title: Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling.
abstract: Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects.
authors.affiliation: Dept. of Cellular and Molecular Physiology, Penn State Univ. College of Medicine, 500 University Dr. (H166 C4600D, Hershey, PA 17033, USA.
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhexi
authors.initials: Z
authors.lastname: Ma
authors.forename: John Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Jae Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Sumner
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Vary
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gardner
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bronson
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000097:blood; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption; D010695:Phlorhizin / Q000494:pharmacology / Q000627:therapeutic use; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; D010695:Phlorhizin; D051744:Protein Kinase C-epsilon; D005947:Glucose