Theories for the mechanisms underlying the development of insulin resistance have included defects in insulin binding, inhibition of insulin receptor tyrosine kinase, and impaired translocation of glucose across the plasma membrane. However, little attention has been paid to the possibility that altered reciprocal regulatory interactions between lipid and carbohydrate fuels may underly the development of insulin resistance. We would like to review recent developments in metabolic regulation which indicate that this neglected aspect of intermediary metabolism may have more widespread physiological significance than hitherto suspected.
The major pathways of glucose utilization are storage (glycogen), non-oxidative degradation (glycolysis) and oxidative degradation. It has been demonstrated in post-absorptive man by indirect calorimetry that the ability of insulin to stimulate non-oxidative disposal of glucose is decreased by the prior oxidation of lipid (Thiebaud, DeFronzo, Jacot et al. 1982). In these studies, a neutral lipid emulsion was infused before insulin concentrations were raised by
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