The methylation data of the nested case-control study were included in order to replicate findings in the analysis performed by the LOLIPOP study. TXNIP (thioredoxin interacting protein) expression is increased due to glucose . Furthermore, in mice studies it was shown that -cell specific Txnip deletion improves -cell mass and protects against diabetes . This is in line with findings by Xu et al. analyzing mice and primary human islets, demonstrating that - cell Txnip is upregulated in diabetes, whereas Txnip deficiency protects against diabetes by preventing -cell apoptosis . Also in a mice study it was shown that an overabundance of Txnip resulted in impaired glucose, insulin, and pyruvate tolerance by upregulating G6pc through interaction with small heterodimer partners . In cell cultured experiments a decreased Txnip mRNA and protein expression due to metformin exposure was observed . For SOCS3 (suppressor of cytokine signaling 3) an inactivation in leptin receptor-expressing cells of mice was shown to protect against diet-induced insulin resistance but not against obesity . This was also demonstrated by other studies, for example one showing the importance of Socs3 for inhibiting insulin resistance in the skeletal muscle of mice , and another revealing that overexpression of this gene in adipose tissue of mice leads to local but not systematic insulin resistance . Furthermore, it was shown that - cell specific Socs3-deficient mice were protected against the development of diabetes induced by streptozotocin . For humans, it was shown that there was no change in SOCS3 levels in muscle when exposing men with T2D to IL-6 compared to the placebo group . Li et al. found that SNPs annotated to SOCS3 were significantly associated with BMI in humans . In contrast, it was found that there is no strong effect of common SNPs within the SOCS3 gene on the development of T2D in humans . For PHOSPHO1 (phosphatase, orphan 1) this study presents first evidence of its role in glucose metabolism. Therefore, further studies are warranted to validate these findings.
Gestational diabetes mellitus during pregnancy has severe implications for the health of the mother and the fetus. Therefore, early prediction and an understanding of the physiology are an important part of prenatal care. Metabolite profiling is a long established method for the analysis and prediction of metabolic diseases. Here, we applied untargeted and targeted metabolomic protocols to analyze plasma and urine samples of pregnant women with and without GDM. Univariate and multivariate statistical analyses of metabolomic profiles revealed markers such as 2-hydroxybutanoic acid (AHBA), 3-hydroxybutanoic acid (BHBA), amino acids valine and alanine, the glucose-alanine-cycle, but also plant-derived compounds like sitosterin as different between control and GDM patients. PLS-DA and VIP analysis revealed tryptophan as a strong variable separating control and GDM. As tryptophan is biotransformed to serotonin we hypothesized whether serotonin metabolism might also be altered in GDM. To test this hypothesis we applied a method for the analysis of serotonin, metabolic intermediates and dopamine in urine by stable isotope dilution direct infusion electrospray ionization mass spectrometry (SID-MS). Indeed, serotonin and related metabolites differ significantly between control and GDM patients confirming the involvement of serotonin metabolism in GDM. Clustered correlation coefficient visualization of metabolite correlation networks revealed the different metabolic signatures between control and GDM patients. Eventually, the combination of selected blood plasma and urine sample metabolites improved the AUC prediction accuracy to 0.99. The detected GDM candidate biomarkers and the related systemic metabolic signatures are discussed in their pathophysiological context. Further studies with larger cohorts are necessary to underpin these observations.
