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

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