Diet-induced obesity prevents interstitial dispersion of insulin in skeletal muscle.
OBJECTIVE
Obesity causes insulin resistance, which has been interpreted as reduced downstream insulin signaling. However, changes in access of insulin to sensitive tissues such as skeletal muscle may also play a role. Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake. When insulin resistance is induced by exogenous lipid infusion, this interstitial diffusion process is curtailed. Thus, the possibility exists that hyperlipidemia, such as that seen during obesity, may inhibit insulin action to muscle cells and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in physiological obesity induced by a high-fat diet (HFD).


METHODS
Dogs were fed a regular diet (lean) or one supplemented with bacon grease for 9-12 weeks (HFD). Basal insulin (0.2 mU x min(-1) x kg(-1)) euglycemic clamps were performed on fat-fed animals (n = 6). During clamps performed under anesthesia, five sequential doses of insulin were injected into the vastus medialis of one hind limb (INJ); the contralateral limb (NINJ) served as a control.


RESULTS
INJ lymph insulin showed an increase above NINJ in lean animals, but no change in HFD-fed animals. Muscle glucose uptake observed in lean animals did not occur in HFD-fed animals.


CONCLUSIONS
Insulin resistance induced by HFD caused a failure of intramuscularly injected insulin to diffuse through the interstitial space and failure to cause glucose uptake, compared with normal animals. High-fat feeding prevents the appearance of injected insulin in the interstitial space, thus reducing binding to skeletal muscle cells and glucose uptake.
Kolka
Cathryn M
CM
Department of Physiology and Biophysics, University of Southern California, Los Angeles, California, USA.
Harrison
L Nicole
LN
Lottati
Maya
M
Chiu
Jenny D
JD
Kirkman
Erlinda L
EL
Bergman
Richard N
RN
D050153:Abdominal Fat / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology; D004285:Dogs; D015309:Glucose Clamp Technique; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007273:Injections, Intramuscular; D007328:Insulin / Q000493:pharmacokinetics*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050151:Subcutaneous Fat / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin