Diet-Induced Obesity Prevents Interstitial Dispersion of Insulin in Skeletal Muscle

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 3; pp. 619 - 626
• Main Authors: KOLKA, Cathryn M, NICOLE HARRISON, L, LOTTATI, Maya, CHIU, Jenny D, KIRKMAN, Erlinda L, BERGMAN, Richard N
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2010
• Subjects: Abdominal Fat - metabolism; Animal Feed; Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight - physiology; Complications and side effects; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - pharmacology; Dogs; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucose; Glucose Clamp Technique; Health aspects; Hyperlipidemias - drug therapy; Hyperlipidemias - metabolism; Hypoglycemic Agents - pharmacokinetics; Injections, Intramuscular; Insulin; Insulin - pharmacokinetics; Insulin resistance; Insulin Resistance - physiology; Laboratory animals; Lipids; Magnetic resonance imaging; Male; Medical sciences; Metabolic diseases; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Nutrition research; Obesity; Obesity - drug therapy; Obesity - metabolism; Original; Plasma; Research design; Risk factors; Signal Transduction - physiology; Skeletal muscle; Striated muscle. Tendons; Subcutaneous Fat - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; United States; Endocrinopathy; Obesity; Pancreatic hormone; Diet; Diabetes mellitus; Nutrition disorder; Striated muscle; Insulin; Nutritional status; Feeding
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0839

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). 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. 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. 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.