title: Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia.
abstract: Changes in tumor necrosis factor-alpha (TNF-alpha) may provide a mechanism to explain impaired glucose metabolism with advancing age. Hyperglycemic clamps (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-alpha production at basal and at the end of 180 min of hyperglycemia and hyperinsulinemia was measured ex vivo from lipopolysaccharide-stimulated (1 ng/ml) peripheral blood mononuclear cells. Plasma glucose, insulin, and C-peptide 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 action among the older subjects. Basal TNF-alpha secretion was similar in older and younger subjects. TNF-alpha was suppressed (P < 0.02) in the younger group (230 +/- 46 vs. 126 +/- 49 pg/ml; basal vs. clamp) but not in the older group (153 +/- 37 vs. 182 +/- 42 pg/ml), with significant group differences in response (P < 0.05). A significant correlation was observed between the level of suppression in TNF-alpha production and insulin action (Kendall's rank, tau = 0.40, P < 0.05). Furthermore, the TNF-alpha response during the clamp was related to fat mass (r = 0.88, P < 0.001) and abdominal fat (r = 0.81, P < 0.003). In conclusion, these findings suggest a possible mechanism by which TNF-alpha may modulate glucose metabolism in younger people. 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 insulin sensitivity in older men.
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio 44109-1998, USA. jkirwan@metrohealth.org
authors.forename: J P
authors.initials: JP
authors.lastname: Kirwan
authors.forename: R K
authors.initials: RK
authors.lastname: Krishnan
authors.forename: J A
authors.initials: JA
authors.lastname: Weaver
authors.forename: L F
authors.initials: LF
authors.lastname: Del Aguila
authors.forename: W J
authors.initials: WJ
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D001786:Blood Glucose / Q000502:physiology; D001823:Body Composition; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha