All Phenotypes Prkaa2<tm1.1Vio> MGI Mouse

homeostasis/metabolism phenotype ( J:81120 )

N	• homozygotes display normal triglyceride levels in liver, gastrocnemius muscle, and pancreas relative to controls • no differences in fed or fasted plasma levels of total and HDL cholesterol, sodium, potassium, creatinine or urea are observed

decreased circulating leptin level ( J:81120 )

• in the fed state, homozygotes exhibit lower plasma leptin levels than controls

• in contrast, fasted plasma leptin levels are normal

increased circulating free fatty acids level ( J:81120 )

• homozygotes exhibit higher plasma FFA levels than controls in both the fasted and fed state

abnormal urine catecholamine level ( J:81120 )

• homozygotes display a significant increase in daily urinary catecholamine (epinephrine, norepinephrine, and dopamine) excretion relative to controls, suggesting a dysregulation in sympathetic tone

abnormal glucose homeostasis ( J:81120 )

• unlike controls, homozygotes are resistant to the hypoglycemic action of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)

• during hyperinsulinemic euglycemic clamp studies, insulin-stimulated whole-body glucose turnover rate is reduced in mutant mice relative to controls, whereas insulin-stimulated whole-body glycolysis is normal

decreased insulin secretion ( J:81120 )

• homozygotes display impaired glucose-stimulated insulin secretion, as determined by plasma insulin levels at 20 min after an oral glucose challenge

• in contrast, basal and glucose- and l-arginine-stimulated insulin secretion are normal in isolated mutant pancreatic islets, with no differences in insulin content relative to control islets

hyperglycemia ( J:81120 )

• in the fed state, homozygotes exhibit higher plasma glucose levels than controls

• in contrast, fasted plasma glucose levels are normal

decreased circulating insulin level ( J:81120 )

• in the fed state, homozygotes exhibit lower plasma insulin levels than controls

• in contrast, fasted plasma insulin levels are normal

impaired glucose tolerance ( J:81120 )

• homozygotes display a significantly higher blood glucose excursion than controls at 20 min after an oral glucose challenge, indicating glucose intolerance

• impaired glucose tolerance is significantly improved after i.p. injection of phentolamine (an alpha-adrenergic receptor antagonist), whereas no change is observed after treatment by propranolol (a beta-adrenergic receptor antagonist)

abnormal glycogen homeostasis ( J:81120 )

• during hyperinsulinemic euglycemic clamp studies, the insulin-stimulated whole-body glycogen synthesis rate is severely reduced in mutant mice relative to controls

• at the end of the clamp, the insulin-stimulated muscle glycogen synthesis rate is severely reduced in mutant mice relative to controls

• in the basal state, both whole-body glycogen synthesis and in vivo muscle glycogen synthesis rates are normal

• no differences in basal and insulin-stimulated glucose uptake are observed in isolated skeletal muscles between mutant and control mice

• no differences in liver glycogen synthesis are observed between mutant and control mice in either basal or clamp studies

decreased skeletal muscle glycogen level ( J:81120 )

• at the end of the clamp, insulin-stimulated total muscle glycogen content is severely reduced in mutant mice relative to controls

• however, no differences in total skeletal muscle glycogen content are observed in the basal state or in random-fed mutant mice relative to controls

• no differences in total liver glycogen content are observed between mutant and control mice in either basal or clamp studies

insulin resistance ( J:81120 )

• during hyperinsulinemic euglycemic clamp studies, homozygotes exhibit reduced whole-body insulin sensitivity, with a severe reduction in insulin-stimulated glycogen synthesis in skeletal muscle relative controls

• in contrast, hepatic insulin sensitivity appears unaffected