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  - 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  - 
TY  - THES
A1  - Gonzalez Camargo, Rodolfo
T1  - Insulin resistance in cancer cachexia and metabolic syndrome
BT  - role of insulin activated macrophages and miRNA-21-5p
N2  - The ever-increasing fat content in Western diet, combined with decreased levels of physical activity, greatly enhance the incidence of metabolic-related diseases. Cancer cachexia (CC) and Metabolic syndrome (MetS) are both multifactorial highly complex metabolism related syndromes, whose etiology is not fully understood, as the mechanisms underlying their development are not completely unveiled. Nevertheless, despite being considered “opposite sides”, MetS and CC share several common issues such as insulin resistance and low-grade inflammation. In these scenarios, tissue macrophages act as key players, due to their capacity to produce and release inflammatory mediators. One of the main features of MetS is hyperinsulinemia, which is generally associated with an attempt of the β-cell to compensate for diminished insulin sensitivity (insulin resistance). There is growing evidence that hyperinsulinemia per se may contribute to the development of insulin resistance, through the establishment of low grade inflammation in insulin responsive tissues, especially in the liver (as insulin is secreted by the pancreas into the portal circulation). The hypothesis of the present study was that insulin may itself provoke an inflammatory response culminating in diminished hepatic insulin sensitivity. To address this premise, firstly, human cell line U937 differentiated macrophages were exposed to insulin, LPS and PGE2. In these cells, insulin significantly augmented the gene expression of the pro-inflammatory mediators IL-1β, IL-8, CCL2, Oncostatin M (OSM) and microsomal prostaglandin E2 synthase (mPGES1), and of the anti-inflammatory mediator IL-10. Moreover, the synergism between insulin and LPS enhanced the induction provoked by LPS in IL-1β, IL-8, IL-6, CCL2 and TNF-α gene. When combined with PGE2, insulin enhanced the induction provoked by PGE2 in IL-1β, mPGES1 and COX2, and attenuated the inhibition induced by PGE2 in CCL2 and TNF-α gene expression contributing to an enhanced inflammatory response by both mechanisms. Supernatants of insulin-treated U937 macrophages reduced the insulin-dependent induction of glucokinase in hepatocytes by 50%. Cytokines contained in the supernatant of insulin-treated U937 macrophages also activated hepatocytes ERK1/2, resulting in inhibitory serine phosphorylation of the insulin receptor substrate. Additionally, the transcription factor STAT3 was activated by phosphorylation resulting in the induction of SOCS3, which is capable of interrupting the insulin receptor signal chain. MicroRNAs, non-coding RNAs linked to protein expression regulation, nowadays recognized as active players in the generation of several inflammatory disorders such as cancer and type II diabetes are also of interest. Considering that in cancer cachexia, patients are highly affected by insulin resistance and inflammation, control, non-cachectic and cachectic cancer patients were selected and the respective circulating levels of pro-inflammatory mediators and microRNA-21-5p, a posttranscriptional regulator of STAT3 expression, assessed and correlated. Cachectic patients circulating cytokines IL-6 and IL-8 levels were significantly higher than those of non-cachectic and controls, and the expression of microRNA-21-5p was significantly lower. Additionally, microRNA-21-5p reduced expression correlated negatively with IL-6 plasma levels. These results indicate that hyperinsulinemia per se might contribute to the low grade inflammation prevailing in MetS patients and thereby promote the development
of insulin resistance particularly in the liver. Diminished MicroRNA-21-5p expression may enhance inflammation and STAT3 expression in cachectic patients, contributing to the development of insulin resistance.
N2  - O teor de gordura cada vez maior na dieta ocidental, combinada com a diminuição dos níveis de atividade física têm marcadamente aumentado à incidência de doenças relacionas ao metabolismo. A caquexia associada ao câncer (CC) e a síndrome metabólica (SM) são síndromes de etiologia complexa e multifatorial, não totalmente compreendida, e com mecanismos subjacentes ao seu desenvolvimento não completamente revelados. No entanto, apesar de serem consideradas "lados opostos", a CC e a MetS apresentam várias características em comum, tais como resistência à insulina e inflamação de baixo grau, com macrófagos teciduais como importantes coadjuvantes, devido à sua capacidade de produzir e liberar mediadores inflamatórios, e microRNAs, descritos como RNAs não-codificantes ligados à regulação da expressão de proteínas e reconhecidos como participantes ativos na geração de várias doenças inflamatórias, tais como o câncer e diabetes tipo II. Uma das principais características da MetS é a hiperinsulinemia, que está geralmente associada com uma tentativa da célula β do pâncreas de compensar a diminuição da sensibilidade à insulina (resistência à insulina). Um número crescente de evidências sugere que a hiperinsulinemia “por si só”, pode contribuir com o desenvolvimento de resistência à insulina através do estabelecimento de um quadro inflamatório de baixo grau, em tecidos sensíveis a insulina, e em particular no fígado, devido ao fato da insulina ser secretada pelo pâncreas na circulação portal. A