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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.

An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves’ of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue., Nature Communications, 7, ISSN:2041-1723

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