Indirect effects of insulin in regulating glucose fluxes

Metabolism of fuels is driven by the energy demand of the organism and its regulation is influenced by many hormonal and metabolic factors. Insulin is of utmost importance in regulating glucose metabolism by promoting glucose uptake in the insulin-sensitive tissues for energy consumption and/or storage. The effects of insulin on glucose metabolism can be both direct and indirect. Ample evidence has indicated that insulin directly stimulates glucose transport systems in the target tissues. However, the changes in glucose fluxes can also be brought out by indirect effects of insulin which are produced secondary to the insulin-induced changes in other hormones and metabolites. In this chapter, we discussed a number of examples of insulin's indirect effects on glucose metabolism. We demonstrated that insulin can indirectly promote muscle glucose uptake during exercise by restraining the release and oxidation of fatty acids and decrease of hyperglycemia. We have presented some evidence for an indirect regulation of glucose cycling by insulin. We have also demonstrated the importance of the peripheral levels of insulin for insulin-induced inhibition of hepatic glucose production. This presumably indirect effects of peripheral insulin might consist of 1) suppression of the release of energy substrates and gluconeogenic precursors; and 2) suppression of glucagon secretion. In a carbachol-induced stress model, insulin is not required for a putatively neural regulation of an increase in systemic glucose uptake but a "permissive" effect of insulin is essential. These studies underscore the importance of the interactions between insulin and other hormones and metabolites as opposed to insulin's direct actions per se.