hipótese do presente estudo foi que a insulina pode induzir uma resposta inflamatória em macrófagos e culminar em diminuição da sensibilidade hepática à insulina. Para confirmar esta hipótese, primeiramente, macrófagos diferenciados da linhagem de células humanas U937 foram expostos à insulina, LPS e PGE2. Nestas células, a insulina aumentou significativamente a expressão gênica dos mediadores pró-inflamatórios IL-1β, IL- 8, CCL2, oncostatina M (OSM) e prostaglandina E2 sintase microssomal (mPGES1), e do mediador anti-inflamatório IL-10. Além disso, o sinergismo entre insulina e LPS aumentou a indução provocada por LPS nos genes da IL-1β, IL-8, IL-6, CCL2 e TNF-α. Quando combinado com PGE2, a insulina aumentou a indução provocada pela PGE2 nos genes da IL-1β, mPGES1 e COX2, e restaurou a inibição induzida pela PGE2 no gene CCL2 e TNF-α.Subsequentemente, sobrenadantes dos macrófagos U937 tratados com insulina modulou negativamente a sinalização da insulina em culturas primárias de hepatócitos de rato, como observado pela atenuação de 50% da indução dependente de insulina da enzima glicoquinase. Citocinas contidas no sobrenadante de macrófagos U937 tratados com insulina também ativaram em hepatócitos ERK1/2, resultando na fosforilação do resíduo de serina inibitório do substrato do receptor de insulina. Adicionalmente, o fator de transcrição STAT3 foi ativado por um elevado grau de fosforilação e a proteína SOCS3, capaz de interromper a via de sinalização do receptor de insulina, foi induzida. Considerando que na caquexia associada ao câncer, pacientes são altamente afetados pela resistência à insulina e inflamação, pacientes controle, não caquéticos e caquéticos foram seleccionados e os respectivos níveis circulantes de mediadores pró-inflamatórios e microRNA-21-5p, um regulador pós-transcricional da expressão de STAT3, avaliados e correlacionados. Pacientes caquéticos exibiram citocinas circulantes IL-6 e IL-8 significativamente maiores do que pacientes não caquéticos e controles, assim como a expressão de microRNA-21-5p significativamente diminuida. Além disso, a reduzida expressão de microRNA-21-5p correlaciona-se negativamente com níveis de IL-6 no plasma. Estes resultados indicam que a hiperinsulinemia pode, por si só contribuir para o desenvolvimento da inflamação de baixo grau prevalente em pacientes com excesso de peso e obesos e, assim, promover o desenvolvimento de resistência à insulina especialmente no fígado e o nível reduzido de miRNA-21-5p pode modular a inflamação e expressão de STAT3 em pacientes caquéticos, contribuindo para o desenvolvimento da resistência à insulina.
N2  - Der stetig steigende Fettgehalt in westlicher Ernährung in Kombination mit reduzierter körperlicher Aktivität hat zu einem dramatischen Anstieg der Inzidenz metabolischer Erkrankungen geführt. Tumorkachexie (Cancer cachexia, CC) und Metabolisches Syndrom (MetS) sind sehr komplexe, multifaktorielle metabolische Erkrankungen, deren Ätiologie nicht vollständig verstanden ist. Die molekularen Ursachen, die zu diesen Symptomkomplexen führen, sind noch unzureichend aufgeklärt. Obwohl ihr äußeres Erscheinungsbild stark gegensätzlich ist, haben MetS und CC etliche Gemeinsamkeiten wie zum Beispiel Insulinresistenz und eine chronische unterschwellige Entzündung. Sowohl bei der Entstehung der Insulinresistenz als auch bei der chronischen Entzündung spielen Makrophagen eine Schlüsselrolle, weil sie in der Lage sind pro-inflammatorische Mediatoren zu produzieren und freizusetzen.
Eine der hervorstechendsten Auffälligkeiten des MetS ist die Hyperinsulinämie, die durch den Versuch der β-Zelle, die verminderte Insulinsensitivität (Insulinresistenz) zu kompensieren, zustande kommt. Es gibt zunehmend Hinweise darauf, dass die Hyperinsulinämie selber an der Entzündungsentstehung in Insulin-abhängigen Geweben beteiligt ist und dadurch zur Entwicklung und Verstärkung der Insulinresistenz beitragen kann. Dies trifft besonders auf die Leber zu, weil hier die Insulinspiegel besonders hoch sind, da Insulin vom Pankreas direkt in den Pfortaderkeislauf gelangt. Daher wurde in dieser Arbeit die Hypothese geprüft, ob Insulin selber eine Entzündungsantwort auslösen und dadurch die hepatische Insulinsensitivität senken kann. Zu diesem Zweck wurde die humane Zelllinie U937 durch PMA-Behandlung zu Makrophagen differenziert und diese Makrophagen mit Insulin, LPS und PGE2 inkubiert. In diesen Zellen steigerte Insulin die Expression der pro-inflammatorischen Mediatoren IL-1β, IL-8, CCL2, Oncostatin M (OSM) signifikant und induzierte die mikrosomale PGE-Synthase 1 (mPGES1) ebenso wie das antiinflammatorische Cytokin IL-10. Ferner verstärkte Insulin die LPS-abhängige Induktion des IL-1β-, IL-8-, IL-6-, CCL2- und TNFα-Gens. Ebenso verstärkte Insulin die PGE2-abhängige Induktion von IL-1β, mPGES1 und COX2. Im Gegensatz dazu schwächte es die Hemmende Wirkung von PGE2 auf Expression von TNFα und CCL2 ab und trug so auf beide Weisen zu einer Verstärkung der Entzündungsantwort bei. Überstände von Insulin-behandelten U937 Makrophagen reduzierten die Insulin-abhängige Induktion der Glukokinase in Hepatocyten um 50%. Die Cytokine, die im Überstand Insulin-behandelter Makrophagen enthalten waren, aktivierten in Hepatocyten ERK1/2, was zu einer inhibitorischen Serin-Phosphorylierung der Insulin Rezeptor Substrats (IRS) führte. Zusätzlich führten die Cytokine zu einer Phosphorylierung und Aktivierung von STAT3 und einer dadurch bedingten Induktion von SOCS3, das seinerseits die Insulinrezeptor-Signalkette unterbrechen kann.
