Graphical Abstract Highlights d Imidazole propionate levels are increased in subjects with type 2 diabetes (T2D) d Imidazole propionate is produced from histidine by T2Dassociated bacteria d Imidazole propionate impairs glucose tolerance and insulin signaling d Imidazole propionate inhibits IRS via activation of p38g/p62/ mTORC1In Brief Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling. SUMMARYInteractions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidinederived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38g MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. 948 Cell 175, 947-961, November 1, 2018 (legend continued on next page) 950 Cell 175, 947-961,

OBJECTIVEThere is growing evidence that periodontitis may affect general health. This study was assigned to explore the robustness of observations that periodontal therapy leads to the improvement of glycemic control in diabetic patients.RESEARCH DESIGN AND METHODSA literature search (until March 2009) was carried out using two databases (MEDLINE and the Cochrane Library) with language restriction to English. Selection of publications was based on 1) original investigations, 2) controlled periodontal intervention studies where the diabetic control group received no periodontal treatment, and 3) study duration of ≥3 months.RESULTSScreening of the initial 639 identified studies and reference checking resulted in five suitable articles. A total of 371 patients were included in this analysis with periodontitis as predictor and the actual absolute change in A1C (ΔA1C) as the outcome. The duration of follow-up was 3–9 months. All studies described a research population of type 2 diabetic patients in whom glycemic control improved after periodontal therapy compared with the control group (range ΔA1C: Δ−1.17 up to Δ−0.05%). The studies in a meta-analysis demonstrated a weighted mean difference of ΔA1C before and after therapy of −0.40% (95% CI −0.77 to −0.04%, P = 0.03) favoring periodontal intervention in type 2 diabetic patients. Nevertheless, this improvement in %A1C must be interpreted with care due to limited robustness as evidenced by heterogeneity among studies (59.5%, P = 0.04).CONCLUSIONSThe present meta-analysis suggests that periodontal treatment leads to an improvement of glycemic control in type 2 diabetic patients for at least 3 months.

Viral infections are associated with coagulation disorders. All aspects of the coagulation cascade, primary hemostasis, coagulation, and fibrinolysis, can be affected. As a consequence, thrombosis and disseminated intravascular coagulation, hemorrhage, or both, may occur. Investigation of coagulation disorders as a consequence of different viral infections have not been performed uniformly. Common pathways are therefore not fully elucidated. In many severe viral infections there is no treatment other than supportive measures. A better understanding of the pathophysiology behind the association of viral infections and coagulation disorders is crucial for developing therapeutic strategies. This is of special importance in case of severe complications, such as those seen in hemorrhagic viral infections, the incidence of which is increasing worldwide. To date, only a few promising targets have been discovered, meaning the implementation in a clinical context is still hampered. This review discusses non-hemorrhagic and hemorrhagic viruses for which sufficient data on the association with hemostasis and related clinical features is available. This will enable clinicians to interpret research data and place them into a perspective.