Objective: Approximately 70% of all cancer patients have elevations in hepatic glucose production and/or reductions in glucose utilization. To identify an explanation for insulin resistance, we measured fasting hepatic glucose production (HGP), leucine appearance (Leu Ra), leucine oxidation (LO), glucose oxidation (GO) and non-oxidative glucose utilization at baseline and after identical insulin infusion rates (2 pmol/kg/minute, 7 pmol/kg/minute, and 70 pmol/kg/minute) in eight head and neck cancer patients and eight weight-matched disease-free volunteers.
Methods: A step increase in insulin administration during a euglycemic clamp protocol was used to measure insulin effects on glucose and leucine metabolism. HGP and Leu Ra were determined by performing a primed, continuous 10-hour intravenous infusion of 6-3H glucose and 1-14C leucine. Baseline insulin, thyroid, TNF, and counter-regulatory hormonal measurements, HGP, GO and Leu Ra were obtained between hours 3 and 4. An insulin infusion was started at hour 4 and increased every 2 hours for 6 hours. Glucose appearance, Leu Ra, GO, LO and insulin concentrations were determined at the end of each 2-hour interval.
Results: Fasting HGP, GO, fat oxidation and Leu Ra were similar between the two groups. Insulin administration in cancer patients and normal volunteers had a similar effect on LO and Leu Ra. The insulin concentration required to stimulate half maximal glucose utilization in cancer patients was significantly increased by 58% (470 +/- 82 pM vs. 741 +/- 124 pM; p < or = 0.05). Non-oxidative glucose utilization was reduced in the cancer patients at both lower doses of insulin infusion (6.4 +/- 2.1 mumol/kg/minute vs. 0.1 +/- 1.6 mumol/kg/minute p < or = 0.05; and 23.7 +/- 1.3 mumol/kg/minute vs. 15.1 +/- 2.0 mumol/kg/minute p < 0.01). Triiodothyronine (T3) was directly correlated in the cancer patients with non-oxidative glucose utilization at the two physiological insulin concentrations (r = 0.673, p < 0.05 and r = 0.731, p < 0.01) and the supraphysiological insulin concentration (r = 0.791, p < 0.01). The insulin sensitivity index from the euglycemic clamp study was significantly reduced in the cancer patients (4.7 +/- 0.7 vs. 2.4 +/- 0.1 (dl/min)/(microU/ml); p < 0.05).
Conclusions: In summary, head and neck cancer patients have an abnormal reduction in non-oxidative glucose utilization which occurs before abnormalities in HGP, GO, or Leu Ra [corrected]. One explanation for the reduced glucose utilization may be the influence of a reduced T3 concentration on non-oxidative glucose metabolism but further work is needed to confirm these preliminary observations.