EFFECTS OF NONESTERIFIED FATTY-ACID AVAILABILITY ON TISSUE-SPECIFIC GLUCOSE-UTILIZATION IN RATS INVIVO

The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P<0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P<0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P<0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P<0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P<0.001) that was directed toward glycogen (+175%, P<0.05) and lipid deposition (+125%, P<0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P<0.005) and brown adipose tissue (e.g., FFA2, +200%, P<0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.