Free fatty acid and glucose metabolism in human aging: Evidence for operation of the Randle cycle

We assessed insulin effects on plasma free fatty acid (FFA) and glucose metabolism in seven elderly (71 ± 2 yr) and in seven younger (21 ± 1 yr) subjects matched for body weight and body mass index but not for percent body fat (32.4 ± 3.8% in elderly vs. 20.4 ± 3.5% in young, P < 0.05), by performing sequential euglycemic clamps at five insulin doses (0.6, 1.5, 3, 6, and 15 pmol · min^-1 · kg^-1) in combination with indirect calorimetry and [1-¹⁴C]palmitate plus [3-³H]glucose infusion. At baseline, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were all increased in the elderly (897 ± 107 vs. 412 ± 50 μmol/l and 11.2 ± 1.4 vs. 5.14 ± 0.86, 3.45 ± 0.65 vs. 1.37 ± 0.25, and 4.63 ± 0.72 vs. 3.01 ± 0.33 μmol · min^-1 · kg^-1 lean body mass, P < 0.05 for all comparisons), whereas glucose turnover was similar as a result of decreased glucose oxidation (8.2 ± 1.4 vs. 13 ± 1.9 μmol · min^-1 · kg^-1 lean body mass, P < 0.05) and increased glucose storage (6.6 ± 1.4 vs. 1.7 ± 1.3 mmol · min^-1 · kg^-1 lean body mass, P < 0.05). At all insulin infusions, plasma FFA reconcentration, turnover and oxidation, and total lipid oxidation were higher in the elderly than in the younger group (P < 0.05). However, if normalized per fat mass, all FFA and lipid metabolic fluxes, both in the postabsorptive state and during hyperinsulinemia, were comparable in the two groups. Insulin-mediated inhibition of hepatic glucose production and stimulation of glucose storage were similar in the two groups, but glucose oxidation was lower in the elderly than in the young at all insulin concentrations tested (P < 0.05). Plasma FFA turnover rate and total lipid oxidation were negatively correlated with whole body glucose uptake and oxidation in the two groups (P < 0.05-0.01). Thus, in human aging, abnormalities in insulin regulation of FFA/lipid metabolism may be secondary to increased fat mass and substrate competition between fat and glucose and may play a role in determining a reduction in insulin-mediated glucose oxidation.