Beate Jessnitzer

Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery

OBJECTIVE Irisin has recently been introduced as a novel an exercise-inducible myokine which improves glucose metabolism in mice. However, regulation of circulating irisin in gestational diabetes mellitus (GDM) and in the peripartal period has not been assessed so far. METHODS Circulating irisin was quantified in 74 GDM patients and in 74 healthy, pregnant, gestational age-matched controls. In a subset of these patients (44 GDM, 41 controls), postpartum follow-up data were also available. In a second study population of 40 healthy women with singleton pregnancies undergoing elective Cesarean section, irisin was assessed in maternal serum before and within 24h after delivery, as well as in umbilical cord blood and in placental tissue. RESULTS In the first study population, median [interquartile range] irisin levels were significantly higher in GDM patients as compared to controls after delivery (previous GDM: 446.3 [146.9]μg/l; controls: 378.0 [111.4]μg/l) but not during pregnancy (GDM: 482.1 [132.1]μg/l; controls: 466.6 [178.0]μg/l). Interestingly, fasting insulin (FI) was independently and positively associated with serum irisin in multivariate analysis during pregnancy. In agreement with these findings, relative changes (ratio) of FI independently and positively predicted relative changes of irisin (ratio) in the second study population. CONCLUSIONS The myokine irisin is independently associated with FI in pregnancy. The physiological significance of these findings needs to be assessed in future experiments.

Amyloid Precursor Protein Expression Is induced by Tumor Necrosis Factor α in 3T3-L1 Adipocytes

Amyloid precursor protein (APP) has been characterized as an adipocyte‐secreted protein that might contribute to obesity‐related insulin resistance, inflammation, and dementia. In the current study, regulation of APP by the proinflammatory and insulin resistance‐inducing cytokine tumor necrosis factor (TNF) α was determined in 3T3‐L1 adipocytes. Interestingly, APP protein synthesis and mRNA expression were significantly increased by TNFα in a time‐dependent manner with maximal induction observed after 24 h of treatment. Furthermore, TNFα induced APP mRNA expression dose‐dependently with maximal 6.4‐fold upregulation seen at 100 ng/ml effector. Moreover, inhibitor experiments suggested that TNFα‐induced APP expression was mediated by nuclear factor κ B. Taken together, we show for the first time a potent upregulation of APP by TNFα suggesting a potential role of this adipocyte‐secreted protein in TNFα‐induced insulin resistance and inflammatory disease. J. Cell. Biochem. 108: 1418–1422, 2009.

Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo

Circulating levels of the adipokine adipocyte fatty acid‐binding protein (AFABP) are increased in obesity. However, the influence of circulating AFABP on insulin sensitivity in vivo remains unclear.

Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin.

OBJECTIVES Conflicting evidence concerning leptin in atherosclerosis has been published. Furthermore, dose-dependent effects of leptin on atherogenesis have not been studied. METHODS Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR(-/-);ob/ob) mice were treated with saline, 0.1, 0.5, or 3.0mg/kg body weight (BW)/d recombinant leptin over 12weeks starting at 8weeks of age. Aortic root and brachiocephalic artery (BCA) atherosclerotic lesions were analyzed by oil red O staining. Furthermore, glucose homeostasis, lipid metabolism, and liver function including tissue studies were assessed in all animals. RESULTS Leptin treatment dose-dependently decreased BW in LDLR(-/-);ob/ob mice as compared to saline. Mice in the 0.1 and 0.5mg/kgBW/d groups remained heavier (i.e. subphysiological leptin dose) and in the 3.0mg/kgBW/d group had similar weight (i.e. physiological leptin dose) as compared to non-leptin-deficient LDLR(-/-) animals. Recombinant leptin dose-dependently reduced plaque area in the aortic root and the BCA by 36% and 58%, respectively. Leptin-mediated reductions of plasma total and LDL-cholesterol (Chol) remained independent predictors for aortic root plaque area. Chol content in liver, as well as hepatic expression of key lipid and proinflammatory genes, were dose-dependently regulated by leptin. Furthermore, leptin treatment increased circulating levels and adipose tissue mRNA expression of the adipokine adiponectin. CONCLUSIONS Leptin administration within the subphysiological to physiological range diminishes atherosclerotic lesions. Leptin appears to mediate its antiatherogenic effects indirectly through reduction of hypercholesterolemia and liver steatosis, as well as upregulation of insulin-sensitizing and atheroprotective adiponectin.

