Nonobese, insulin-deficient Ins2Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling Article (Web of Science)

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 Ins2Akitamice leads to pancreatic β-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 Ins2Akitaand wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2Akitamice developed insulin resistance, as indicated by an ∼80% reduction in glucose infusion rate during clamps. Insulin resistance was due to ∼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 PKCε levels in Ins2Akitamice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCε levels in Ins2Akitamice, 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 Ins2Akitamice. Overall, we report for the first time that nonobese, insulin-deficient Ins2Akitamice 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

  • Hong, Eun-Gyoung
  • Jung, Dae Young
  • Ko, Hwi Jin
  • Zhang, Zhiyou
  • Ma, Zhexi
  • Jun, John Y
  • Kim, Jae Hyeong
  • Sumner, Andrew D.
  • Vary, Thomas C.
  • Gardner, Thomas W.
  • Bronson, Sarah K.
  • Kim, Jason K.

publication date

  • 2007

webpage

published in

start page

  • E1687

end page

  • E1696

volume

  • 293

issue

  • 6