Andrew A. Wheeler

We provide evidence that neuraminidase, which is elevated in plasma from males and females with type 2 diabetes (T2D), is involved in the activation of endothelial ADAM17 and shedding of the mechanosensor glypican-1. We also provide evidence that neuraminidase-induced ADAM17 activation and consequent glypican-1 shedding are mediated by ANO6 scramblase externalization of phosphatidylserine. Together, this work suggests the neuraminidase-ANO6-ADAM17 axis may be a mechanism underlying impaired endothelial shear stress mechanotransduction in T2D.

Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

This work provides the first evidence that neuraminidase, an enzyme increased in the circulation of men and women with type 2 diabetes (T2D), promotes anoctamin-6 (ANO6)-dependent externalization of phosphatidylserine in endothelial cells, which in turn leads to activation of a disintegrin and metalloproteinase-17 (ADAM17) and consequent shedding of the insulin receptor-α from the cell surface. Hence, this work supports that consideration should be given to the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.

Duodenal diverticulitis is a relatively uncommon finding in patients. Treatment of complications of duodenal diverticulitis may be challenging in patients with altered intestinal anatomy such as those with altered anatomy from weight loss procedures involving intestinal bypass. We present a case report describing the management of duodenal diverticulitis following a biliopancreatic diversion, our decision-making process, and our final treatment strategy.

Single-anastomosis duodenal switch (SADI-S) is effective for weight loss with low reported rates of complications. Bile reflux into the stomach or esophagus is an uncommonly reported complication but can lead to significant symptoms for patients suffering from this complication. Concurrent paraesophageal hernia can exacerbate the symptoms of biliary reflux gastritis. We present a case report describing the management of biliary reflux gastritis with concurrent paraesophageal hernia, our decision-making process, and technical pearls and possible pitfalls.

The interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis. However, the specific microbial and metabolic mediators contributing to non-alcoholic steatohepatitis remain to be identified. Here, a choline-low high-fat and high-sugar diet, representing a typical western diet, named CL-HFS, successfully induces male mouse non-alcoholic steatohepatitis with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Metataxonomic and metabolomic studies identify Blautia producta and 2-oleoylglycerol as clinically relevant bacterial and metabolic mediators contributing to CL-HFS-induced non-alcoholic steatohepatitis. In vivo studies validate that both Blautia producta and 2-oleoylglycerol promote liver inflammation and hepatic fibrosis in normal diet- or CL-HFS-fed mice. Cellular and molecular studies reveal that the GPR119/TAK1/NF-κB/TGF-β1 signaling pathway mediates 2-oleoylglycerol-induced macrophage priming and subsequent hepatic stellate cell activation. These findings advance our understanding of non-alcoholic steatohepatitis pathogenesis and provide targets for developing microbiome/metabolite-based therapeutic strategies against non-alcoholic steatohepatitis.

To our knowledge, this is the first study to investigate the involvement of ADAM17 in causing impaired insulin-induced vasodilation in T2D. We provide evidence that ADAM17 activity is increased in the vasculature of patients with T2D and support the notion that ADAM17-mediated shedding of endothelial IRα ectodomains is a novel mechanism causing vascular insulin resistance. Our results highlight that targeting ADAM17 activity may be a potential therapeutic strategy to correct vascular insulin resistance in T2D.