Serum levels of growth arrest specific protein 6 are increased in preeclampsia

Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest specific protein (Gas) 6 has been introduced as a novel metabolic risk factor with anti-angiogenic, pro-atherogenic, and pro-adipogenic properties. In the current study, we investigated serum concentrations of Gas6 in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of Gas6 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was assessed in all individuals. Median maternal Gas6 serum levels adjusted for body mass index and gestational age at blood sampling were significantly increased in PE patients (5.7 μg/l) as compared to healthy, age-matched pregnant women (4.6 μg/l) (p<0.05). Furthermore, Gas6 concentrations positively correlated with blood pressure, creatinine, free fatty acids, C-reactive protein, leptin, and adiponectin during pregnancy. Moreover, leptin and adiponectin remained independently associated with Gas6 levels in multivariate analysis. Gas6 serum levels 6 months after pregnancy were not significantly different between former PE and control patients. Taken together, maternal Gas6 serum concentrations are significantly increased in PE during pregnancy. Furthermore, the adipokines leptin and adiponectin are independent predictors of circulating Gas6 in pregnant women.

Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes

Fractalkine has recently been introduced as an adipokine that improves glucose tolerance. Regulation of fractalkine in gestational diabetes, as well as its association with markers of obesity, glucose and lipid metabolism, inflammation and renal function, has not been elucidated.

Relationship between serum levels of angiopoietin-related growth factor and metabolic risk factors.

Angiopoietin-related growth factor (AGF, also known as angiopoietin-like protein 6) has been introduced as a novel hepatocyte-derived factor, which antagonizes obesity and insulin resistance in mice. However, human studies show conflicting results and are limited to a small cohort of patients. In the current study, we therefore sought to investigate AGF serum levels in a large metabolically well-characterized cohort. AGF serum concentrations were determined by commercial enzyme-linked immunosorbent assay in 697 patients of a cohort from Eastern Germany (Sorbs). Correlations of AGF serum levels with clinical and biochemical measures of glucose and lipid metabolism, as well as markers of renal function, were investigated. In nondiabetic subjects (n=627), AGF was positively correlated with markers of insulin resistance and negatively correlated with high-density lipoprotein cholesterol in univariate analyses (p<0.05). After adjustment for age, gender, and body mass index, none of these factors remained independently associated with AGF, neither in nondiabetic subjects nor in patients with type 2 diabetes mellitus (T2DM) (n=70). However, we confirmed existing data of significantly higher AGF concentrations in patients with T2DM as compared to controls in this large cohort. Circulating AGF is elevated in subjects with T2DM and related to the type of antidiabetic treatment, but is not independently associated with anthropometric parameters, indices of insulin sensitivity and secretion, or a number of other adipokines.

Serum Levels of Copeptin are Decreased in Gestational Diabetes Mellitus.

OBJECTIVE Copeptin, the c-terminal part of pro-Arginine vasopressin, has recently been introduced as a novel risk factor to develop facets of the metabolic syndrome. However, regulation of copeptin in pregnancy-associated metabolic disease, i. e., gestational diabetes mellitus (GDM), has not been fully understood, so far. PATIENTS AND MEASUREMENTS For this study, 74 GDM patients and 74 healthy, pregnant, age-, body mass index-, and gestational age-matched controls were recruited. Serum levels of copeptin were quantified by an illuminometric assay. Furthermore, copeptin concentrations were correlated to biochemical and anthropometric markers of obesity, glucose and lipid metabolism, renal function, and inflammation. RESULTS Median [interquartile range] serum copeptin levels were significantly lower in subjects with GDM (3.5 [2.0] pmol/l) as compared to controls (4.4 [3.2] pmol/l) (p<0.05). Furthermore, GDM remained an independent predictor of circulating copeptin in multivariate regression analysis (p<0.05). Moreover, copeptin was independently associated with gestational age at blood sampling (p<0.05). CONCLUSIONS Copeptin serum levels are significantly lower in GDM as compared to healthy pregnant controls. Further studies are needed to better clarify the pathophysiological role of copeptin in GDM.

