[Usefulness of biomarkers of sepsis in the ICU]. / Utilité des biomarqueurs du sepsis en réanimation.

Despite some progress, the mortality of severe sepsis and septic shock remains high. Immunotherapy directed against inflammatory mediators failed, but new treatments more specifically tailored to individual situations are actively investigated. C-reactive protein (CRP) and procalcitonin (PCT) have not demonstrated to be useful for individual prognostic stratification. New biomarkers such as pancreatic stone protein (PSP) or growth arrest specific protein 6 (Gas6) could improve this prediction. Combined with the clinical course, "PCT" allows to tailor individually the duration of antibiotic therapy in ICU patients. This still contested innovative approach significantly reduces overall exposure to antibiotics.

Stress and metabolism.

Obesity, lipid disorders, type 2 diabetes, high blood pressure and coronary heart disease are frequently encountered in wealthy populations. All these disorders frequently occur as clusters, constituting the metabolic syndrome. It is currently admitted that insulin resistance plays a central role in the pathogenesis of this syndrome. Stress responses include activation of the sympathetic nervous system and stimulation of epinephrine and cortisol release. These hormones may over the long term reduce insulin sensitivity. Cortisol may also favour the development of central obesity. In healthy individuals, mental stress increases heart rate, but simultaneously decreases vascular resistance in skeletal muscle. This results in a moderate increase in blood pressure, and an acute increase in insulin-mediated glucose disposal. In obese patients, mental stress elicits responses which differ widely from those of healthy individuals. While mental stress enhances catecholamine-mediated energy expenditure in obese patients to the same extent as in lean subjects, it fails to decrease systemic vascular resistance due to endothelial dysfunction. This leads to enhanced blood pressure responses and the absence of stimulation of glucose disposal in obese subjects during mental stress. It can be hypothesized that repeated professional or social stress may activate the sympathoadrenal system, resulting in high cortisol levels, stimulation of the sympathetic nervous system, and epinephrine secretion. All these factors may eventually lead to the development of central obesity and insulin resistance. Furthermore, the blood pressure responses to mental stress may be enhanced in insulin-resistant individuals, favouring the development of vascular complications.

Effect of metformin on insulin sensitivity and insulin secretion in female obese patients with normal glucose tolerance.

OBJECTIVES: Metformin is recognized as the treatment of chronic obese, insulin-resistant type 2 diabetic patients. Whether it improves insulin sensitivity in obese patients with normal glucose tolerance remains unknown. METHODS: Eight obese female patients with normal glucose tolerance were studied during a double blinded, randomized cross-over study including a 2-week administration of metformin and a 2-week administration of placebo. Insulin secretion and insulin sensitivity were assessed after metformin and placebo by means of a 3-hour hyperglycemic clamp. RESULTS: The plasma insulin and C-peptide concentrations during the hyperglycemic clamp were identical after placebo or metformin (both first and second phases). Insulin-mediated glucose disposal, stimulation of glucose oxidation and suppression of endogenous glucose production were identical after metformin and placebo. CONCLUSIONS: Metformin does not improve insulin sensitivity nor insulin secretion in obese female patients with normal glucose tolerance.

Effects of dexamethasone on the metabolic responses to mental stress in humans.

The haemodynamic effects of the sympathetic nervous system (SNS) activations elicited by hypoglycaemia, acute alcohol administration, or insulin can be prevented by a pretreatment with dexamethasone in humans. This suggests a possible role of central corticotropin releasing hormone (GRIT) release. Mental stress activates the SNS, and decreases systemic vascular resistances though a beta-adrenergic-mediated vasodilation thought to involve vascular nitric oxide release. It also increases insulin-mediated glucose disposal, an effect presumably related to vasodilation. In order to evaluate whether activation of SNS by mental stress is glucocorticoid-sensitive, we monitored the haemodynamic and metabolic effects of mental stress during hyperinsulinaemia in healthy humans with and without a 2-day treatment with 8 mg day(-1) dexamethasone. Mental stress decreased systemic vascular resistances by 21.9% and increased insulin-mediated glucose disposal by 2 8.4% without dexamethasone pretreatment. After 2 days of dexamethasone treatment, whole body insulin-mediated glucose disposal was decreased by 40.8%. The haemodynainic effects of mental stress were however, not affected. Mental stress acutely increased insulin-mediated glucose disposal by 28.0%. This indicates that mental stress elicits a stimulation of SNS through dexamethasone-insensitive pathway, distinct of those activated by insulin, alcohol, or hyperglycaemia.

Effects of free fatty acids on insulin sensitivity and hemodynamics during mental stress.

Mental stress is known to decrease systemic vascular resistance and increase muscle blood flow and to acutely enhance insulin-mediated glucose disposal in healthy humans. These effects are abolished in obese patients. We therefore proposed the hypothesis that elevated free fatty acid levels may be responsible for the abnormal responses to mental stress in obesity by inhibiting endothelial cell function. To test this hypothesis, we studied a group of eight lean females during a hyperinsulinemic clamp study with and without lipid infusion. A 30-min mental stress was applied during 30 min after 150 min of hyperinsulinemia. In the study without lipid infusion, mental stress increased heart rate by 26.5%, blood pressure by 7.9%, and cardiac index (measured with thoracic bioimpedance) by 35.9%; it decreased systemic vascular resistance by 21.9% and increased insulin-mediated glucose disposal by 18.9%. During lipid infusion, the increase in heart rate was not affected, but the increase in cardiac index, the decrease in systemic vascular resistance, and the increase in insulin-mediated glucose disposal were all inhibited. In contrast, the rise in blood pressure was increased about 2-fold (control plus 6 mm Hg vs. lipid plus 13 mm Hg, P: < 0.01). These results indicate that lipid inhibits the stimulation of glucose uptake and enhances the pressor effect of mental stress, presumably by altering endothelial cell function.

