Phenotypes Associated with This Genotype

Genotype
MGI:5766645

• Allelic Composition: Clec16a^tm1.1Hhak/Clec16a^tm1.1Hhak; Tg(Pdx1-cre)1Herr/0
• Genetic Background: involves: C57BL/6 * C57BL/6J * CBA/J * SJL

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

homeostasis/metabolism

abnormal mitophagy ( J:214528 )

• accumulation of unhealthy mitochondria, coupled with dysregulation of the Nrdp1/Parkin pathway, suggests defective mitophagy/autophagy leading to impaired glucose-stimulated OCR and insulin secretion

decreased insulin secretion ( J:214528 )

• mice show reduced basal and blunted insulin release at 0 and 3 min after glucose administration in vivo and in isolated islets

• no differences in peripheral insulin sensitivity are observed

hyperglycemia ( J:214528 )

• mice exhibit hyperglycemia due to functional defects in beta cells

decreased oxygen consumption ( J:214528 )

• pancreatic islets show reduced glucose-stimulated oxygen consumption rate (OCR) as well as maximal OCR following FCCP treatment (to induce mitophagy) relative to wild-type islets

impaired glucose tolerance ( J:214528 )

• intraperitoneal glucose tolerance testing (IPGTT) revealed that mice are significantly hyperglycemic relative to controls

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:214528 )

N • no signs of exocrine pancreatic dysfunction, such as weight loss, steatorrhea, or abnormal acinar or ductal cell histology

N • no evidence of infiltrating lymphocytes into the pancreatic islets

N • normal islet architecture and beta cell mass

abnormal pancreatic alpha cell morphology ( J:214528 )

• pancreatic alpha cells exhibit rounded mitochondria with a severely disordered and amorphous structure

abnormal pancreatic beta cell morphology ( J:214528 )

• at 3 months, TEM revealed an accumulation of vacuolated structures, some containing partially degraded cytoplasmic material consistent with autophagic vacuoles, not observed in wild-type beta cells

• beta cells exhibit rounded mitochondria with a severely disordered and amorphous structure, including an increased number of distorted cristae and inclusions not observed in wild-type cells

• 3D EM reconstruction tomography showed accumulation of electron lucent vacuolated structures, including large interconnected vacuoles (likely dilated ER), and smaller spherical vacuoles (possibly endosomes)

abnormal pancreatic beta cell physiology ( J:214528 )

• mice show a significant increase in total pancreatic insulin content at age 12 weeks

decreased insulin secretion ( J:214528 )

• mice show reduced basal and blunted insulin release at 0 and 3 min after glucose administration in vivo and in isolated islets

• no differences in peripheral insulin sensitivity are observed

cellular

abnormal endoplasmic reticulum morphology ( J:214528 )

• pancreatic beta cells show age-dependent alterations in ER morphology, indicative of ER stress

abnormal mitochondrial morphology ( J:214528 )

• pancreatic beta cells exhibit rounded mitochondria with a severely disordered and amorphous structure, including an increased number of distorted cristae and inclusions not observed in wild-type cells

disorganized mitochondrial cristae ( J:214528 )

• distorted mitochondrial cristae in pancreatic beta cells

increased mitochondrial size ( J:214528 )

• increased mitochondrial mass in pancreatic islets, as shown by increased mtDNA levels and levels of the mitochondrial proteins succinate dehydrogenase A and mitochondrial complex IV subunit I

abnormal mitophagy ( J:214528 )

• accumulation of unhealthy mitochondria, coupled with dysregulation of the Nrdp1/Parkin pathway, suggests defective mitophagy/autophagy leading to impaired glucose-stimulated OCR and insulin secretion