No abstract

1. beta 2-Adrenoceptor agonists have been shown to increase rapidly lean body mass and reverse muscle wasting in several animal models of human illness. However, no published information is available for humans. In the present study, we investigated the effects of a slow-release preparation of salbutamol or a placebo on skeletal muscle functional capacity in 12 healthy men. The strength of different muscle groups was measured on two occasions before and after 14 and 21 days of treatment. 2. No significant changes in muscle strength were observed with placebo during the trial. In contrast, the strength of both quadriceps muscles increased significantly (12 +/- 3%) after 14 days on salbutamol, and remained elevated at 21 days. Whereas the strength of the hamstring muscles of the dominant leg significantly increased after 21 days on salbutamol (22 +/- 6%), the strength of the non-dominant hamstring muscles returned to baseline values. 3. There was no significant change in the grip strength of either hand in these subjects during the trial. The maximal static inspiratory mouth pressure increased significantly (7 +/- 2%) after 14 days on salbutamol, and increased further after 21 days (15 +/- 4%); the expiratory mouth pressure remained constant. No significant changes in body weight, skinfold thickness, lean body mass or limb circumferences were measured in either group. 4. These data demonstrate that short-term administration of salbutamol increases voluntary muscle strength in man. However, the magnitude and duration of this effect vary between muscle groups. This study implies that the beta 2-adrenoceptor agonists may be of therapeutic potential in altering skeletal muscle function in humans.

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile saline (n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.

Infection results in a state of insulin resistance, but the pathogenesis is poorly understood. Intravenous administration of bacterial lipopolysaccharide (LPS) has been used to mimic the febrile and systemic inflammatory responses to infection, but it is unclear whether LPS induces insulin resistance in man. To investigate the effects of LPS on insulin sensitivity and substrate utilization, we administered, in paired cross-over studies, either 20 U/kg Escherichia coli endotoxin or saline control to healthy volunteers (n = 6) 120 min after the start of a 10-h euglycemic hyperinsulinemic clamp (insulin infusion rate, 80 mU/m2 x min). LPS induced a fever, tachycardia, and mild arterial hypotension. Glucose utilization increased abruptly 120 min after LPS administration (+64.1+/-12.0%; P < 0.003), but then declined progressively, and insulin resistance was evident by 420 min (+1.9+/-3.5%; P < 0.05). The reduction in glucose utilization, like that observed in sepsis, was related to impaired nonoxidative glucose disposal and not abnormal glucose oxidation. The cortisol and GH responses to LPS were of sufficient duration and magnitude to explain the insulin resistance. LPS administration results in metabolic responses very similar to those observed in sepsis and could provide a useful model for the study of insulin resistance in human critical illness.