The role of FOXO3 in DNA damage response in thyrocytes

Members of the forkhead box-O (FOXO) transcription factors family play an important role in stress defence. FOXO3 deregulation has recently been identified as a hallmark of thyroid carcinogenesis. In this study, we explore the role of FOXO3 in defence of oxidative stress in normal thyrocytes. Stable rat thyroid cell lines were generated expressing either the human wild-type FOXO3, a constitutively activating FOXO3 mutant, or the empty control vector. Cell clones were characterised for proliferation, function and morphology. Hydrogen peroxide and UV irradiation were used to induce oxidative stress. Changes in FOXO3 activity, induction of cell cycle arrest or apoptosis and kinetics of DNA damage repair were analysed. Upregulation of FOXO3 in thyrocytes resulted in decreased proliferation and changes in morphology, but did not affect differentiation. Hydrogen peroxide stimulated the expression of the FOXO3 target genes growth arrest and DNA damage-inducible protein 45 α (Gadd45α) and Bcl-2 interacting mediator of cell death (BIM) and induced programmed cell death in cells with overexpression of the human wild-type FOXO3. In contrast, UV irradiation resulted in a distinct cellular response with activation of FOXO3-c-Jun-N-terminal kinase-Gadd45α signalling and induction of cell cycle arrest at the G(2)-M-checkpoint. This was accompanied by FOXO3-induced DNA damage repair as evidenced by lower DNA breaks over time in a comet assay in FOXO3 cell clones compared with control cells. In conclusion, FOXO3 is a pivotal relay in the coordination of the cellular response to genotoxic stress in the thyroid. Depending on the stimulus, FOXO3 induces either cell cycle arrest or apoptosis. Conversely, FOXO3 inactivation in thyroid cancers is consistent with genomic instability and loss of cell cycle control.

Serum levels of sclerostin in cardiometabolic disorders during pregnancy.

OBJECTIVE Sclerostin has recently been introduced as a novel osteocyte-secreted factor which is associated with an adverse metabolic profile. However, regulation of circulating sclerostin in cardiometabolic disorders during pregnancy including gestational diabetes mellitus (GDM) and preeclampsia (PE) has not been comprehensively assessed, so far. METHODS Serum levels of sclerostin were quantified in 72 women with GDM and in 72 healthy, pregnant, gestational age-matched controls (study population 1). Furthermore, circulating sclerostin was assessed in 51 women with PE as compared to 51 pregnant controls in a second cohort (study population 2). RESULTS In the first study population (GDM), median [interquartile range] sclerostin levels were not significantly different in women with GDM as compared to controls (GDM: 19.2 [8.1]pmol/l; controls: 18.6 [7.1]pmol/l; p=0.906). Interestingly, C reactive protein was a negative and independent predictor of circulating sclerostin in the GDM cohort in multivariate analysis. In study population 2 (PE), serum levels of sclerostin were not different between women with PE and controls (PE: 18.8 [9.2]pmol/l; controls: 19.3 [8.8]pmol/l; p=0.504). Furthermore, the osteocyte-secreted factor was not related to any metabolic and gestational parameter in this cohort. CONCLUSIONS Sclerostin serum levels are not associated with an adverse metabolic profile during pregnancy in women with GDM and PE. The physiological significance of different associations of circulating sclerostin between pregnancy and non-pregnant status needs to be determined in future experiments.