Counterregulatory responses to hypoglycemia in patients with maturity-onset diabetes of the young caused by HNF-1alpha gene mutations (MODY3).

Mutations of HNF-1alpha lead to severe beta cell dysfunction, resulting in decreased glucose-induced insulin secretion. HNF-1alpha is also expressed in liver, kidney and pancreatic alpha cells, but the functional consequences of HNF-1alpha mutations in these organs remain unknown. We therefore assessed the counterregulatory responses to hypoglycemia in six patients with HNF-1alpha mutations (MODY3), five patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine healthy controls. Plasma glucagon concentrations and endogenous glucose production were measured every 15 min during a hyperinsulinemic clamp with progressive hypoglycemia. Plasma glucagon concentrations were similar at basal glycemia (73+/-6, 69+/-5 and 69+/-7 ng/l) and reached peak values of 88+/-9, 88+/-11 and 89+/-7 ng/l at a glycemia of 3.6 mmol/l in MODY3 patients, patients with NIDDM and controls respectively (NS). Suppression of endogenous glucose production by insulin was blunted in MODY3 patients (3.3+/-1.2 micromol/kg per min) and in patients with NIDDM (4.4+/-0.6 micromol/kg per min) compared with controls (1.7+/-0.5 micromol/kg per min, P<0.05 compared with both MODY3 patients and patients with NIDDM). During hypoglycemia, endogenous glucose production increased to 8.6+/-2.1, 8.8+/-0.7 and 7.0+/-1.0 micromol/kg per min in MODY3 patients, patients with NIDDM and controls respectively (all NS). These data indicate that mutations of HNF-1alpha in MODY3 do not result in a decreased glucagon secretion or alterations of glucose production during hypoglycemia.

Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations.

The glucokinase gene is expressed not only in pancreatic B cells and in the liver, but also in pancreatic alpha cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(- 2) H glucose) were monitored during an hyperinsulinemic clamp at about 2.4 pmol.kg(- 1).min(- 1) insulin with progressive hypoglycemia in 7 maturity onset diabetes of the young (MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subjects. Basal glucose concentrations were significantly higher in MODY2 patients (7.6 +/- 0.4 mmol.l(- 1) ) and type 2 diabetic patients (12.4 +/- 2.3 mmol.l(- 1) ) than in healthy subjects (5.3 +/- 0.1 mmol.l(- 1), p<0.01) but counterregulatory hormones concentrations were identical. Insulin-mediated glucose disposal and suppression of endogenous glucose production at euglycemia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. During progressive hypoglycemia, the glycemic thresholds of MODY2 patients for increasing glucose production (5.0 +/- 0.4 mmol.l(- 1) ) and for glucagon stimulation (4.5 +/- 0.4 mmol. l(- 1) ) were higher than those of healthy subjects and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(- 1) respectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(- 1) for glucagon stimulation, p <0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may be secondary to decreased glucokinase activity in hypothalamic neuronal cells, or to alterations of glucose sensing in pancreatic alpha cells and liver cells.

Effects of mental stress on insulin-mediated glucose metabolism and energy expenditure in lean and obese women.

The effects of the sympathetic activation elicited by a mental stress on insulin sensitivity and energy expenditure (VO(2)) were studied in 11 lean and 8 obese women during a hyperinsulinemic-euglycemic clamp. Six lean women were restudied under nonselective beta-adrenergic blockade with propranolol to determine the role of beta-adrenoceptors in the metabolic response to mental stress. In lean women, mental stress increased VO(2) by 20%, whole body glucose utilization ([6,6-(2)H(2)]glucose) by 34%, and cardiac index (thoracic bioimpedance) by 25%, whereas systemic vascular resistance decreased by 24%. In obese women, mental stress increased energy expenditure as in lean subjects, but it neither stimulated glucose uptake nor decreased systemic vascular resistance. In the six lean women who were restudied under propranolol, the rise in VO(2), glucose uptake, and cardiac output and the decrease in systemic vascular resistance during mental stress were all abolished. It is concluded that 1) in lean subjects, mental stress stimulates glucose uptake and energy expenditure and produces vasodilation; activation of beta-adrenoceptors is involved in these responses; and 2) in obese patients, the effects of mental stress on glucose uptake and systemic vascular resistance, but not on energy expenditure, are blunted.

Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects.

OBJECTIVE: To determine the effects of excess carbohydrate or fat intake on plasma leptin concentrations and energy expenditure. DESIGN: Ten healthy lean females were studied: (a) during a 3 day isoenergetic diet (ISO); (b) during 3 day carbohydrate overfeeding (CHO OF); and (c) during 3 day fat overfeeding (FAT OF). During each test, basal metabolic rate, the energy expended during mild physical activity and recovery, and 24 h energy expenditure (24 h EE) were measured with indirect calorimetry. The concentrations of glucose and lactate were monitored in subcutaneous interstitial fluid over a 24 h period using microdialysis. Plasma hormone and substrate concentrations were measured in a blood sample collected in the morning of the fourth day. RESULTS: CHO OF increased plasma leptin concentrations by 28%, and 24 h EE by 7%. Basal metabolic rate and the energy expended during physical activity were not affected. FAT OF did not significantly change plasma leptin concentrations or energy expenditure. There was no relationship between changes in leptin concentrations and changes in energy expenditure, suggesting that leptin is not involved in the stimulation of energy metabolism during overfeeding. Interstitial subcutaneous glucose and lactate concentrations were not altered by CHO OF and FAT OF. CONCLUSIONS: CHO OF, but not FAT OF, increases energy expenditure and leptin concentration.