TY - JOUR A1 - Kessler, Katharina A1 - Hornemann, Silke A1 - Rudovich, Natalia A1 - Weber, Daniela A1 - Grune, Tilman A1 - Kramer, Achim A1 - Pfeiffer, Andreas F. H. A1 - Pivovarova-Ramich, Olga T1 - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers JF - Nutrients N2 - Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies. KW - meal timing KW - saliva KW - circadian clock KW - adiponectin KW - resistin KW - visfatin KW - insulin KW - melatonin KW - cortisol KW - cytokines Y1 - 2020 U6 - https://doi.org/10.3390/nu12020340 SN - 2072-6643 IS - 2 SP - 1 EP - 12 PB - MDPI CY - Basel ER - TY - JOUR A1 - Henkel, Janin A1 - Klauder, Julia A1 - Statz, Meike A1 - Wohlenberg, Anne-Sophie A1 - Kuipers, Sonja A1 - Vahrenbrink, Madita A1 - Püschel, Gerhard Paul T1 - Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E-2 JF - Biomedicines N2 - Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E-2 (PGE(2)) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE(2) to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE(2) synthesis. PGE(2) in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE(2) in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle. KW - macrophages KW - insulin KW - prostaglandin E-2 KW - interleukin-8 KW - inflammation Y1 - 2021 U6 - https://doi.org/10.3390/biomedicines9050449 SN - 2227-9059 VL - 9 IS - 5 PB - MDPI CY - Basel ER - TY - JOUR A1 - Aga-Barfknecht, Heja A1 - Hallahan, Nicole A1 - Gottmann, Pascal A1 - Jähnert, Markus A1 - Osburg, Sophie A1 - Schulze, Gunnar A1 - Kamitz, Anne A1 - Arends, Danny A1 - Brockmann, Gudrun A1 - Schallschmidt, Tanja A1 - Lebek, Sandra A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Joost, Hans-Georg A1 - Schürmann, Annette A1 - Vogel, Heike T1 - Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning JF - Frontiers in genetics N2 - Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control. KW - type 2 diabetes KW - beta-cell loss KW - insulin KW - positional cloning KW - transcriptomics KW - haplotype Y1 - 2020 U6 - https://doi.org/10.3389/fgene.2020.567191 SN - 1664-8021 VL - 11 PB - Frontiers Media CY - Lausanne ER - TY - JOUR A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Agyapong, Wilson A1 - Jonas, Wenke A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schwarz, Maria A1 - Kipp, Anna Patricia A1 - Blüher, Matthias A1 - Kleinridders, André T1 - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling JF - Antioxidants N2 - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo. KW - selenite KW - insulin KW - adipose tissue KW - obesity KW - insulin resistance Y1 - 2022 U6 - https://doi.org/10.3390/antiox11050862 SN - 2076-3921 VL - 11 SP - 1 EP - 16 PB - MDPI CY - Basel, Schweiz ET - 5 ER - TY - JOUR A1 - Henkel-Oberländer, Janin A1 - Klauder, Julia A1 - Statz, Meike A1 - Wohlenberg, Anne-Sophie A1 - Kuipers, Sonja A1 - Vahrenbrink, Madita A1 - Püschel, Gerhard T1 - Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E₂ JF - Biomedicines : open access journal N2 - Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E₂ (PGE₂) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE₂ to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE₂ synthesis. PGE₂ in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE₂ in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle. KW - macrophages KW - insulin KW - prostaglandin E2 KW - interleukin-8 KW - inflammation Y1 - 2021 U6 - https://doi.org/10.3390/biomedicines9050449 SN - 2227-9059 VL - 9 IS - 5 PB - MDPI CY - Basel ER - TY - JOUR A1 - Moehlig, M. A1 - Floeter, A. A1 - Spranger, Joachim A1 - Weickert, Martin O. A1 - Schill, T. A1 - Schloesser, H. W. A1 - Brabant, G. A1 - Pfeiffer, Andreas F. H. A1 - Selbig, Joachim A1 - Schoefl, C. T1 - Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Polycystic ovary syndrome (PCOS) is a risk factor of type 2 diabetes. Screening for impaired glucose metabolism (IGM) with an OGTT has been recommended, but this is relatively time-consuming