Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog

<jats:sec><jats:title>Objective</jats:title><jats:p>Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Metabolic assessment was performed in healthy dogs (<jats:italic>n</jats:italic> = 90). Whole‐body sensitivity from euglycemic clamps (SI<jats:sub>CLAMP</jats:sub>) was the primary outcome variable, and was measured independently by IVGTT (<jats:italic>n</jats:italic> = 36). Adiposity was measured by MRI (<jats:italic>n</jats:italic> = 90), and glucose‐stimulated insulin response was measured from hyperglycemic clamp or IVGTT (<jats:italic>n</jats:italic> = 86 and 36, respectively).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>SI<jats:sub>CLAMP</jats:sub> was highly variable (5.9‐75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight‐fold and was inversely correlated with SI<jats:sub>CLAMP</jats:sub> (<jats:italic>P</jats:italic> < 0.025). SI<jats:sub>CLAMP</jats:sub> was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (<jats:italic>r</jats:italic> = 0.53, <jats:italic>P</jats:italic> < 0.00001), whether calculated from clamp or IVGTT.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.</jats:p></jats:sec>