The dose-response relationship between plasma insulin concentration and total glucose uptake, glucose oxidation, and glucose storage was examined in 22 healthy young volunteers by employing the euglycemic insulin clamp technique in combination with indirect calorimetry. Insulin was infused at five rates to achieve steady-state hyperinsulinemic plateaus of 62 ± 4, 103 ± 5, 170 ± 10, 423 ± 16, and 1132 ± 47 μU/ml. With increasing plasma insulin concentrations within the physiologic range, there was a linear increase in glucose uptake with a half maximally effective insulin concentration of 72 μU/ml. Glucose uptake by all tissues of the body reached 80% of its maximum value (12.6 mg/kg · min) at a plasma insulin concentration of ∼200 μU/ml. In contrast to total glucose uptake, glucose oxidation plateaued more quickly, achieved a maximum rate of only 4.0 mg/kg · min, and displayed a lower half maximally effective insulin concentration of 40 μU/ml. The increase in glucose uptake with progressively increasing plasma insulin levels was primarily the result of an increase in glucose storage, with a half maximally effective insulin concentration of 105 μU/ml and maximum rate of 8.7 mg/kg · min. Glucose storage represented over 60–70% of total glucose uptake at all insulin concentrations. After achieving maximum rates of insulin-mediated glucose uptake (plasma insulin concentration = 1132 μU/ml), hyperglycemia (+125 mg/dl) was superimposed on hyperinsulinemia to further enhance glucose transport. Under these conditions, total glucose uptake (32.5 mg/kg · min, P < 0.001) was markedly augmented but no significant increase in glucose oxidation was observed. These results indicate a true saturation of the glucose oxidation pathway. With pro-gressively increasing doses of insulin, the glucose storage represents the major route of glucose disposal.

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We studied the acute phase response, including specific cytokine production, [interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha(TNF alpha)] following a single dose of Aredia (disodium pamidronate) in patients with increased bone turnover and, in vitro, the role played by specific cytokines in the acute-phase reaction which may follow the administration of aminobisphosphonates. An in vivo exploratory study was done on 24 in- and outpatients with increased bone turnover given a single intravenous dose of pamidronate 60 mg. Measurements were taken at baseline and at 24, 48, and 72 hours. The main outcome measures were changes from baseline in serum IL-1, IL-6, and TNF alpha. In addition, C-reactive protein (CRP), white blood cell count (WCC), lymphocyte count, and elastase concentration were measured. Symptomatic evaluation was made of fever, bone pain, and rigors. In vitro, whole blood from eight healthy volunteers was exposed to various concentrations of the three bisphosphonates--pamidronate, clodronate, and zoledronate. Measurements were taken immediately before and at 3, 6, and 10 hours after exposure to drugs. The main outcome measures were changes in serum IL-1, IL-6, and TNF alpha. In vivo, there was a statistically significant (P < 0.001) increase in median values of TNF alpha in all post-baseline measurements. Median values for IL-6 also showed a significant (P < 0.001) increase at 24 hours after dosing. There were no statistically significant changes in median IL-1 values. Few patients showed any change from baseline in total WCC or in lymphocyte count, but 62.5% of patients with normal range baseline values for CRP increased to above normal levels after treatment. Fourteen patients experienced fever; 2 reported rigors. There was no correlation between fever and changes in cytokines. There were no serious adverse experiences or premature discontinuations due to poor tolerability, and 91% of the patients expressed willingness to receive pamidronate again. In vitro, an increase in TNF alpha and a mild increase in IL-6 was seen with all bisphosphonates, with the greatest effects seen with the highest concentration of both pamidronate and zoledronate. No changes were observed in IL-1 with any agent. Significant changes in both TNF alpha and IL-6 were observed within 3 days of a single dose of pamidronate in patients treated for the first time confirming previous findings. However, the lack of change in IL-1 in vivo and in vitro does not support the hypothesis that this cytokine plays a major role in the acute phase reaction. The cellular mechanism of the interaction among aminobisphosphonates, IL-6, and TNF alpha requires further investigations. The results of the in vitro study are consistent with the in vivo findings.

Segmental body composition assessed by bioelectrical impedance analysis and DEXA in humans. J. Appl. Physiol. 81(6): 2580-2587, 1996.-The present study assessed the relative contribution of each body segment to whole body fat-free mass (FFM) and impedance and explored the use of segmental bioelectrical impedance analysis to estimate segmental tissue composition. Multiple frequencies of whole body and segmental impedances were measured in 51 normal and overweight women. Segmental tissue composition was independently assessed by dual-energy X-ray absorptiometry. The sum of the segmental impedance values corresponded to the whole body value (100.5 6 1.9% at 50 kHz). The arms and legs contributed to 47.6 and 43.0%, respectively, of whole body impedance at 50 kHz, whereas they represented only 10.6 and 34.8% of total FFM, as determined by dual-energy X-ray absorptiometry. The trunk averaged 10.0% of total impedance but represented 48.2% of FFM. For each segment, there was an excellent correlation between the specific impedance index (length 2 /impedance) and FFM (r 5 0.55, 0.62, and 0.64 for arm, trunk, and leg, respectively). The specific resistivity was in a similar range for the limbs (159 6 23 cm for the arm and 193 6 39 cm for the leg at 50 kHz) but was higher for the trunk (457 6 71 cm). This study shows the potential interest of segmental body composition by bioelectrical impedance analysis and provides specific segmental body composition equations for use in normal and overweight women. dual-energy X-ray absorptiometry; body segments; body fat; fat-free mass