Diet-induced obesity prevents interstitial dispersion of insulin in skeletal muscle

Abstract

Objective: Obesity causes insulin resistance, which has been interpreted as reduced downstream insulin signaling. But, changes in access of insulin to sensitive tissues like 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 the insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in physiological obesity induced by a high fat diet.

Research design and methods: Dogs were fed a regular diet (lean) or one supplemented with bacon grease for 9-12 weeks (high fat diet, HFD). Basal insulin (0.2mU/min/kg) euglycemic clamps were performed on fat-fed animals (n=6). During clamps done under anesthesia, 5 sequential doses of insulin were injected into the vastus medialis of one hindlimb (INJ); the contra-lateral limb (NINJ) served as a control.

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

Conclusions: Insulin resistance induced by HFD caused a failure of intra-muscularly injected insulin to diffuse through the interstitial space and failure to cause glucose uptake, compared to 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.