MicroRNAs, nicht-codierende RNAs, die an der Regulation der Proteinexpression beteiligt sind und deren Beteiligung an der Regulation der Entzündungsantwort bei zahlreichen Erkrankungen, unter anderem Tumorerkrankungen und Typ II Diabetes gezeigt wurde, sind auch von Interesse. Unter dem Blickwinkel, dass Tumor-Kachexie Patienten sich durch eine Insulinresistenz und eine systemische Entzündung auszeichnen, wurden in nichtkachektische und tumorkachektische Patienten Plasmaspiegel von pro-inflammatorischen Mediatoren und der microRNA-21-5p bestimmt, von der bekannt ist, dass sie ein posttranskriptioneller Regulator der STAT3 Expression ist. Die Spiegel der proinflammatorischen Mediatoren und der miRNA-21-5p wurden korreliert. In kachektischen Patienten waren die Spiegel der Cytokine IL-6 und IL-8 signifikant höher, die der miRNA-21- 5p signifikant niedriger als in nicht-kachektischen Patienten. Die Plasma IL-6-Spiegel korrelierten negativ mit den miRNA21-5p Spiegeln.
Insgesamt zeigen die Ergebnisse, dass eine Hyperinsulinämie selber zu der Entwicklung einer unterschwellingen Entzündung, wie sie in Patienten mit einem MetS vorherrscht, beitragen, und dadurch besonders in der Leber eine Insulinresistenz auslösen oder verstärken kann. Eine verringerte Expression der MicroRNA-21-5p kann in kachektischen Patienten die Entzündungsantwort, im Speziellen die STAT3 Expression, verstärken und dadurch zur Entwicklung einer Insulinresistenz beitragen
KW  - cachexia
KW  - metabolic syndrome
KW  - inflammation
KW  - insulin resistance
KW  - microRNAs
KW  - insulin
KW  - liver
KW  - macrophages
KW  - caquexia
KW  - síndrome metabólica
KW  - inflamação
KW  - resistência à insulina
KW  - microRNAs
KW  - insulina
KW  - fígado
KW  - macrófagos
KW  - Kachexie
KW  - metabolisches Syndrom
KW  - Entzündung
KW  - Insulinresistenz
KW  - MicroRNAs
KW  - Insulin
KW  - Leber
KW  - Makrophagen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-100973
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  - GEN
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
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1267 
KW  - selenite
KW  - insulin
KW  - adipose tissue
KW  - obesity
KW  - insulin resistance
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-561709
SN  - 1866-8372
SP  - 1
EP  - 16
PB  - Universitätsverlag Potsdam
CY  - Potsdam
ER  - 
TY  - THES
A1  - Henkel-Oberländer, Janin
T1  - Einfluss von Prostaglandin E2 auf die Entstehung von Insulinresistenz und die Regulation der Entzündungsantwort bei der Diät-induzierten nicht-alkoholischen Fettlebererkrankung
N2  - Weltweit sind fast 40 % der Bevölkerung übergewichtig und die Prävalenz von Adipositas, Insulinresistenz und den resultierenden Folgeerkrankungen wie dem Metabolischen Syndrom und Typ-2-Diabetes steigt rapide an. Als häufigste Ursachen werden diätetisches Fehlverhalten und mangelnde Bewegung angesehen. Die nicht-alkoholische Fettlebererkrankung (NAFLD), deren Hauptcharakteristikum die exzessive Akkumulation von Lipiden in der Leber ist, korreliert mit dem Body Mass Index (BMI). NAFLD wird als hepatische Manifestation des Metabolischen Syndroms angesehen und ist inzwischen die häufigste Ursache für Leberfunktionsstörungen. Die Erkrankung umfasst sowohl die benigne hepatische Steatose (Fettleber) als auch die progressive Form der nicht-alkoholischen Steatohepatitis (NASH), bei der die Steatose von Entzündung und Fibrose begleitet ist. Die Ausbildung einer NASH erhöht das Risiko, ein hepatozelluläres Karzinom (HCC) zu entwickeln und kann zu irreversibler Leberzirrhose und terminalem Organversagen führen. Nahrungsbestandteile wie Cholesterol und Fett-reiche Diäten werden als mögliche Faktoren diskutiert, die den Übergang einer einfachen Fettleber zur schweren Verlaufsform der Steatohepatitis / NASH begünstigen. Eine Ausdehnung des Fettgewebes wird von Insulinresistenz und einer niedrig-gradigen chronischen Entzündung des Fettgewebes begleitet. Neben Endotoxinen aus dem Darm gelangen Entzündungsmediatoren aus dem Fettgewebe zur Leber. Als Folge werden residente Makrophagen der Leber, die Kupfferzellen, aktiviert, die eine Entzündungsantwort initiieren und weitere pro-inflammatorische Mediatoren freisetzen, zu denen Chemokine, Cytokine und Prostanoide wie Prostaglandin E2 (PGE2) gehören. In dieser Arbeit soll aufgeklärt werden, welchen Beitrag PGE2 an der Ausbildung von Insulinresistenz, hepatischer Steatose und Entzündung im Rahmen von Diät-induzierter NASH im komplexen Zusammenspiel mit der Regulation der Cytokin-Produktion und anderen Co-Faktoren wie Hyperinsulinämie und Hyperlipidämie hat. In