Sarah Taudorf

IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Aims/hypothesisDecreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer’s disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism.Subjects and methodsWe included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic–euglycaemic clamp.ResultsPlasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain.Conclusions/interpretationLow levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

Human Endotoxemia as a Model of Systemic Inflammation

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimers disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.

Association between Interleukin-15 and Obesity: Interleukin-15 as a Potential Regulator of Fat Mass

OBJECTIVE IL-15 decreases lipid deposition in preadipocytes and decreases the mass of white adipose tissue in rats, indicating that IL-15 may take part in regulating this tissue. IL-15 is expressed in human skeletal muscle and skeletal muscle may be a source of plasma IL-15 and in this way regulate adipose tissue mass. DESIGN The relation between skeletal muscle IL-15 mRNA expression, plasma IL-15, and adipose tissue mass was studied in 199 humans divided into four groups on the basis of obesity and type 2 diabetes. Furthermore, using a DNA electrotransfer model, we assessed the effect of IL-15 overexpression in skeletal muscle of mice. RESULTS In humans, multiple regression analysis showed a negative association between plasma IL-15 and total fat mass (P<0.05), trunk fat mass (P<0.01), and percent fat mass (P<0.05), independent of type 2 diabetes. Negative associations were also found between muscle IL-15 mRNA and obesity parameters. IL-15 overexpression in skeletal muscle of mice reduced trunk fat mass but not sc fat mass. CONCLUSIONS Our results indicate that IL-15 may be a regulator of trunk fat mass.

Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

AbstractAims/hypothesisClear evidence exists that TNF-α inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-α in type 2 diabetes.MethodsWe obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n = 96) and healthy controls matched for age, sex and BMI (n = 103).ResultsPatients with type 2 diabetes had higher plasma levels of fasting insulin (p < 0.0001) and glucose (p < 0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-α (p = 0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-α after adjustment for age, sex, obesity, WHR, neutrophils, IL-6 and maximum O2 uptake

Calprotectin — A Novel Marker of Obesity

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Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

in the diabetes group (p < 0.05). The TNF mRNA content of adipose or muscle tissue did not differ between the groups, whereas muscle TNF-α protein content, evaluated by western blotting, was higher in type 2 diabetic patients. Immunohistochemistry revealed more TNF-α protein in type 2 than in type 1 muscle fibres.Conclusions/interpretationAfter adjustment for multiple confounders, plasma TNF-α is associated with insulin resistance. This supports the idea that TNF-α plays a significant role in the pathogenesis of chronic insulin resistance in humans. However, findings on the TNF-α protein levels in plasma and skeletal muscle indicate that measurement of TNF mRNA content in adipose or muscle tissue provides no information with regard to the degree of insulin resistance.

Human Models of Low-Grade Inflammation: Bolus versus Continuous Infusion of Endotoxin

OBJECTIVE—YKL-40 is produced by macrophages, and plasma YKL-40 is elevated in patients with diseases characterized by inflammation. In the present study, YKL-40 was examined in relation to obesity, inflammation, and type 2 diabetes. RESEARCH DESIGN AND METHODS—Plasma YKL-40 and adipose tissue YKL-40 mRNA levels were investigated in 199 subjects who were divided into four groups depending on the presence or absence of type 2 diabetes and obesity. In addition, plasma YKL-40 was examined in healthy subjects during a hyperglycemic clamp, in which the plasma glucose level was kept at 15 mmol/l for 3 h, and during a hyperinsulinemic-euglycemic clamp. RESULTS—Patients with type 2 diabetes had higher plasma YKL-40 (76.7 vs. 45.1 ng/ml, P = 0.0001) but not higher expression in adipose tissue YKL-40 mRNA (1.20 vs. 0.98, P = 0.2) compared with subjects with a normal glucose tolerance. Within the groups with normal glucose tolerance and type 2 diabetes, obesity subgroups showed no difference with respect to either plasma YKL-40 or adipose tissue YKL-40 mRNA levels. Multivariate regression analysis showed that plasma YKL-40 was associated with fasting plasma glucose (β = 0.5, P = 0.0014) and plasma interleukin (IL)-6 (β = 0.2, P = 0.0303). Plasma YKL-40 was not related to parameters of obesity. There were no changes in plasma YKL-40 in healthy subjects during either hyperglycemic or hyperinsulinemic-euglycemic clamps. CONCLUSIONS—Plasma YKL-40 was identified as an obesity-independent marker of type 2 diabetes related to fasting plasma glucose and plasma IL-6 levels.