Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia

Changes in tumor necrosis factor-alpha (TNF-alpha) may provide a mechanism to explain impaired glucose metabolism with advancing age. Hyperglycemic cl amps (180 min, 10 mM) were performed on seven older [67 +/-2 yr; body mass index (BMI) 24.7 +/-1.0 kg/m(2)] and seven younger (22 +/-1 yr; BMI 21.8 +/ -1.3 kg/m(2)) healthy sedentary males with normal glucose tolerance. TNF-al pha production at basal and at the end of 180 min of hyperglycemia and hype rinsulinemia was measured ex vivo from lipopolysaccharide-stimulated (1 ng/ ml) peripheral blood mononuclear cells. Plasma glucose, insulin, and C-pept ide levels were similar in both groups at basal and during the last 30 min of the hyperglycemic clamp. Glucose infusion rates were lower (P<0.004) in the older group compared with the young, indicating decreased insulin actio n among the older subjects. Basal TNF-<alpha> secretion was similar in olde r and younger subjects. TNF-alpha was suppressed (P<0.02) in the younger gr oup (230<plus/minus>46 vs. 126 +/- 49 pg/ml; basal vs. clamp) but not in th e older group (153 +/- 37 vs. 182 +/- 42 pg/ml), with significant group dif ferences in response (P<0.05). A significant correlation was observed betwe en the level of suppression in TNF-<alpha> production and insulin action (K endall's rank, tau = 0.40, P<0.05). Furthermore, the TNF-<alpha> response d uring the clamp was related to fat mass (r = 0.88, P<0.001) and abdominal f at (r = 0.81, P<0.003). In conclusion, these findings suggest a possible me chanism by which TNF-alpha may modulate glucose metabolism in younger peopl e. Aging and modest increases in adiposity prevent the "normal" suppression of TNF-alpha production after a sustained postprandial-like hyperglycemic- hyperinsulinemic stimulus, which may contribute in part to the decline in i nsulin sensitivity in older men.