murinen und humanen Makrophagen-Populationen wurde untersucht, welche Faktoren die Bildung von PGE2 fördern und wie PGE2 die Entzündungsantwort aktivierter Makrophagen reguliert. In primären Hepatozyten der Ratte sowie in isolierten humanen Hepatozyten und Zelllinien wurde der Einfluss von PGE2 allein und in Kombination mit Cytokinen, deren Bildung durch PGE2 beeinflusst werden kann, auf die Insulin-abhängige Regulation des Glucose- und Lipid-stoffwechsels untersucht. Um den Einfluss von PGE2 im komplexen Zusammenspiel der Zelltypen in der Leber und im Gesamtorganismus zu erfassen, wurden Mäuse, in denen die PGE2-Synthese durch die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1) vermindert war, mit einer NASH-induzierenden Diät gefüttert. In Lebern von Patienten mit NASH oder in Mäusen mit Diät-induzierter NASH war die Expression der PGE2-synthetisierenden Enzyme Cyclooxygenase 2 (COX2) und mPGES1 sowie die Bildung von PGE2 im Vergleich zu gesunden Kontrollen gesteigert und korrelierte mit dem Schweregrad der Lebererkrankung. In primären Makrophagen aus den Spezies Mensch, Maus und Ratte sowie in humanen Makrophagen-Zelllinien war die Bildung pro-inflammatorischer Mediatoren wie Chemokinen, Cytokinen und Prostaglandinen wie PGE2 verstärkt, wenn die Zellen mit Endotoxinen wie Lipopolysaccharid (LPS), Fettsäuren wie Palmitinsäure, Cholesterol und Cholesterol-Kristallen oder Insulin, das als Folge der kompensatorischen Hyperinsulinämie bei Insulinresistenz verstärkt freigesetzt wird, inkubiert wurden. Insulin steigerte dabei synergistisch mit LPS oder Palmitinsäure die Synthese von PGE2 sowie der anderen Entzündungsmediatoren wie Interleukin (IL) 8 und IL-1β. PGE2 reguliert die Entzündungsantwort: Neben der Induktion der eigenen Synthese-Enzyme verstärkte PGE2 die Expression der Immunzell-rekrutierenden Chemokine IL-8 und (C-C-Motiv)-Ligand 2 (CCL2) sowie die der pro-inflammatorischen Cytokine IL-1β und IL-6 in Makrophagen und kann so zur Verstärkung der Entzündungsreaktion beitragen. Außerdem förderte PGE2 die Bildung von Oncostatin M (OSM) und OSM induzierte in einer positiven Rückkopplungsschleife die Expression der PGE2-synthetisierenden Enzyme. Andererseits hemmte PGE2 die basale und LPS-vermittelte Bildung des potenten pro-inflammatorischen Cytokins Tumornekrosefaktor α (TNFα) und kann so die Entzündungsreaktion abschwächen. In primären Hepatozyten der Ratte und humanen Hepatozyten beeinträchtigte PGE2 direkt die Insulin-abhängige Aktivierung der Insulinrezeptor-Signalkette zur Steigerung der Glucose-Verwertung, in dem es durch Signalketten, die den verschiedenen PGE2-Rezeptoren nachgeschaltet sind, Kinasen wie ERK1/2 und IKKβ aktivierte und eine inhibierende Serin-Phosphorylierung der Insulinrezeptorsubstrate bewirkte. PGE2 verstärkte außerdem die IL-6- oder OSM-vermittelte Insulinresistenz und Steatose in primären Hepatozyten der Ratte. Die Wirkung von PGE2 im Gesamtorganismus sollte in Mäusen mit Diät-induzierter NASH untersucht werden. Die Fütterung einer Hochfett-Diät mit Schmalz als Fettquelle, das vor allem gesättigte Fettsäuren enthält, verursachte Fettleibigkeit, Insulinresistenz und eine hepatische Steatose in Wildtyp-Mäusen. In Tieren, die eine Hochfett-Diät mit Sojaöl als Fettquelle, das vor allem (ω-6)-mehrfach-ungesättigte Fettsäuren (PUFAs) enthält, oder eine Niedrigfett-Diät mit Cholesterol erhielten, war lediglich eine hepatische Steatose nachweisbar, jedoch keine verstärkte Gewichtszunahme im Vergleich zu Geschwistertieren, die eine Standard-Diät bekamen. Im Gegensatz dazu verursachte die Fütterung einer Hochfett-Diät mit PUFA-reichem Sojaöl als Fettquelle in Kombination mit Cholesterol sowohl Fettleibigkeit und Insulinresistenz als auch hepatische Steatose mit Hepatozyten-Hypertrophie, lobulärer Entzündung und beginnender Fibrose in Wildtyp-Mäusen. Diese Tiere spiegelten alle klinischen und histologischen Parameter der humanen NASH im Metabolischen Syndrom wider. Nur die Kombination von hohen Mengen ungesättigter Fettsäuren aus Sojaöl und Cholesterol in der Nahrung führte zu einer exzessiven Akkumulation des Cholesterols und der Bildung von Cholesterol-Kristallen in den Hepatozyten, die zur Schädigung der Mitochondrien, schwerem oxidativem Stress und schließlich zum Absterben der Zellen führten. Als Konsequenz phagozytieren Kupfferzellen die Zelltrümmer der Cholesterol-überladenen Hepatozyten, werden dadurch aktiviert, setzen Chemokine, Cytokine und PGE2 frei, die die Entzündungsreaktion verstärken und die Infiltration von weiteren Immunzellen initiieren können und verursachen so eine Progression zur Steatohepatitis (NASH). Die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1), dem induzierbaren Enzym der PGE2-Synthese aus Cyclooxygenase-abhängigen Vorstufen, reduzierte die Diät-abhängige Bildung von PGE2 in der Leber. Die Fütterung der NASH-induzierenden Diät verursachte in Wildtyp- und mPGES1-defizienten Mäusen eine ähnliche Fettleibigkeit und Zunahme der Fettmasse sowie die Ausbildung von hepatischer Steatose mit Entzündung und Fibrose (NASH) im histologischen Bild. In mPGES1-defizienten Mäusen waren jedoch Parameter für die Infiltration von Entzündungszellen und die Diät-abhängige Schädigung der Leber im Vergleich zu Wildtyp-Tieren erhöht, was sich auch in einer stärkeren Diät-induzierten systemischen Insulinresistenz widerspiegelte. Die Bildung des pro-inflammatorischen und pro-apoptotischen Cytokins TNFα war in mPGES1-defizienten Mäusen durch die Aufhebung der negativen Rückkopplungshemmung verstärkt, was einen gesteigerten Diät-induzierten Zelluntergang gestresster Lipid-überladener Hepatozyten und eine nach-geschaltete Entzündungsantwort zur Folge hatte. Zusammenfassend wurde unter den gewählten Versuchsbedingungen in vivo eine anti-inflammatorische Rolle von PGE2 verifiziert, da das Prostanoid vor allem indirekt durch die Hemmung der TNFα-vermittelten Entzündungsreaktion die Schädigung der Leber, die Verstärkung der Entzündung und die Ausbildung von Insulinresistenz im Rahmen der Diät-abhängigen Fettlebererkrankung abschwächte.
N2  - Obesity is a worldwide problem affecting almost 40 % of the population. The prevalence of obesity, insulin resistance and the consequent diseases such as type-2-diabetes and metabolic syndrome is increasing rapidly. The main underlying reasons are high caloric diets and reduced physical exercise. The incidence of non-alcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation, is correlated with the body mass index. NAFLD is generally considered to be the hepatic manifestation of metabolic syndrome and is the most frequent cause of functional disorders of the liver. NAFLD comprises both the mild form of benign hepatic steatosis (fatty liver) as well as the progressive form of non-alcoholic steatohepatitis (NASH), in which hepatic steatosis is accompanied by inflammation and fibrosis. The development of NASH may result in hepatocellular carcinoma, liver cirrhosis and terminal organ failure. High fat diets and dietary cholesterol might impact the transistion from fatty liver to NASH. The diet induced expansion of the white adipose tissue is associated with the development of insulin resistance as well as low-grade chronic inflammation. Inflammatory mediators from the adipose tissue in combination with dietary components from the gut reach the liver and activate Kupffer cells, the resident liver macrophages. As a consequence, macrophages initiate an inflammatory response that involves secretion of immune cell recruiting chemokines, pro-inflammatory cytokines and prostanoids like prostaglandin E2 (PGE2). The aim of the study was to elucidate the impact of PGE2 in the development of insulin resistance, hepatic steatosis and inflammation in diet-induced NASH. These processes implicate a complex interplay of various cell types in the liver, the PGE2-mediated regulation of cytokine synthesis, as well as factors like hyperinsulinemia and hyperlipidemia. In vitro studies with murine and human macrophage populations characterise the generation of PGE2 and the PGE2-mediated regulation of the inflammatory response. Primary rat and human hepatocytes, in addition to immortal cell lines, were incubated with PGE2 alone and in combination with PGE2-dependent generated cytokines. The intent of this experimental series was to clarify the impact of these mediators on the activation of the insulin signaling chain and resulting metabolic processes in glucose and lipid metabolism. The role of PGE2 in vivo was examined in mice with reduced PGE2 synthesis due to the genetic deletion of microsomal PGE synthase 1 (mPGES1), which were additionally fed a NASH-inducing diet. The hepatic expression of the PGE2-generating enzymes cyclooxygenase 2 (COX2) and mPGES1 was increased in mice with diet-induced NASH as well as in liver biopsies of patients with NASH compared to patients with simple hepatic steatosis or non-steatotic controls, indicating an enlarged capacity for PGE2 synthesis in NASH. Furthermore, the expression of COX2 and mPGES1 in the human study cohort correlated with the severity of the hepatic disease.. Treatment of macrophages with endotoxins like lipopolysaccharide (LPS), fatty acids like palmitic acid, cholesterol and