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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/E1687    most recent 00256.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Hong, E.-G. Articles by Kim, J. K. Search for Related Content PubMed PubMed Citation Articles by Hong, E.-G. Articles by Kim, J. K.

Nonobese, insulin-deficient Ins2^Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

¹Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; ²Department of Internal Medicine, Section of Endocrinology, Hallym University College of Medicine, Seoul, South Korea; ³Division of Endocrinology, Diabetes and Metabolism, ⁴Cardiology, and ⁵Ophthalmology, Department of Internal Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Submitted 24 April 2007 ; accepted in final form 24 September 2007

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 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 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 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 PKC levels in Ins2^Akita mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKC 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.

type 1 diabetes; mouse model; hyperglycemia; ventricular hypertrophy

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