Many current studies show that the antidiabetic effect is present very early after bariatric surgery before any significant weight loss occurs and that it is not specific for any type of intervention. A strong and significant improvement in glucose metabolism just 3 days after LSG was described by Rizzello et al. in a study of 17 T2DM patients with obesity . In the study of Schauer PR et al. on 240 T2DM patients who underwent RYGB and were treated with medications and/or insulin before surgery, 30 % of patients could stop diabetic treatment immediately after discharge from the hospital before any significant weight loss . In a study by Umeda LM et al. conducted in 10 obese T2DM patients it was shown that there was a significant improvement in HOMA-IR index 7 days after RYGB without significant weight loss . Many trials document that the rate of diabetic remission after bariatric surgery in less obese patients (BMI < 35 kg/m 2 ) is similar to that in morbidly obese patients  and therefore the term “bariatric surgery” is currently being replaced by the term “metabolic surgery” when this form of therapy is used to treat diabetes in non-morbidly obese patients. The non-significant association between the rate of T2DM remission and degree of weight loss after bariatric surgery was also described in many studies [23, 27]. The stronger improvement in glucose metabolism after bariatric surgery than after the marked weight loss from other non-surgical interventions indicated weight loss-independent antidiabetic effects of bariatric surgery. Laferrère B et al. designed a study to compare the effects of weight loss by RYGB versus calorie-restricted diet on glucose metabolism in T2DM patients. This study showed that although weight loss was equivalent in both groups, the improvement on postprandial blood glucose was markedly stronger in the RYGB group . All this indicates that diabetic remission after bariatric surgery may be mediated by additional factors and independent to weight loss.
This study has several limitations. First of all, the sample size is relatively small. However, according to sam- ple size calculations based on our previous reports, the included number of patients was sufficient to observe assumed differences in hepatic energy metabolism 14 . Also for the assessment of ectopic lipid content in insulin sensitive tissue previous reports of our study group showed significant differences between groups of similar sam- ple size due to the high sensitivity and low inter- and intraobserver variability of high resolution state of the art MRS techniques 23 , 24 . Moreover, we are not able to prove our hypothesis that the observed differences in hepatic energy metabolismand lipid content are because of a loss of the physiological portal to peripheral insulin ratio in T1DM during subcutaneous insulin therapy, since only peripheral blood samples were drawn at the study days.
However, the way how maternal obesity and eventually pregnancy induced dyslipidemia de- veloping normally in the last trimester concretely impacts availability of substrates to the fetus and in which degree enhances fetal macrosomia is not completely understood. There is strong evidence, in particular by the data of the HAPO study, that hyperglycemia is associated with the risk for birth weight above the 90th percentile (23). However, macrosomia was also preva- lent in offspring of pregestational type-1-diabetes as well GDM women with satisfactory gly- cemic control during pregnancy (4,5). Hence other factors particularly maternal obesity as well as lipids attracted attention as potential intermediators that contribute to the persisting preva- lence of macrosomia. In our previous study we already showed a significant association of serum triglyceride levels with abnormal fetal growth in pregnancies affected by type 1 as well as type 2 diabetes compared to uncomplicated pregnancies similarly to previously reported re- sults for well-controlled GDM (20). Langer et al demonstrated that pregestational obesity sig- nificantly increases the risk for macrosomia in well-controlled GDM pregnancies. Of note, the rate of macrosomia in obese women with GDM was lowered in cases receiving insulin therapy compared to the normal-weight reference group (24). This effect of insulin therapy may be due to the reduction of lipolysis by insulin action (24). Apart from GDM, in pregnancies with nor- mal glucose tolerance it is already recognized that offspring of obese and overweight show higher risk for macrosomia compared to those of lean women apparently due to increase in neonatal fat and not lean body mass (25). Concrete mechanisms are not clear but it is suggested that elevated levels of triglycerides as it is the case in obese and insulin resistant women, in- crease the availability of free fatty acids for the fetus via hydralization by placental lipoprotein lipase and enhanced placental transport (26). Indicative for this theory, in our study population neonatal birth weight percentiles were increased in obese and overweight women, who com- pared to lean pregnant mothers also showed a dyslipidemic profile in particular elevated tri- glycerides during pregnancy course, however, our sample size regarding this aspect is sparse due to only a few number of LGA cases.