cholesterol crystals, or insulin, which is released as a consequence of insulin resistance in the context of a compensatory hyperinsulinemia, resulted in an enhanced production of pro-inflammatory mediators such as chemokines, cytokines and PGE2. A combinatory treatment of human macrophages with insulin and LPS or palmitic acid induced a synergistic increase in PGE2 synthesis and production of interleukins (IL) like IL-8 and IL-1β. PGE2 itself modulates the inflammatory response: The prostanoid induced the enzymes involved in its own synthesis, in addition to immune cell recruiting chemokines such as IL-8 and (C-C-motiv) ligand 2 (CCL2), and pro-inflammatory cytokines such as IL-1β and IL-6 in macrophages. This may result in an amplification of the inflammatory response. Furthermore, PGE2 induced the production of oncostatin M (OSM), which in turn enhanced the expression of the enzymes generating PGE2 in a positive feedback loop. On the other hand, PGE2 inhibited the basal and LPS-mediated synthesis of the potent pro-inflammatory cytokine tumor necrosis factor α (TNFα). This may result in a reduced inflammatory response. In primary rat and human hepatocytes PGE2 directly interfered with the insulin mediated activation of the insulin receptor signaling chain and impaired glucose utilisation. Mechanistically, through interaction with different PGE2 receptors, PGE2 activated serine kinases including ERK1/2 and IKKβ, which cause inhibitory phosphorylations at serine residues of the insulin receptor substrates and force their degradation. PGE2 enhanced the insulin resistance and increased hepatic steatosis induced by IL-6 or OSM in primary rat hepatocytes. A murine model of diet-induced NASH was established to elucidate the impact of PGE2 in the complex in vivo regulation. Lard-based high fat diets containing mainly saturated fatty acids initiated a strong body weight gain, obesity, insulin resistance and hepatic steatosis without further damage of the liver in mice. Furthermore, mice fed a high fat diet based on soybean oil with high amounts of (ω-6)-poly-unsaturated fatty acids (PUFAs) or a low fat diet with high cholesterol did not result in increased body weight gain compaired to mice fed a chow (low fat) diet, but did cause mild hepatic steatosis. In contrast, mice fed a high fat diet based on PUFA-rich soybean oil in combination with high dietary cholesterol caused body weight gain, obesity, insulin resistance and hepatic steatosis accompanied by hepatocyte hypertrophy, lobular inflammation and fibrosis in wildtype mice. This dietary model displayed all clinical and histological parameters of human NASH in the metabolic syndrome. Only the combination of soybean oil derived fatty acids and dietary cholesterol provoked an excessive accumulation of cholesterol in hepatocytes and the generation of cholesterol crystals that caused mitochondrial damage, severe oxidative stress, and subsequently hepatocyte death. Hepatic macrophages phagocytose hepatocyte debris, lipids and cholesterol crystals and thereby were activated to produce pro-inflammatory mediators like chemokines, cytokines and prostanoids like PGE2 that initiate an inflammatory response. This included immune cell infiltration, inflammation and fibrogenic processes that determine the progression to steatohepatitis (NASH). The deletion of microsomal PGE synthase 1 (mPGES1), the inducible enzyme generating PGE2 from COX2 derived PGH2, reduced the diet-dependent increase in hepatic PGE2 production in mice fed a NASH-inducing diet. While body weight gain, obesity and histological parameters of NASH including steatosis, inflammation and fibrosis were comparable in wild type and mPGES1-deficient mice fed a NASH inducing diet, parameters of immune cell infiltration and hepatic damage were augmented only in mPGES1-deficient mice. This results in a more pronounced diet-induced glucose intolerance and insulin resistance index in mPGES1-deficient mice compared to wild type littermates. In parallel, hepatic production of the potent pro-inflammatory and pro-apoptotic cytokine TNFα was enhanced in mice with the deletion of mPGES1 due to the abolished PGE2-mediated negative feedback loop. This was accompanied by increased diet induced cell death of lipid loaded stressed hepatocytes and could result in an intensified inflammatory response. In summary, in vivo studies verify an anti-inflammatory role of PGE2. The prostanoid PGE2 acts mainly indirectly and could attenuate the TNFα-mediated liver damage, immune response and the resulting insulin resistance in the context of diet induced fatty liver diseases.
