnormal mitochondrial morphology ( J:220742 )

• mouse embryonic fibroblast (MEF) mitochondria exhibit structural abnormalities characterized by intra-cristal swelling and reduced electron density in the mitochondrial matrix

abnormal mitochondrial crista morphology ( J:220742 )

• MEF mitochondria exhibit intra-cristal swelling

abnormal mitochondrial matrix morphology ( J:220742 )

• electron density of mitochondrial matrix is reduced in MEFs

increased mitochondrial number ( J:220742 )

• beta cells exhibit an increased number of mitochondria

decreased pancreatic beta cell proliferation ( J:220742 )

• mice show a decrease in cell proliferation of beta cells at 4 and 11 weeks of age

• however, level of apoptosis in islets is similar to wild-type levels

abnormal mitochondrial physiology ( J:220742 )

• response of islets to carbonyl cyanide m-chlorophenyl hydrazine, a mitochondrial respiration uncoupler, is delayed and the maximum capacity is decreased

homeostasis/metabolism

decreased insulin secretion ( J:220742 )

• insulin secretion from islets upon either glucose or KCl stimulation in reduced in 4 and 11 week old mutants

decreased oxygen consumption ( J:220742 )

• glucose stimulation increases oxygen consumption rate by only 1.3-fold in mutant islets compared to 2.1-fold in wild-type islets

impaired glucose tolerance ( J:220742 )

• in a glucose tolerance test, mice develop glucose intolerance at 4 weeks of age, characterized by a decrease in insulin secretion in response to glucose stimulation

• however, insulin sensitivity remains normal at 11 weeks of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:220742