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However, the molecular mechanisms are mostly unknown, and a suitable animal model with internal increased ACR does not exist for in vivo studying so far. Several enzyme systems are responsible for acrolein detoxification, such as Aldehyde Dehydrogenase (ALDH), Aldo\u2010Keto Reductase (AKR), and Glutathione S\u2010Transferase (GST). To evaluate the function of ACR in glucose homeostasis and diabetes, <jats:italic>akr1a1a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> zebrafish mutants are generated using CRISPR\/Cas9 technology. Accumulated endogenous acrolein is confirmed in <jats:italic>akr1a1a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> larvae and livers of adults. Moreover, a series of experiments are performed regarding organic alterations, the glucose homeostasis, transcriptome, and metabolomics in <jats:italic>Tg(fli1:EGFP<\/jats:italic>) zebrafish. <jats:italic>Akr1a1a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> larvae display impaired glucose homeostasis and angiogenic retina hyaloid vasculature, which are caused by reduced acrolein detoxification ability and increased internal ACR concentration. The effects of acrolein on hyaloid vasculature can be reversed by acrolein\u2010scavenger <jats:sc>l<\/jats:sc>\u2010carnosine treatment. In adult <jats:italic>akr1a1a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mutants, impaired glucose tolerance accompanied by angiogenic retina vessels and glomerular basement membrane thickening, consistent with an early pathological appearance in diabetic retinopathy and nephropathy, are observed. Thus, the data strongly suggest impaired ACR detoxification and elevated ACR concentration as biomarkers and inducers for diabetes and diabetic complications.<\/jats:p>","DOI":"10.1002\/advs.202101281","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T01:22:33Z","timestamp":1626657753000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reduced Acrolein Detoxification in <i>akr1a1a<\/i> Zebrafish Mutants Causes Impaired Insulin Receptor Signaling and Microvascular Alterations"],"prefix":"10.1002","volume":"8","author":[{"given":"Haozhe","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Vascular Biology and Tumor Angiogenesis European Center for Angioscience (ECAS) Medical Faculty Mannheim Heidelberg University  Mannheim 68167 Germany"},{"name":"Department of Vascular Surgery Renji Hospital School of Medicine Shanghai Jiaotong University  Shanghai 200127 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