Our findings on the positive association between copep- tin and incident prediabetes/T2D among normogly- caemic participants at baseline are in accordance with findings from the DESIR study [ 15 ] showing a positive association between copeptin and incident IFG/T2D among participants with normal fasting glucose at base- line. However, in the present study, copeptin was not significantly associated with incident T2D among nondi- abetic participants at baseline. Similar to our finding, the FINRISK study [ 8 ] also observed no significant associa- tions between copeptin and incident T2D among nondia- betic participants at baseline. In contrast, investigations from the MDC study [ 14 ] and the British Regional Heart Study [ 35 ] reported positive associations between copep- tin and incident T2D among nondiabetic participants at baseline. These associations were stronger in partici- pants without IFG than in all nondiabetic participants at baseline. Recently, higher copeptin levels were reported in participants with prediabetes than in participants with T2D [ 7 ]. This finding corroborates our results on a more pronounced association of copeptin with incident pre- diabetes alone than with the combined incident predia- betes/T2D. Unfortunately, our study is underpowered to examine the association between copeptin and incident T2D alone among participants with normoglycaemia at baseline.
The safety and efficacy of sodium‐glucose cotransporter 2 inhibitors in posttrans‐ plantation diabetes mellitus is unknown. We converted stable kidney transplant pa‐ tients to 10 mg empagliflozin, aiming at replacing their insulin therapy (<40 IU/d). N = 14 participants (the required sample size) completed the study visits through 4 weeks and N = 8 through 12 months. Oral glucose tolerance test (OGTT)–derived 2‐hour glucose (primary end point) increased from 232 ± 82 mg/dL (baseline) to 273 ± 116 mg/dL (4 weeks, P = .06) and to 251 ± 71 mg/dL (12 months, P = .41). Self‐ monitored blood glucose and hemoglobin A1c were also clinically inferior with empa‐ gliflozin monotherapy, such that insulin was reinstituted in 3 of 8 remaining participants. Five participants (2 of them dropouts) vs nine of 24 matched reference patients developed bacterial urinary tract infections (P = .81). In empagliflozin‐ treated participants, oral glucose insulin sensitivity decreased and beta‐cell glucose sensitivity increased at the 4‐week and 12‐month OGTTs. Estimated glomerular fil‐ tration rate and bioimpedance spectroscopy‐derived extracellular and total body fluid volumes decreased by 4 weeks, but recovered. All participants lost body weight. No participant developed ketoacidosis; 1 patient developed balanitis. In conclusion, although limited by sample size and therefore preliminary, these results suggest that empagliflozin can safely be used as add‐on therapy, if posttransplant diabetes pa‐ tients are monitored closely (NCT03113110).
Importantly, the occurrence of heart failure has a major impact on cardiac metabolismand causes a shift in cardiac substrate utilization from fatty acids to glucose oxidation, and therefore is the opposite from what is happening in the diabetic situation. 38 Metabolic pro ﬁling of cardiac tissue from patients with advanced heart failure revealed decreased cellular abundance of fatty acids, with suppression of the fatty acid oxidation machinery. 39 The failing heart conse- quently relies more on the oxidation of glucose. Occurrence of insulin resistance in this situation has the potential to limit energetic supply and further impair cardiac function. Sys- temic insulin resistance is further promoted by heart failure, which has been attributed to increased sympathetic tone and stress-dependent perturbation within metabolic pathways. 40 Heart failure has therefore been considered “an engine out of fuel, ” 38 whereas insulin resistance proves to be an inde- pendent predictor of poor prognosis in patients with heart failure. 41 Interestingly, cardiac ketone body metabolism was recently identi ﬁed as an alternative energy supply for the failing heart. 42 Circulating concentrations of ketone bodies are increased in heart failure and enter the cell in an insulin- independent manner. Induction of ketone body eprocessing enzymes, including b -hydroxybutyrate dehydrogenase 1, is
Türkischstämmige Frauen in Schweden haben ein 3-fach höhe- res Diabetesrisiko im Vergleich zu schwedischen Frauen, wohinge- gen es bei Männern kaum einen Unterschied gibt. Dies gilt auch für das Hospitalisierungsrisiko aufgrund von Typ-2-Diabetes, wo- bei sich dieser Effekt bei der zweiten Generation abschwächt . Eine in 7 europäischen Ländern für 30 Migrantengruppen durch- geführte Studie zeigt eine um 90 % bzw. 120 % höhere Diabetes- Mortalitätsrate für Männer und Frauen im Vergleich zur einheimi- schen Bevölkerung . Darüber hinaus haben Menschen mit Typ-2-Diabetes aus Asien, dem Nahen Osten und Subsahara- Afrika im Vergleich zu europäischen Populationen ein besonders hohes Risiko für mikrovaskuläre Komplikationen: diabetische Reti- nopathie, Nephropathie und periphere Neuropathie .
