All Phenotypes Sdhb<tm1c(EUCOMM)Hmgu> MGI Mouse

decreased insulin secretion ( J:326592 )

• young mice exhibit reduced insulin release following glucose administration

• islets fail to secrete insulin in response to leucine in 5-week-old mice

• islets show reduced glucose-stimulated first- and second-phase insulin secretion in 5-week-old mice

• exendin-4-augmented insulin secretion is slightly impaired in islets, while potassium chloride-induced insulin secretion is not altered, indicating an intact insulin secretion mechanism downstream of mitochondrial metabolism

• rapamycin treatment enhances insulin secretion under high glucose with no changes at resting glucose level

increased fasting circulating glucose level ( J:326592 )

• mice show increased fasting glucose levels at 20 weeks of age

hyperglycemia ( J:326592 )

• mice show a progressive rise in fed glucose levels; while young mice are normoglycemic and normoinsulinemic until 6 weeks, hyperglycemia is evident by 10 weeks

decreased circulating insulin level ( J:326592 )

• mice develop insulinopenic diabetes at pubertal age

• mice show low fasting serum insulin levels at 20 weeks of age

impaired glucose tolerance ( J:326592 )

• young mice are mildly glucose intolerant with unchanged insulin sensitivity when challenged by intraperitoneal glucose tolerance test

• acute treatment with rapamycin marginally improves glucose intolerance

abnormal pancreatic islet morphology ( J:326592 )

• by 20 weeks, but not at 5 weeks, islets exhibit large membraned vacuoles containing engulfed organelles, including insulin granules and damaged mitochondria

decreased pancreatic beta cell mass ( J:326592 )

• mice show a progressive reduction in beta-cell mass without alterations in alpha-cell mass

abnormal endocrine pancreas physiology ( J:326592 )

• islets show nearly undetectable mitochondrial electron transport chain complex CII activity, elevated succinate levels, increase in protein lysine succinylation and increase in expression of the dessucinylation enzyme SIRT5

• islets show reduced basal and glucose-stimulated respiration and reduced maximal respiration and spare reserve capacity

• islets show a more than 50% reduction in ATP synthase-related oxygen consumption rate following oligomycin injection

• glucose-exposed islets fail to increase the ATP to ADP ratio

• islets show accumulation of succinate, with no change in fumarate levels, fatty acid intermediates, nucleic acid building blocks and precursors of protein synthesis despite a deficit of free amino acid pool

abnormal pancreatic beta cell physiology ( J:326592 )

• homeostatic model assessment of beta-cell function as a percentage is reduced

• glucose-stimulated beta-cell replication is impaired in islets of prediabetic 5-week-old mice