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High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect

Diabetes. 1997 Feb;46(2):215-23. doi: 10.2337/diab.46.2.215.

Abstract

Glucose transport in skeletal muscle can be mediated by two separate pathways, one stimulated by insulin and the other by muscle contraction. High-fat feeding impairs glucose transport in muscle, but the mechanism remains unclear. FVB mice (3 weeks old) were fed a high-fat diet (55% fat, 24% carbohydrate, 21% protein) or standard chow for 3-4 weeks or 8 weeks. Insulin-stimulated glucose transport, assessed with either 2-deoxyglucose or 3-O-methylglucose was decreased 35-45% (P < 0.001) in isolated soleus muscle, regardless of diet duration. Similarly, glucose transport stimulated by okadaic acid, a serine/threonine phosphatase inhibitor, was also 45% lower with high-fat feeding, but the glucose transport response to hypoxia or N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (which are stimulators of the "contraction pathway") was intact. Hexokinase I, II, and total activity were normal in soleus muscle from high-fat-fed mice. GLUT4 expression in soleus muscle from the high-fat-fed mice was also normal, but the insulin-stimulated cell surface recruitment of GLUT4 assessed by exofacial photolabeling with [3H]-ATB bis-mannose was reduced by 50% (P < 0.001). Insulin-receptor substrate 1 (IRS-1) associated phosphatidylinositol (PI) 3-kinase activity stimulated by insulin was also reduced by 36% (P < 0.001), and expression of p85 and p110b subunits of PI 3-kinase was normal. In conclusion, high-fat feeding selectively impairs insulin-stimulated, but not contraction-pathway-mediated, glucose transport by reducing GLUT4 translocation to the plasma membrane. This appears to result from an acquired defect in insulin activation of PI 3-kinase. Since effects of okadaic acid on glucose transport are independent of PI 3-kinase, a second signaling defect may also be induced.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Blood Glucose / metabolism
  • Cell Compartmentation
  • Dietary Fats / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Glucose Transporter Type 4
  • Hexokinase / metabolism
  • Hypoxia / metabolism
  • Insulin / physiology*
  • Insulin Resistance*
  • Male
  • Mice
  • Monosaccharide Transport Proteins / metabolism*
  • Muscle Proteins*
  • Muscle, Skeletal / metabolism
  • Okadaic Acid / pharmacology
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase C / physiology
  • Signal Transduction
  • Sulfonamides / pharmacology

Substances

  • Blood Glucose
  • Dietary Fats
  • Enzyme Inhibitors
  • Glucose Transporter Type 4
  • Insulin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Slc2a4 protein, mouse
  • Sulfonamides
  • Okadaic Acid
  • W 7
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Hexokinase
  • Protein Kinase C