and inconvenient. Thus, a strategy that could minimise the need for an OGTT would be beneficial. Materials and methods Consecutive PCOS patients (n=118) with fasting glucose < 6.1 mmol/l were included in the study. Parameters derived from medical history, clinical examination and fasting blood samples were assessed by decision tree modelling for their ability to discriminate women with IGM (2-h OGTT value >= 7.8 mmol/l) from those with NGT. Results According to the OGTT results, 93 PCOS women had NGT and 25 had IGM. The best decision tree consisted of HOMA-IR, the proinsulin:insulin ratio, proinsulin, 17-OH progesterone and the ratio of luteinising hormone:follicle-stimulating hormone. This tree identified 69 women with NGT. The remaining 49 women included all women with IGM (100% sensitivity, 74% specificity to detect IGM). Pruning this tree to three levels still identified 53 women with NGT (100% sensitivity, 57% specificity to detect IGM). Restricting the data matrix used for tree modelling to medical history and clinical parameters produced a tree using BMI, waist circumference and WHR. Pruning this tree to two levels separated 27 women with NGT (100% sensitivity, 29% specificity to detect IGM). The validity of both trees was tested by a leave-10%-out cross-validation. Conclusions/interpretation Decision trees are useful tools for separating PCOS women with NGT from those with IGM. They can be used for stratifying the metabolic screening of PCOS women, whereby the number of OGTTs can be markedly reduced. KW - decision tree KW - HOMA KW - impaired glucose tolerance KW - insulin KW - insulin resistance KW - polycystic ovary syndrome KW - proinsulin KW - type 2 diabetes mellitus Y1 - 2006 U6 - https://doi.org/10.1007/s00125-006-0395-0 SN - 0012-186X VL - 49 SP - 2572 EP - 2579 PB - Springer CY - Berlin ER - TY - JOUR A1 - Manowsky, Julia A1 - Camargo, Rodolfo Gonzalez A1 - Kipp, Anna Patricia A1 - Henkel, Janin A1 - Püschel, Gerhard Paul T1 - Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes JF - American journal of physiology : Endocrinology and metabolism N2 - Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the beta-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1 beta, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1 beta was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-kappa B. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKK beta, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. KW - metabolic syndrome KW - type 2 diabetes KW - inflammation KW - macrophage KW - insulin KW - cytokines Y1 - 2016 U6 - https://doi.org/10.1152/ajpendo.00427.2015 SN - 0193-1849 SN - 1522-1555 VL - 310 SP - E938 EP - E946 PB - American Chemical Society CY - Bethesda ER - TY - JOUR A1 - Fruscalzo, Arrigo A1 - Londero, Ambrogio P. A1 - Driul, Lorenza A1 - Henze, Andrea A1 - Tonutti, Laura A1 - Ceraudo, Maria A1 - Zanotti, Giuseppe A1 - Berni, Rodolfo A1 - Schweigert, Florian J. A1 - Raila, Jens T1 - First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus JF - Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine N2 - Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy. Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean +/- SD: TTR 3.96 +/- 0.89 mu mol/L vs. 4.68 +/- 1.21 mu mol/L, RBP4 1.13 +/- 0.25 mu mol/L vs. 1.33 +/- 0.38 mu mol/L and ROH 1.33 +/- 0.17 mu mol/L vs. 1.62 +/- 0.29 mu mol/L, p < 0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p < 0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87-0.98, p < 0.05). Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM. KW - first trimester KW - gestational diabetes mellitus (GDM) KW - insulin KW - large for gestational age fetus (LGA) KW - protein microheterogeneity KW - retinol (ROH) KW - serum retinol binding protein (RBP4) KW - transthyretin (TTR) Y1 - 2015 U6 - https://doi.org/10.1515/cclm-2014-0929 SN - 1434-6621 SN - 1437-4331 VL - 53 IS - 10 SP - 1643 EP - 1651 PB - De Gruyter CY - Berlin ER -