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Reduced Access to Insulin-Sensitive Tissues in Dogs With Obesity Secondary to Increased Fat Intake

¹ Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California
² Medical University Graz, Department of Internal Medicine, Diabetes and Metabolism, Graz, Austria

Address correspondence and reprint requests to Richard N. Bergman, PhD, Keck Professor of Medicine, Department of PhysiologyBiophysics, University of Southern California School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90033. E-mail rbergman{at}usc.edu

Abbreviations: MRI, magnetic resonance imaging

Physiological hyperinsulinemia provokes hemodynamic actions and augments access of macromolecules to insulin-sensitive tissues. We investigated whether induction of insulin resistance by a hypercaloric high-fat diet has an effect on the extracellular distribution of macromolecules to insulin-sensitive tissues. Male mongrel dogs were randomly selected into two groups: seven dogs were fed an isocaloric control diet (3,900 kcal, 35% from fat), and six dogs were fed a hypercaloric high-fat diet (5,300 kcal, 54% from fat) for a period of 12 weeks. During hyperinsulinemic-euglycemic clamps, we determined transport parameters and distribution volumes of [¹⁴C]inulin by applying a three-compartment model to the plasma clearance data of intravenously injected [¹⁴C]inulin (0.8 µCi/kg). In another study with direct cannulation of the hindlimb skeletal muscle lymphatics, we investigated the effect of physiological hyperinsulinemia on the appearance of intravenously injected [¹⁴C]inulin in skeletal muscle interstitial fluid and compared the effect of insulin between control and high-fat diet groups. The hypercaloric high-fat diet resulted in significant weight gain (18%; P < 0.001) associated with marked increases of subcutaneous (140%; P < 0.001) and omental (83%; P < 0.001) fat depots, as well as peripheral insulin resistance, measured as a significant reduction of insulin-stimulated glucose uptake during clamps (–35%; P < 0.05). Concomitantly, we observed a significant reduction of the peripheral distribution volume of [¹⁴C]inulin (–26%; P < 0.05), whereas the vascular distribution volume and transport and clearance parameters did not change as a cause of the diet. The second study directly confirmed our findings, suggesting a marked reduction of insulin action to stimulate access of macromolecules to insulin-sensitive tissues (control diet 32%, P < 0.01; high-fat diet 18%, NS). The present results indicate that access of macromolecules to insulin-sensitive tissues is impaired during diet-induced insulin resistance and suggest that the ability of insulin itself to stimulate tissue access is diminished. We speculate that the observed diet-induced defects in stimulation of tissue perfusion contribute to the development of peripheral insulin resistance.

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