Hans P. Sauerwein

Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

Selective parasympathetic innervation of subcutaneous and intra-abdominal fat — functional implications

The wealth of clinical epidemiological data on the association between intra-abdominal fat accumulation and morbidity sharply contrasts with the paucity of knowledge about the determinants of fat distribution, which cannot be explained merely in terms of humoral factors. If it comes to neuronal control, until now, adipose tissue was reported to be innervated by the sympathetic nervous system only, known for its catabolic effect. We hypothesized the presence of a parasympathetic input stimulating anabolic processes in adipose tissue. Intra-abdominal fat pads in rats were first sympathetically denervated and then injected with the retrograde transneuronal tracer pseudorabies virus (PRV). The resulting labeling of PRV in the vagal motor nuclei of the brain stem reveals that adipose tissue receives vagal input. Next, we assessed the physiological impact of these findings by combining a fat pad-specific vagotomy with a hyperinsulinemic euglycemic clamp and RT-PCR analysis. Insulin-mediated glucose and FFA uptake were reduced by 33% and 36%, respectively, whereas the activity of the catabolic enzyme hormone-sensitive lipase increased by 51%. Moreover, expression of resistin and leptin mRNA decreased, whereas adiponectin mRNA did not change. All these data indicate an anabolic role for the vagal input to adipose tissue. Finally, we demonstrate somatotopy within the central part of the autonomic nervous system, as intra-abdominal and subcutaneous fat pads appeared to be innervated by separate sympathetic and parasympathetic motor neurons. In conclusion, parasympathetic input to adipose tissue clearly modulates its insulin sensitivity and glucose and FFA metabolism in an anabolic way. The implications of these findings for the (patho)physiology of fat distribution are discussed.

Assessment of malnutrition parameters in head and neck cancer and their relation to postoperative complications.

Malnutrition is reported frequently in head and neck cancer patients. The impact of malnutrition on surgical outcome is not clearly understood. The purpose of this study was to define the usefulness of six different parameters in scoring malnutrition and to determine the nutritional parameter primarily related to postoperative complications.

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

Type 2 diabetes and insulin resistance syndromes are associated with an increased risk for cardiovascular and thrombotic complications. A disturbed balance between coagulation and fibrinolysis has been implicated in the pathogenesis hereof. To determine the selective effects of hyperglycemia and hyperinsulinemia on coagulation and fibrinolysis, six healthy humans were studied on four occasions for 6 h: 1) lower insulinemic-euglycemic clamp, 2) lower insulinemic-hyperglycemic clamp, 3) hyperinsulinemic-euglycemic clamp, and 4) hyperinsulinemic-hyperglycemic clamp. In the hyperglycemic clamps, target levels of plasma glucose were 12 versus 5 mmol/l in the normoglycemic clamps. In the hyperinsulinemic clamps, target plasma insulin levels were 400 versus 100 pmol/l in the lower insulinemic clamps. Hyperglycemia exerted a procoagulant effect irrespective of insulin levels, as reflected by mean twofold rises in thrombin-antithrombin complexes and soluble tissue factor, whereas hyperinsulinemia inhibited fibrinolysis irrespective of glucose levels, as reflected by a decrease in plasminogen activator activity levels due to a mean 2.5-fold rise in plasminogen activator inhibitor type 1. The differential effects of hyperglycemia and hyperinsulinemia suggest that patients with hyperglycemia due to insulin resistance are especially susceptible to thrombotic events by a concurrent insulin-driven impairment of fibrinolysis and a glucose-driven activation of coagulation.

Insulin Sensitivity and Insulin Clearance in Human Immunodeficiency Virus-Infected Men

To test whether clinically stable human immunodeficiency virus (HIV) infection, like other infections, is associated with insulin resistance and increased insulin clearance, we measured the sensitivity to insulin and insulin clearance using the euglycemic insulin clamp technique in 10 clinically stable outpatients with symptomatic HIV infection (Centers for Disease Control [CDC] group IV) and 10 healthy controls. During administration of 0.8 and 4 mU insulin.kg-1.min-1, HIV-infected men had 40% (P less than .02) and 83% (P less than .01) higher rates of insulin clearance when compared with healthy controls. Despite significantly lower steady-state insulin concentrations (42 +/- 2 v 52 +/- 4 microU/mL, P less than .05, and 255 +/- 17 v 392 +/- 14 microU/mL, P less than .001, patients v controls), patients and controls had similar total glucose uptake (7.99 +/- 0.81 v 7.92 +/- 0.44 mg.kg-1.min-1 and 14.00 +/- 0.81 v 13.65 +/- 0.65 mg.kg-1.min-1, patients v controls). In the postabsorptive state, no differences were found between patients and controls in insulin levels (7 +/- 1 microU/mL in both) and endogenous glucose production (2.52 +/- 0.07 and 2.24 +/- 0.17 mg.kg-1.min-1, respectively), but plasma glucose levels in the patients (5.02 +/- 0.15 mmol/L) were significantly lower when compared with controls (5.46 +/- 0.14 mmol/L, P less than .05). The results indicate that HIV-infected men have increased rates of insulin clearance and increased sensitivity of peripheral tissues to insulin, which makes HIV infection unique with regard to glucose and insulin metabolism.

Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia

Type 2 diabetes is associated with altered immune and hemostatic responses. We investigated the selective effects of hyperglycemia and hyperinsulinemia on innate immune, coagulation, and fibrinolytic responses during systemic inflammation. Twenty-four healthy humans were studied for 8 hours during clamp experiments in which either plasma glucose, insulin, both, or none was increased, depending on randomization. Target plasma concentrations were 5 versus 12 mM for glucose, and 100 versus 400 pmol/L for insulin. After 3 hours, 4 ng/kg Escherichia coli endotoxin was injected intravenously to induce a systemic inflammatory and procoagulant response. Endotoxin administration induced cytokine release, activation of neutrophils, endothelium and coagulation, and inhibition of fibrinolysis. Hyperglycemia reduced neutrophil degranulation (plasma elastase levels, P < .001) and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < .001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activator-inhibitor-1 levels (P < .001). Endothelial cell activation markers and cytokine concentrations did not differ between clamps. We conclude that in humans with systemic inflammation induced by intravenous endotoxin administration hyperglycemia impairs neutrophil degranulation and potentiates coagulation, whereas hyperinsulinemia inhibits fibrinolysis. These data suggest that type 2 diabetes patients may be especially vulnerable to prothrombotic events during inflammatory states.

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term up- and down-labeling with 2H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool.

Lipodystrophy in Hiv-1-positive patients is associated with insulin resistance in multiple metabolic pathways

BackgroundTreatment for HIV-1 infection is complicated by fat redistribution (lipodystrophy). This is associated with insulin resistance concerning glucose uptake. Our aim was to characterize glucose metabolism more comprehensively in HIV-1-infected patients with lipodystrophy. We assessed glucose disposal and its pathways, glucose production, plasma free fatty acid (FFA) levels, and the degree to which these parameters could be suppressed by insulin. MethodsSix HIV-1-infected men on protease inhibitor-based HAART with lipodystrophy (HIV+LD) were studied. The results were compared with those in six matched healthy male volunteers. Insulin sensitivity was quantified by hyperinsulinemic euglycaemic clamp. Glucose production and uptake were assessed by tracer dilution employing 6,6d2-glucose. ResultsAt post-absorptive insulin concentrations, glucose production was 47% higher in HIV+LD than controls (P = 0.025). During clamp, glucose production was suppressed by 53% in HIV+LD, but by 85% in controls (P = 0.004). Glucose disposal increased in both groups, but by only 27% in HIV+LD versus 201% in controls (P = 0.004). Consequently, insulin-stimulated total glucose disposal was lower in HIV+LD patients (P = 0.006). Non-oxidative glucose disposal as percentage of total disposal did not differ significantly between groups (63% in HIV+LD and 62% in controls). Baseline plasma FFA concentrations were higher (0.60 versus 0.35 mmol/l;P = 0.024), whereas FFA decline during hyperinsulinemia was less (65 versus 85%;P = 0.01) in HIV+LD versus controls . ConclusionsPost-absorptive glucose production is increased in HIV-1-infected patients with lipodystrophy. Moreover, both the ability of insulin to suppress endogenous glucose production and lipolysis, and to stimulate peripheral glucose uptake and its metabolic pathways is reduced, indicating severe resistance concerning multiple effects of insulin.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T3 microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T3 vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T3 microdialysis versus 8 ± 3% in vehicle-treated rats (T3 vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T3 administration. Effects of PVN T3 microdialysis were independent of plasma T3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T3 microdialysis on EGP. We conclude that stimulation of T3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Increased resting energy expenditure in human immunodeficiency virus-infected men

Even in the absence of anorexia and malabsorption, weight loss is frequently observed in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). To investigate whether increased resting energy expenditure (REE) might be responsible for this weight loss, indirect calorimetry was performed in 18 human immunodeficiency virus (HIV)-infected men free of clinically active opportunistic infections for at least 2 months. Patients with AIDS (n = 11) or ARC (n = 7) had 9% higher rates of REE when compared with 11 healthy volunteers (P less than .05) with similar food intake and of the same body composition. The results obtained from patients with AIDS or ARC were identical. As no differences were found between patients and controls in plasma concentrations of catecholamines, thyroid hormones, cortisol, or tumor necrosis factor, except for lower concentrations of norepinephrine in the patients (mean +/- SD, 233 +/- 111 v 367 +/- 125 ng/L, patients v controls, P less than .01), this hypermetabolism is not explained by higher levels of these catabolic hormones. The results indicate that even in the absence of acute concomitant infections, increased REE may contribute to the weight loss in patients with AIDS or ARC.