Molecular mechanisms for insulin resistance in Ossabaw miniature swine

The metabolic syndrome is characterized by obesity, insulin resistance/hyperinsulinemia, glucose intolerance, dyslipidemia and hypertension. Previous studies have noted obesity and decreased insulin sensitivity in Ossabaw swine, thus representing a novel model of the metabolic syndrome. The aim of the present study was to determine whether several steps in the insulin signaling pathway are impaired. Pigs 3 months old were randomly assigned to a lean diet or an excess high fat‐high cholesterol atherogenic diet that elicited obesity and the metabolic syndrome. Animals were sacrificed after 55 weeks on the respective diet, and skeletal muscle samples were collected for determination of the key components of the insulin signaling pathway. The obese group had a 4 fold increase in the phosphorylation of insulin receptor substrate (IRS)‐1 (Ser636/639) compared to the lean diet group; these serine phosphorylation sites confer inactivation of IRS‐1 and development of insulin resistance. The obese group also showed elevated mTOR signaling, reflected by 160% increase in mTOR phosphorylation (Ser2448) (p<0.01) and 25% increase in p70S6k phosphorylation (Thr389) (p=0.06) This suggests that negative feedback by mTOR‐p70S6k signaling on IRS‐1 may be casual in the development of insulin resistance in these swine. We hypothesize decreased AMP‐activated kinase activity is associated with a missense mutation in the AMPKγ3 subunit (Val199→Ile) in the Ossabaw pigs and leads to altered skeletal muscle AMP‐kinase activity, causing increased mTOR activity. Support: NIH RR013223 , HL062552 , Riley Children’s Foundation.