Stratifizierung des kardiovaskulären Risikos
Patienten mit Diabetes mellitus haben in aller Regel ein deutlich erhöhtes kardiovaskuläres Risiko . Dennoch wird empfohlen, dieses auch weiter zu differenzieren. Dabei kommen dieselben Risikofaktoren wie bei Patienten ohne Diabetes zum Tragen ( ▶ Tab. 1). Zu beachten ist, dass sich das Vorliegen mehrerer Risikofaktoren überadditiv auf das Gesamtrisiko auswirkt . Das geschätzte Gesamtrisiko ist eine wesentliche Determinante, ob und gegebenenfalls wie intensiv eine lipidsenkende Therapie durchgeführt werden soll.
• Eine ungestörte Hypoglykämiewahrnehmung ist Voraussetzung für die Fahreignung. • Menschen mit Diabetes, die mehr als eine fremdhilfebedürftige Hypoglykämie im
Wachzustand in den letzten 12 Monaten hatten, dürfen in der Regel für 3 Monate kein Fahrzeug der Gruppe 1 führen. In einem fachärztlichen Gutachten und durch regelmäßige ärztliche Kontrollen muss eine stabile Stoffwechsellage und eine sichere Unterzuckerungswahrnehmung bescheinigt werden, um erneut eine Fahreignung zu erlangen. Für Fahrzeuge der Gruppe 2 gilt, dass 12 Monate lang nach einer zweiten fremdhilfebedürftigen Unterzuckerung keine Fahreignung und damit keine Fahrerlaubnis bestehen. Im Einzelfall kann von dieser Regel abgewichen werden, wenn im ärztlichen Gutachten günstige Umstände erkennbar sind. Mindestens aber für 3 Monate gilt der Fahrzeugführer als nicht geeignet, ein Fahrzeug der Gruppe 2 zu führen. Er ist zum Führen eines Kraftfahrzeugs solange ungeeignet, bis wieder eine hinreichende Stabilität der Stoffwechsellage sowie eine zuverlässige Wahrnehmung von Hypoglykämien sichergestellt ist.
Bei einem Antrag auf Erteilung oder Verlängerung der Fahrer- laubnis für Kraftfahrzeuge der Führerscheingruppe 2 wird von Menschen mit Diabetes immer ein verkehrsmedizinisches Gutach- ten verlangt. Dabei hat sich der Gutachter an die durch die Fahr- erlaubnisbehörde vorgegebene Fragestellung zur Kraftfahreig- nung zu halten. Diese Untersuchung darf nur nach anerkannten wissenschaftlichen Grundsätzen vorgenommen werden (FeV, An- lage 4a, Abs. 1c). Das Gutachten muss in allgemeinverständlicher Sprache abgefasst, nachvollziehbar und nachprüfbar sein. Alle zur Beurteilung führenden wesentlichen Befunde müssen wiederge- geben werden. Untersuchungsverfahren müssen angegeben wer- den. Das Gutachten muss in allen wesentlichen Punkten insbeson- dere im Hinblick auf die gestellten Fragen vollständig sein. Es muss zwischen Vorgeschichte und gegenwärtigem Befund un- terschieden werden. Die Kosten der Begutachtung trägt die zu untersuchende Person. Das Gutachten erhält der Untersuchte, sofern der Gutachter nicht von einem Gericht beauftragt wurde.