KW  - Prostaglandine
KW  - Entzündung
KW  - Insulin
KW  - Leber
KW  - Fettleibigkeit
KW  - prostaglandins
KW  - inflammation
KW  - insulin
KW  - liver
KW  - obesity
Y1  - 2021
ER  - 
TY  - GEN
A1  - Henkel-Oberländer, Janin
A1  - Klauder, Julia
A1  - Statz, Meike
A1  - Wohlenberg, Anne-Sophie
A1  - Kuipers, Sonja
A1  - Vahrenbrink, Madita
T1  - Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E₂
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1149 
KW  - macrophages
KW  - insulin
KW  - prostaglandin E2
KW  - interleukin-8
KW  - inflammation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-518377
SN  - 1866-8372
IS  - 1149
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  - GEN
A1  - Igual Gil, Carla
A1  - Ost, Mario
A1  - Kasch, Juliane
A1  - Schumann, Sara
A1  - Heider, Sarah
A1  - Klaus, Susanne
T1  - Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1090 
KW  - skeletal-muscle
KW  - growth
KW  - induction
KW  - insulin
KW  - activation
KW  - increases
KW  - glucagon
KW  - health
KW  - gene
KW  - diet
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460541
SN  - 1866-8372
IS  - 1090
ER  - 
TY  - GEN
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
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1425 
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  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-512079
SN  - 1866-8372
IS  - 2
ER  - 
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  - THES
A1  - Klauder, Julia
T1  - Makrophagenaktivierung durch Hyperinsulinämie als Auslöser eines Teufelkreises der Entzündung im Kontext des metabolischen Syndroms
T1  - Macrophage activation by hyperinsulinemia as a trigger of a vicious cycle of inflammation in the context of the metabolic syndrome
N2  - Insulinresistenz ist ein zentraler Bestandteil des metabolischen Syndroms und trägt maßgeblich zur Ausbildung eines Typ-2-Diabetes bei. Eine mögliche Ursache für die Entstehung von Insulinresistenz ist eine chronische unterschwellige Entzündung, welche ihren Ursprung im Fettgewebe übergewichtiger Personen hat. Eingewanderte Makrophagen produzieren vermehrt pro-inflammatorische Mediatoren, wie Zytokine und Prostaglandine, wodurch die Konzentrationen dieser Substanzen sowohl lokal als auch systemisch erhöht sind. Darüber hinaus weisen übergewichtige Personen einen gestörten Fettsäuremetabolismus und eine erhöhte Darmpermeabilität auf. Ein gesteigerter Flux an freien Fettsäuren vom Fettgewebe in andere Organe führt zu einer lokalen Konzentrationssteigerung in diesen Organen. Eine erhöhte Darmpermeabilität erleichtert das Eindringen von Pathogenen und anderer körperfremder Substanzen in den Körper. 
Ziel dieser Arbeit war es, zu untersuchen, ob hohe Konzentrationen von Insulin, des bakteriellen Bestandteils Lipopolysaccharid (LPS) oder der freien Fettsäure Palmitat eine Entzündungsreaktion in Makrophagen auslösen oder verstärken können und ob diese Entzündungsantwort zur Ausbildung einer Insulinresistenz beitragen kann. Weiterhin sollte untersucht werden, ob Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind, die Produktion des Prostaglandins (PG) E2 begünstigen können und ob dieses wiederum die Entzündungsreaktion und seine eigene Produktion in Makrophagen regulieren kann. Um den Einfluss dieser Faktoren auf die Produktion pro-inflammatorischer Mediatoren in Makrophagen zu untersuchen, wurden Monozyten-artigen Zelllinien und primäre humane Monozyten, welche aus dem Blut gesunder Probanden isoliert wurden, in Makrophagen differenziert und mit Insulin, LPS, Palmitat und/ oder PGE2 inkubiert. Überdies wurden primäre Hepatozyten der Ratte isoliert und mit Überständen Insulin-stimulierter Makrophagen inkubiert, um zu untersuchen, ob die Entzündungsanwort in Makrophagen an der Ausbildung einer Insulinresistenz in Hepatozyten beteiligt ist. 
Insulin induzierte die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien wahrscheinlich vorrangig über den Phosphoinositid-3-Kinase (PI3K)-Akt-Signalweg mit anschließender Aktiverung des Transkriptionsfaktors NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells). Die dabei ausgeschütteten Zytokine hemmten in primären Hepatozyten der Ratte die Insulin-induzierte Expression der Glukokinase durch Überstände Insulin-stimulierter Makrophagen. 
Auch LPS oder Palmitat, deren lokale Konzentrationen im Zuge des metabolischen Syndroms erhöht sind, waren in der Lage, die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien zu stimulieren. Während LPS seine Wirkung, laut Literatur, unbestritten über eine Aktivierung des Toll-ähnlichen Rezeptors (toll-like receptor; TLR) 4 vermittelt, scheint Palmitat jedoch weitestgehend TLR4-unabhängig wirken zu können. Vielmehr schien die de novo-Ceramidsynthese eine entscheidene Rolle zu spielen. Darüber hinaus verstärkte Insulin sowohl die LPS- als auch die Palmitat-induzierte Ent-zündungsantwort in beiden Zelllinien. Die in Zelllinien gewonnenen Ergebnisse wurden größtenteils in primären humanen Makrophagen bestätigt.
Desweiteren induzierten sowohl Insulin als auch LPS oder Palmitat die Produktion von PGE2 in den untersuchten Makrophagen. Die Daten legen nahe, dass dies auf eine gesteigerte Expression PGE2-synthetisierender Enzyme zurückzuführen ist.
PGE2 wiederum hemmte auf der einen Seite die Stimulus-abhängige Expression des pro-inflammatorischen Zytokins Tumornekrosefaktor (TNF) α in U937-Makrophagen. Auf der anderen Seite verstärkte es jedoch die Expression der pro-inflammatorischen Zytokine Interleukin- (IL-) 1β und IL-8. Darüber hinaus verstärkte es die Expression von IL-6-Typ-Zytokinen, welche sowohl pro- als auch anti-inflammatorisch wirken können. Außerdem vestärkte PGE2 die Expression PGE2-synthetisierender Enzyme. Es scheint daher in der Lage zu sein, seine eigene Synthese zu verstärken. 
