Protein kinetics in human endotoxaemia and their temporal relation to metabolic, endocrine and proinflammatory cytokine responses.

BACKGROUND: Sepsis is associated with profound alterations in protein metabolism. The unpredictable time course of sepsis and the multiplicity of confounding factors prevent studies of temporal relations between the onset of endocrine and proinflammatory cytokine responses and the onset of protein catabolism. This study aimed to determine the time course of whole-body protein catabolism, and relate it to the endocrine, metabolic and cytokine responses in a human endotoxaemia model of early sepsis. METHODS: Six healthy male volunteers were studied twice in random order, before and for 600 min after administration of either an intravenous bolus of Escherichia coli lipopolysaccharide (LPS) or sterile saline. Whole-body protein synthesis, breakdown and net protein breakdown were measured by amino acid tracer infusion, and related to changes in plasma levels of growth hormone, glucagon, cortisol, insulin-like growth factor (IGF) 1, tumour necrosis factor (TNF) α and interleukin (IL) 6. RESULTS: Protein synthesis, breakdown and net protein breakdown increased and peaked 120 min after LPS administration (P < 0·001), the alterations persisting for up to 480 min. These peaks coincided with peaks in plasma growth hormone, TNF-α and IL-6 concentrations (P = 0·049, P < 0·001 and P < 0·001 for LPS versus saline), whereas plasma cortisol concentration peaked later. No alterations in plasma insulin or glucagon concentrations, or in the IGF axis were observed during the period of abnormalities of protein metabolism. CONCLUSION: LPS administration induced an early protein catabolic response in young men and this coincided with changes in plasma growth hormone, TNF-α and IL-6 concentrations, rather than changes in cortisol, glucagon, insulin or the IGF axis. Surgical relevance Sepsis in surgical patients is common and remains associated with substantial mortality. Although sepsis is a heterogeneous condition and its pathophysiology therefore difficult to study, a universal and profound clinical problem is protein catabolism not responsive to nutritional support. Human experimental endotoxaemia is a promising model of clinical sepsis that can be used to elucidate underlying pathophysiology and explore novel therapeutic approaches. This study demonstrates that human experimental endotoxaemia replicates the changes in whole-body protein turnover seen in clinical sepsis. Frequent measurements allowed identification of tumour necrosis factor (TNF) α, interleukin (IL) 6 and growth hormone as putative mediators. Human experimental endotoxaemia is a valid model for further study of mechanisms and putative therapies of catabolism associated with sepsis. In particular, effects of TNF-α and IL-6 blockade should be evaluated.

The effect of metformin on blood glucose control in overweight patients with Type 1 diabetes.

AIMS: In a randomized, double-blind, cross-over study, we investigated the effect of metformin on blood glucose control and daily insulin dose in overweight patients with Type 1 diabetes. METHODS: We studied 15 C-peptide-negative patients, aged 48 +/- 12 years, with a body mass index of 31.3 +/- 2.6 kg/m(2). Each patient had a 'screening visit', followed by a 4-week 'run-in' period. This was followed by two separate 16-week 'study' (treatment) periods, separated by a 4-week 'wash-out' period. Patients received either metformin or placebo during the 'study' periods, in random order. RESULTS: HbA(1c) was significantly lower following 16 weeks of treatment with metformin (7.8 +/- 1.1%) compared with baseline (8.5 +/- 1.4%; P < 0.005) and placebo (8.6 +/- 1.2%; P < 0.005). Fasting plasma glucose, following 16 weeks of metformin treatment, was significantly lower (8.3 +/- 2.8 mmol/l) compared with baseline (12.4 +/- 3.0 mmol/l; P < 0.01) and placebo (12.6 +/- 3.4 mmol/l; P < 0.01). Compared with baseline (60 +/- 14 units), total daily insulin dose was significantly lower following the addition of metformin (50 +/- 13 units; P < 0.05) and this final total daily insulin dose in the metformin group was lower compared with placebo (58 +/- 12 units, P < 0.05). Body weight did not change following metformin or placebo treatment. CONCLUSION: Metformin can effectively improve glycaemic control and reduce the total daily insulin dose in overweight people with Type 1 diabetes.

Evaluation of a bedside blood ketone sensor: the effects of acidosis, hyperglycaemia and acetoacetate on sensor performance.

AIMS: To assess the performance of a handheld bedside ketone sensor in the face of likely metabolic disturbances in diabetic ketoacidosis, namely: pH, glucose and acetoacetate. METHODS: The effects of pH (7.44-6.83), glucose (5-50 mmol/l) and acetoacetate (0-5 mmol/l) were examined in venous blood to investigate the accuracy of betahydroxybutyrate measurement (0-5 mmol/l) by a handheld ketone sensor. Sensor results were compared with a reference method. Linear regression models were fitted to the difference between the methods with the concentration of metabolite as the explanatory factor. RESULTS: Decreasing pH and increasing glucose had no effect on the accuracy of the handheld ketone sensor; the gradients of the fitted lines were -0.14 and -0.003, respectively. The 95% confidence intervals were -0.7-0.4 and -0.01-0.004, respectively (P = 0.59 and 0.4, respectively). In the acetoacetate study, a positive relationship between the sensor and reference method results was found, the gradient was 0.09. The 95% confidence interval was 0.05-0.14 (P < or = 0.001), indicating that high concentrations of acetoacetate interfere with the sensor performance. CONCLUSIONS: Acidosis and hyperglycaemia have minimal effects on the sensor performance. However, high concentrations of acetoacetate result in some overestimation of betahydroxybutyrate. This bedside ketone sensor provides useful data over a broad range of conditions likely to be encountered during moderate to severe diabetic ketoacidosis.