Im Dezember 2018 wurde von Katsanos eine Metaanalyse veröffentlicht, in der anhand gepoolter Daten aus 3 Studien, die sowohl DEB als auch DES einschlossen, 2 bis 5 Jahre nach Anwen- dung eine statistisch signifikant höhere Gesamtmortalität im Ver- gleich zu mit unbeschichteten Systemen behandelten Patienten nachgewiesen wurde . Im Januar 2019 publizierte die US Food and Drug Administration (FDA) erstmals Empfehlungen be- züglich des Einsatzes von mit Paclitaxel beschichteten Ballons und Stents, in der sie den Anwendern aus Gründen des vorsorglichen Gesundheitsschutzes eine sorgfältige Nutzen-Risiko-Abwägung empfahl. Insbesondere wurde die präinterventionelle Aufklärung betroffener Patienten empfohlen, da es unklar ist, ob es im Zu- sammenhang mit der Verwendung paclitaxelbeschichteter Syste-
In Bezug auf die blutzuckersenkende Therapie konnten die Stu- dien mit Empagliflozin, Canagliflozin und Dapagliflozin eine signi- fikante Reduktion der Hospitalisierung für Herzinsuffizienz zeigen, sodass diese Substanzen bei Patienten mit hohem Risiko für eine Herzinsuffizienz und bei Patienten mit Vorliegen einer Herzinsuffizienz zur Blutzuckersenkung und Reduktion der kardiovaskulären Morbidität und Mortalität eingesetzt werden sollten. Für Patienten mit HFrEF liegt zudem seit dem letzten Jahr die DAPA-HF-Studie vor, die bei Patienten mit und ohne Diabetes durchgeführt wurde. Die Gabe von Dapagliflozin führte unabhän- gig vom Vorliegen eines Diabetes mellitus zu einer signifikanten Reduktion der Verschlechterung der Herzinsuffizienz, des kardio- vaskulären Todes oder der Gesamtmortalität . Aufgrund des erhöhten Risikos einer Hospitalisierung für Herzinsuffizienz sind Glitazone sowie der DPP4-Inhibitor Saxagliptin bei Patienten mit Herzinsuffizienz kontraindiziert.
Bislang ist noch keine pharmakologische Therapie der NAFLD zugelassen. Falls ein Typ-2-Diabetes vorliegt, kann man aber gezielt Medikamente zur Therapie des Diabetes einsetzen, um auch die NAFLD zu behandeln. Diesbezüglich empfehlen die gemeinsamen Leitlinien der Fachgesellschaften European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) und European Association for the Study of Obesity (EASO) sowie jene der American Association for
While great strides have been made in the past years, the complete picture of Mn metabolismand homeostasis remains to be mapped out. Advanced biomarkers or measuring techniques are needed to monitor body Mn levels, especially for chronic Mn accumulation. As blood Mn is very dynamic and only represents current body Mn levels in a relatively short term, patients with low blood Mn after chelation therapy might still suffer from Mn-induced neurotoxicity due to slow release of Mn from other tissues accumulated in the past. Bone Mn is a good biomarker for this purpose, given that bone stores the largest amount of Mn in human body and bone Mn has a long half-life (skeleton bone 8.5. years). Recent techniques such as in vivo neutron activation analysis (IVNAA) allow non-invasive measurement of bone Mn levels, thus are of great help to access chronic Mn accumulation and monitor Mn levels across developmental stages in children. Brain is the primary target of Mn poisoning. As for regulation of Mn homeostasis, although we have identified a few transporters capable to transport Mn, a large numbers of regulator proteins remain to be identify. Besides, among these known transporters, actually none of them has been proved as a Mn specific transporter. Most of them facilitate couple metal ions influx or efflux with highest affinity to other metals rather than Mn. SLC30A10 could be a potential candidate, but more research is needed to confirm that. In addition, within a cell, the nucleus is the largest Mn storage site with the highest Mn concentration. However, regulation of Mn homeostasis in this organelle remain blank due to very few intracellular transporters identified there. A forward or reverse genetic screen to find these transporters or regulators is of great interest and priority to understand Mn homeostasis in cells and in human body.