Zusammenfassend kann die Freisetzung pro-inflammatorischer Mediatoren aus Makro-phagen im Zuge einer Hyperinsulinämie die Entstehung einer Insulinresistenz begünstigen. Insulin ist daher in der Lage, einen Teufelskreis der immer stärker werdenden Insulin-resistenz in Gang zu setzen. 
Auch Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind (zum Beispiel LPS, freie Fettsäuren und PGE2), lösten Entzündungsantworten in Makrophagen aus. Das wechselseitige Zusammenspiel von Insulin und diesen Metaboliten und Signalsubstanzen löste eine stärkere Entzündungsantwort in Makrophagen aus als jeder der Einzelkomponenten. Die dadurch freigesetzten Zytokine könnten zur Manifestation einer Insulinresistenz und des metabolischen Syndroms beitragen.
N2  - Insulin resistance is a central component of the metabolic syndrome and is a major contributor to the development of type 2 diabetes. One possible cause of insulin resistance is chronic low-grade inflammation, which originates in the adipose tissue of obese individuals. Immigrated macrophages produce increased levels of pro-inflammatory mediators such as cytokines and prostaglandins, resulting in increased concentrations of these substances both locally and systemically. In addition, obese individuals exhibit impaired fatty acid metabolism and increased intestinal permeability. Increased flux of free fatty acids from adipose tissue to other organs results in increased local concentrations in these organs. Increased intestinal permeability facilitates the entry of pathogens and other exogenous substances into the body. 
The aim of this work was to investigate whether high concentrations of insulin, the bacterial component lipopolysaccharide (LPS), or the free fatty acid palmitate can induce or enhance an inflammatory response in macrophages and whether this inflammatory response can contribute to the development of insulin resistance. Furthermore, to investigate whether metabolites and signaling substances whose concentrations are elevated in the metabolic syndrome can promote the production of prostaglandin (PG) E2 and whether this in turn can regulate the inflammatory response and its own production in macrophages. To investigate the influence of these factors on the production of pro-inflammatory mediators in macrophages, monocyte-like cell lines and primary human monocytes, that were isolated from the blood of healthy volunteers, were differentiated into macrophages and incubated for with insulin, LPS, palmitate and/ or PGE2. In addition, primary rat hepatocytes were isolated and incubated with supernatants of insulin-stimulated macrophages to investigate whether the inflammatory response in macrophages is involved in the development of insulin resistance in hepatocytes. 
Insulin induced the expression of pro-inflammatory cytokines in macrophage-like cell lines probably primarily via the phosphoinositide 3-kinase (PI3K)-Akt pathway with subsequent activation of the transcription factor NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells). The cytokines released in this process inhibited insulin-induced expression of glucokinase by supernatants of insulin-stimulated macrophages in primary rat hepatocytes. 
Also, LPS or palmitate, whose local concentrations are increased in the course of metabolic syndrome, were able to stimulate the expression of pro-inflammatory cytokines in macrophage-like cell lines. While LPS, according to the literature, undisputedly mediates its effect via activation of toll-like receptor (TLR) 4, palmitate, however, appears to be able to act mainly in a TLR4-independent manner. Rather, de novo ceramide synthesis appeared to play a crucial role. Moreover, insulin enhanced both LPS- and palmitate-induced inflammatory responses in both cell lines. The results obtained in macrophage-like cell lines were largely confirmed in primary human macrophages.
Furthermore, both insulin and LPS or palmitate induced PGE2 production in the macrophages studied. The data suggest that this was not due to increased expression of arachidonic acid-synthesizing enzymes but rather to increased expression of PGE2-synthesizing enzymes.
On the one hand PGE2 inhibited the stimulus-dependent expression of the pro-inflammatory cytokine tumor necrosis factor (TNF) α in U937 macrophages. However, on the other hand, it enhanced the expression of the pro-inflammatory cytokines interleukin- (IL-) 1β and IL-8. In addition, it enhanced the expression of IL-6-type cytokines, which can be both pro- and anti-inflammatory. In addition, PGE2 enhanced the expression of PGE2-synthesizing enzymes. It therefore appears to be able to enhance its own synthesis. 
In conclusion, the release of pro-inflammatory mediators from macrophages in the course of hyperinsulinemia may favor the development of insulin resistance. Thus, the hyperinsulinemia might be augmented in a vicious cycle feed forward loop. 
Metabolites and signaling substances whose concentrations are elevated in the metabolic syndrome (for example, LPS, free fatty acids, and PGE2) also triggered inflammatory responses in macrophages. The synergistic interaction of insulin and these metabolites and signaling substances triggered a stronger inflammatory response in macrophages than any of the individual components. The released cytokines could contribute to the manifestation of insulin resistance and the metabolic syndrome.
KW  - Metabolisches Syndrom
KW  - Entzündung
KW  - Makrophagen
KW  - Insulin
KW  - Zytokine
KW  - Typ-2-Diabetes
KW  - Prostaglandin
KW  - inflammation
KW  - insulin
KW  - macrophages
KW  - metabolic syndrom
KW  - prostaglandine
KW  - Type-2-diabetes
KW  - cytokines
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-520199
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  - 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  -