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Aims/hypothesis Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4−/− mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. Methods We chronically fed wild-type (WT) and Angptl4−/− mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. Results Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4−/− mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4−/− mice. Conclusions/interpretation Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism. Electronic supplementary material The online version of this article (10.1007/s00125-018-4583-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS.Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels.We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice.We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance.

A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

Background: Given the important role of ERCC4 gene in multiple DNA repair systems, we hypothesized that genetic variations within this gene may be a cervical squamous cell carcinoma (CSCC) risk and disease modulatory factor.Methods: In population-based, case-control association study including 143 CSCC patients and 207 healthy women, two ERCC4tagSNPs were studied.Results: A significant protective effect against CSCC was observed assuming a dominant model in case of ERCC4rs3136176 ([AA]+[AT]vs.[TT]: p=0.04,OR=0.43), and genotype [AA] strongly protects against poorly (G3) differentiated CSCC (pcorreced=0.008,OR=0.15) and significantly increased the disease remission rate (p=0.05,OR=0.48).A statistically significant increase frequency of ERCC4rs1799798 [A] allele was seen in patients with well differentiated (G1) CSCC (p=0.02, OR=2.40). Contrary, an opposite trend was observed when G1 was compared with G2 (moderately differentiated) CSCC (p=0.06). Furthermore, ERCC4rs1799798 [A] allele tended to be increased in patients with carcinoma planoepitheliale keratodes (Cpk) (p=0.07).Haplotype ERCC4rs3136176[A]/ERCC4rs1799798[G] significantly decreased risk of G1 as well as G3 CSCC (p=0.02,OR=0.50, and p=0.017,OR=0.42, respectively) and only tended to decrease risk of CSCC (p=0.07,OR=0.758) as well as carcinoma planoepitheliale akeratodes (Cpa) (p=0.059,OR=0.71).In contrast haplotype AA significantly increased risk of G1 CSCC and risk of Cpk (p=0.01, OR=2.51, and p=0.049, OR=1.96, respectively), whereas haplotype TG increased risk of G3 CSCC (p=0.037, OR=2.17).The overall survival rates showed similar mean survival rates according to patients' genotypes at both studied SNPs.Conclusion: The above findings consistently suggested that genetic variants in ERCC4 gene may play significant role in CSCC pathophysiology.

Purpose The purpose of this study was assessment of nailfold capillary changes and their possible relation to polymorphism of a gene encoding endothelial nitric oxide synthase (eNOS) in normal tension glaucoma (NTG) patients Methods The study included 35 normal-tension glaucoma (NTG) patients (23 female and 12 male). Capillaroscopic examination of the nailfold capillaries of II to V fingers of both hands was performed (before and after the cold provocation test) by means of a videocapillaroscope. T786C eNOS gene polymorphism was determined by RT- PCR methods. Results 31 (88.6%) patients suffered from cold extremities. In 24 (68.5%) patients nailfold capillaroscopy was within normal limits, in 11 (31.5%) patients the results were abnormal, 4 (11.4%) of them mimicked changes observed in sclerodermia. The cold provocation test was positive in 43.5% of NTG patients. The patients with NTG presented the following nailfold capillaries: megacapilaries or dilatated capillaries (44.4%), ramified/bushy (18.9%), coiled (17.1%). Assessing the T786C polymorphism of eNOS gene in NTG patients, TT genotype was present in 36% patients, TC in 52.6% and CC in 11.3%. There were no correlation between SNP variants and capillaroscopy results nor cold provocation test ( p=0.9 and 0.5, respectively). Conclusion The T786C polymorphism of eNOS gene does not influence the capillaroscopy results. The high incidence of sclerodermia - like changes in capillaroscopy in NTG needs further studies.

NMDA receptor dependent anti-diabetic effects Jan Marquard, Silke Otter, Alena Welters, Diran Herebian, Fatih Demir, Annett Schroeter, Olaf Kletke, Martin Kragl, Daniel Eberhard, Barbara Bartosinska, Masa Skelin Klemen, Andraz Stozer, Martin Kohler, Alin Stirban, Freimut Schliess, Tim Heise, Stephan Wnendt, Marjan Slak Rupnik, Per-Olof Berggren, Nikolaj Klocker, Thomas Meissner, Ertan Mayatepek, Eckhard Lammert