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ZusammenfassungParagangliome im Kopf-Hals-Bereich sind seltene Tumoren und treten sowohl sporadisch als auch hereditär auf. Sie können Systemerkrankungen darstellen und sollten interdisziplinär abgeklärt werden. Nach internistischen, radiologischen und genetischen Gesichtspunkten lassen sich Niedrig-/und Hochrisikopatienten identifizieren. Klinische Herausforderungen sind eine mögliche Metastasierung, multilokuläre Manifestationen und Rezidive. Hereditäre Paragangliome können im Rahmen einer Disposition zusammen mit weiteren Tumorerkrankungen auftreten. Der vorliegende Artikel soll relevante Aspekte zu Paragangliomen der A. carotis zusammenfassen und einen praktikablen Algorithmus zu Diagnostik, Therapie und Nachsorge liefern.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat. All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p

The liver is the major metabolic hub, ensuring appropriate nutrient supply during fasting and feeding. In obesity, accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease. Understanding the signaling mechanisms that enable hepatocytes to quickly adapt to dietary cues, might help to restore balance in liver diseases. Post-translational modification by attachment of the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. Here, we demonstrate that the specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly modified by SUMOylation on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was strongly abolished upon fasting. In a context of diet-induced obesity, Prox1 SUMOylation became insensitive to fasting cues. Hepatocyte-selective knock in of a SUMOylation-deficient Prox1 mutant into mice fed a high fat/high fructose diet led to reduction of systemic cholesterol levels, associated with the induction of bile acid detoxifying pathways in mutant livers during fasting. As appropriate and controlled fasting protocols have been shown to exert beneficial effects on human health, tools to maintain the nutrient-sensitive SUMOylation switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the maintenance of metabolic health.

ZUSAMMENFASSUNGForschende des DZD (Deutsches Zentrum für Diabetesforschung) arbeiten daran, die unterschiedlichen Untergruppen des Diabetes und Prädiabetes zu identifizieren und für diese Untergruppen jeweils eine passende Vorbeugung zu entwickeln. Das zentrale Thema und Motto des Forschungsschwerpunkts Prävention des Typ-2-Diabetes ist es, die Hindernisse auf dem Weg hin zu einer erfolgreichen Diabetesprävention zu überwinden. Im Einzelnen werden grundlegende Mechanismen, die für Präventionsprozesse wesentlich sind, untersucht und diese in klinischen Studien getestet. Außerdem wird Prävention in die gesundheitliche Versorgung implementiert, unter Berücksichtigung der Patientenperspektive und wirtschaftlicher Aspekte. Somit verbinden sich Grundlagenforschung, klinische Forschung und Versorgungsforschung auf dem Gebiet der Prävention.

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.

ObjectiveFibrotic organ responses have recently been identified as long-term complication in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date.MethodsBased on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single cell liver sequencing.ResultsHepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice. Single cell RNA sequencing revealed a distinct gene signature identifying an upregulation of mitochondrial-related processes. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models.ConclusionsTogether, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Cell-specific reduction of TSC22D4 improves hepatic steatosis, inflammation and promotes hepatocyte survival thus paving the way for further preclinical therapy developments.

Transforming Growth Factor β 1 Stimulated Clone 22 D4 (TSC22D4) is an intrinsically disordered protein that regulates cellular and physiological processes such as cell proliferation, cellular senescence as well as hepatic glucose and lipid metabolism. The molecular mechanism of TSC22D4 action in these cellular and metabolic functions, however, remains largely elusive. Here, we identified TSC22D4 as a novel protein kinase B/Akt1 interacting protein, a critical mediator of insulin/PI3K signaling pathway implicated in diverse set of diseases including type 2 diabetes, obesity and cancer. TSC22D4 interacts with Akt1 not constitutively but rather in a regulatory manner. While glucose and insulin stimulation of cells or refeeding of mice impair the hepatic TSC22D4-Akt1 interaction, inhibition of mitochondria and oxidative stress, promote it; indicating that extra- and intra-cellular cues play a key role in controlling TSC22D4-Akt1 interaction. Our results also demonstrate that together with its dimerization domain, i.e. the TSC box, TSC22D4 requires its intrinsically disordered region (D2 domain) to interact with Akt1. To understand regulation of TSC22D4 function further, we employed tandem mass spectrometry and identified 15 novel phosphorylation sites on TSC22D4. Similar to TSC22D4-Akt1 interaction, TSC22D4 phosphorylation also responds to environmental signals such as starvation, mitochondrial inhibition and oxidative stress. Interestingly, 6 out of the 15 novel phosphorylation sites lie within the TSC22D4 D2 domain, which is required for TSC22D4-Akt1 interaction. Characterization of the regulation and function of these novel phosphorylation sites, in the future, will shed light on our understanding of the role of TSC22D4-Akt1 interaction in both cell biological and physiological functions. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate cell proliferation, cellular senescence as well as maintain metabolic homeostasis.

Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1

Type 2 Diabetes mellitus (T2 D) is an independent risk factor for cardiovascular diseases and non-ischemic heart failure, an underestimated complication of T2 D. Diastolic dysfunction is an early sign of diabetes-related heart failure preceding its progression to systolic damage. The etiology of heart failure in these patients has recently been partially unveiled. Along with other mechanisms, hyperinsulinemia and hyperlipidemia cause increased myocardial lipid accumulation and oxidation, which leads to lipotoxicity, oxidative stress, inflammatory response and eventually impaired mitochondrial efficiency, fibrosis, apoptosis and contractile dysfunction. These myocardial alterations resemble the cellular mechanisms underlying the development of non-alcoholic fatty liver disease (NAFLD), a frequent comorbidity of T2 D and another risk factor for cardiovascular diseases and heart failure. Control of risk factors, lifestyle intervention and antihyperglycemic treatment are the recommended treatment for patients with T2 D and heart failure. While thiazolidindiones and some dipeptidyl peptidase 4 (DPP4) inhibitors may be detrimental for patients with heart failure, recent studies provided evidence for safe use of glucagon-like peptide 1 (GLP1) receptor agonists and for possible beneficial effects of sodium glucose co-transporter 2 (SGLT2) inhibitors on mortality and hospitalization of T2 D patients with heart failure. Treatment of NAFLD could also be beneficial for the cardiovascular outcome of patients with T2D-related heart failure. This article provides a brief summary of the current research on underlying mechanisms, clinical features and recently recommended therapeutic approaches for T2D-related heart failure.Typ-2-Diabetes-mellitus (T2 D) ist ein unabhängiger Risikofaktor für Herzinsuffizienz, die als Komplikation oftmals unterschätzt wird. Bei T2 D kann sich früh eine diastolische Funktionsstörung ausbilden, die sich später zu einer Herzinsuffizienz entwickeln kann. Von einer ischämischen Kardiomyopathie ist eine Diabetes-bedingte Herzinsuffizienz aktuell nicht abgrenzbar.Hyperglykämie, Hyperinsulinämie und Hyperlipidämie bei T2 D verändern den myokardialen Stoffwechsel. Daraus resultieren oxidativer Stress, reduzierte mitochondriale Effizienz, Lipotoxizität und Apoptose im Herzen. Die T2D-assoziierte nicht-alkoholische Fettlebererkrankung (NAFLD) zeigt ähnliche Pathomechanismen und stellt einen potenziellen Risikofaktor dar.Zur Verbesserung der Herzfunktion wird die Kontrolle kardiovaskulärer Risikofaktoren sowie Reduktion der Insulinresistenz durch Bewegung und Gewichtsabnahme empfohlen. Neben Metformin scheinen SGLT2-Inhibitoren als zusätzliche Therapieoption besonders geeignet zu sein. Auch die NAFLD könnte ein Angriffspunkt zukünftiger Therapieansätze werden.

Shunting of glycolytic intermediates into the pentose phosphate pathway has been suggested to protect from hyperglycaemia-induced microvascular damage. We hypothesized that genetic variability in the gene encoding transketolase, a key pentose phosphate pathway enzyme, contributes to early nerve dysfunction in recent-onset diabetes.In this cross-sectional study, we assessed nine single nucleotide polymorphisms (SNPs) in the transketolase gene, plasma methylglyoxal concentrations, and clinical and quantitative measures of peripheral nerve function in 165 type 1 and 373 type 2 diabetic patients with a diabetes duration up to 1 year.The Total Symptom Score was associated with transketolase SNPs rs7648309, rs62255988, and rs7633966, while peroneal motor nerve conduction velocity (MNCV) correlated only with rs7648309 (P 0.01). Cold thermal detection threshold (TDT) (foot) was associated with transketolase SNPs rs11130362 and rs7648309, while warm TDT (hand) correlated with rs62255988 and rs7648309 (P 0.01). After Bonferroni correction, the correlations of transketolase SNP rs7648309 with Total Symptom Score and rs62255988 with warm TDT (hand) remained statistically significant. Among subgroups, men with type 2 diabetes showed the strongest associations. No associations were observed between each of the nine tagged transketolase SNPs and plasma methylglyoxal concentrations.The observed associations of genetic variation in transketolase enzyme with neuropathic symptoms and reduced thermal sensation in recent-onset diabetes suggest a role of pathways metabolizing glycolytic intermediates in early diabetic neuropathy. Copyright © 2016 John WileySons, Ltd.

The adipose tissue stores excess energy but also produces a series of substances including cytokines (adipocytokines) which participate in regulatory processes. The physiologic and pathophysiologic relevance of these factors has only recently been described in more detail. Defects in adiponectin as well as overproduction of free fatty acids play an important role in the development of insulin resistance typical for obesity. Rare forms of obesity or lipodystrophy can now be explained by defects in the leptin system. The contribution of adipose tissue and its cytokines to the relationship between inflammation and the metabolic syndrome is currently under investigation.