Intramyocyte Lipids May Impair Insulin Signaling

Skeletal muscle clears the bulk of glucose from the circulation after a meal. Although physicians have long been aware of links among high-calorie diets, obesity, and resistance of skeletal muscle to insulin, details of this interaction were obscure until recently. Several lines of evidence suggest that accumulation of intracellular fat in the form of triglycerides may provide a biomarker for skeletal muscle insulin resistance. According to this hypothesis, excess intracellular long-chain fatty acids can be stored as intracellular triglycerides or oxidized to generate energy. However, small amounts of spillover metabolites may interfere with insulin signaling and thus cause insulin resistance. Nuclear magnetic resonance (NMR) technology, developed and validated over the last 15 years, will provide new methods to test this hypothesis.

Skeletal myocytes ( Figure A ) contain small amounts of triglyceride stored as droplets in the cytosol and are detected in a biopsy by an oil-red-O stain. NMR spectroscopy provides an alternative to invasive biopsies in quantifying myocyte triglycerides. At relatively low magnetic fields such as conventional clinical 1.5 T instruments, individual signals from intracellular and extracellular fat can be identified because the two anatomical compartments experience slightly different magnetic fields. (T or Tesla is an index of magnetic field strength.) At high fields such as 3.0 T and especially 7.0 T, the separation is much easier to detect and to use for clinical research. Acquired from a 1 × 1 × 1 cm voxel in the soleus muscle ( Figure B ), this 7.0 T spectrum ( Figure C ) shows multiple signals or resonances that can be assigned to small aqueous metabolites such as carnitine, carnosine, creatine, or taurine, as well as the CH ₂ and CH ₃ signals from intracellular and extracellular triglyceride stores. The concentration of intracellular triglycerides may be estimated by indexing to intracellular metabolites or to external standards. Since these studies are well tolerated by almost all subjects, ¹ H NMR spectroscopy may provide a new method to monitor the effects of drugs on body composition and fat distribution and may be informative about insulin resistance.