consists of 13 IFNα subtypes (14 in mice), one single IFNβ gene, and some further poorly analyzed genes ( 2 ). The sole representa- tive of class II IFN is IFNγ, which is mainly produced by T cells and NK cells ( 2 ). IFNγ generally activates innate responses by augmenting inflammatory cytokine and chemokine production, microbial killing, and antigen presentation of macrophages and dendritic cells ( 3 ). Upon stimulation of extra- and intracellular pattern recognition receptors (PRR), including Toll-like recep- tors (TLR), nucleotide-binding oligomerization domain-like receptors, and retinoic acid-inducible gene I-like receptors, many immune cells, but also non-hematopoietic cells, are capable of inducing type I IFNs by a concerted activation of transcription factors called IFN-regulatory factors (IRFs) ( 4 ). Expression of IFNs is also dependent on the sensing of the extra- and intracel- lular microenvironment by the mammalian target of rapamycin (mTOR) network ( 5 ). mTOR complex 1 (mTORC1) integrates the main classes of nutrients and energy sources [amino acids, glucose, lipids, and adenosine triphosphate (ATP)] to couple the environmental status with cellular activation and translation ( 5 ). Activation of mTORC1 is required to induce the translation as well as the activation of IRFs, including IRF5 and IRF7, to maximize type I IFN production ( 6 – 9 ). IFNα and IFNβ bind a heterodimeric membrane receptor consisting of the interferon alpha and beta receptor subunit 1 (IFNAR1) and IFNAR2 ( 10 ). Receptor engagement activates the receptor-associated protein tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which phosphorylate and activate the transcription fac- tors signal transducer and activator of transcription 1 (STAT1) and STAT2 ( 10 ). In contrast, the dimeric IFNγ receptor consists of the interferon gamma receptor 1 (IFNGR1) and IFNGR2 and activates the receptor-associated tyrosine kinases, JAK1 and JAK2, which solely activate STAT1 ( 11 ).
Increased ARG expression during lung fibrosis was of functional relevance, as it correlated with decreased levels of free lung cellular L-arginine (Figure 4.7.). The highest depletion of the amino acid was observed seven and fourteen days after drug administration. It is well-established that IPF may be affected by Th2-mediated inflammation, which leads to progressive deposition of ECM, fibrogenesis, and destruction of the pulmonary parenchyma. Similar patterns can be observed in a bleomycin-induced lung fibrosis model, where approximately seven days after drug administration, a strong inflammatory response is evident, followed by the onset of fibrosis two weeks after treatment with bleomycin. Recently, it has been also demonstrated that iNOS and ARG activities can be differentially modulated by Th1 and Th2 cells and their cytokines 103 . Th1 cytokines (e.g. INF-γ) activate iNOS 120 , whereas Th2 cytokines (e.g. IL-4, IL-13) promote ARG activity 121 . Thus, the upregulation of the ARG expression observed during bleomycin-induced lung fibrosis may be explained by the fact that mice inflammatory response is dominated by the production of Th2-associated cytokines, including IL-4, IL-5, IL-10 and IL-13.
The majority of commercial weed control chem icals interfere with hormone-induced cell elonga tion, cell division and with chloroplast metabo lism. Within these three domains of action the chloroplast is the target site of unrivaled impor tance. Most of the plant-specific reactions for which active and specific inhibitors are known are located in this organelle. Its electron transport, the carbon dioxide fixation and photosynthate alloca tion, pigment biosynthesis, or the build-up of es sential amino and fatty acids can be inhibited or deregulated. Older, established herbicides like atrazine, metribuzin, bentazone, propanil, or gly- phosate are prominent inhibitors. Also more re cent developments, like the sulfonylureas, imid- azolinones, the phenoxyphenoxypropanoates or oxime-type cyclohexanediones are addressed to wards plastidic reactions. The same holds for the peroxidizing herbicides like nitrodiphenyl ethers, cyclic imides or certain pyrazoles. The “classic” bleaching herbicide norflurazone has been fol lowed by more recent xenobiotics attacking the phytoene desaturase, the membrane-bound key enzyme of carotenogenesis.