Reduced access to insulin-sensitive tissues in dogs with obesity secondary to increased fat intake.
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 ( approximately 3,900 kcal, 35% from fat), and six dogs were fed a hypercaloric high-fat diet ( approximately 5,300 kcal, 54% from fat) for a period of 12 weeks. During hyperinsulinemic-euglycemic clamps, we determined transport parameters and distribution volumes of [(14)C]inulin by applying a three-compartment model to the plasma clearance data of intravenously injected [(14)C]inulin (0.8 microCi/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 [(14)C]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 [(14)C]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.
Ellmerer
Martin
M
Department of Physiology and Biophysics, University of Southern California School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90033, USA.
Hamilton-Wessler
Marianthe
M
Kim
Stella P
SP
Huecking
Katrin
K
Kirkman
Erlinda
E
Chiu
Jenny
J
Richey
Joyce
J
Bergman
Richard N
RN
D000818:Animals; D002250:Carbon Radioisotopes; D004041:Dietary Fats / Q000008:administration & dosage*; D004285:Dogs; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006614:Hindlimb / Q000378:metabolism; D006946:Hyperinsulinism / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007333:Insulin Resistance / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D011897:Random Allocation; D014018:Tissue Distribution / Q000187:drug effects
D002250:Carbon Radioisotopes; D004041:Dietary Fats; D007328:Insulin; D005947:Glucose