Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

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

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47 Scopus citations

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 Ins2Akita mice 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 Ins2Akita and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2Akita mice 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 Ins2 Akita mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCε levels in Ins2Akita 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 Ins2Akita mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2Akita 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.

Original languageEnglish (US)
Pages (from-to)E1687-E1696
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume293
Issue number6
DOIs
StatePublished - Dec 1 2007

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Hong, E. G., Dae, Y. J., Hwi, J. K., Zhang, Z., Ma, Z., Jun, J. Y., Jae, H. K., Sumner, A. D., Vary, T. C., Gardner, T. W., Bronson, S. K., & Kim, J. K. (2007). Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling. American Journal of Physiology - Endocrinology and Metabolism, 293(6), E1687-E1696. https://doi.org/10.1152/ajpendo.00256.2007