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Hepatic insulin resistance is an important pathophysiology in type 2 diabetes, and the mechanisms by which high-caloric diets induce insulin resistance are unclear. Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein called Thioredoxin-Interacting Protein (TXNIP) to bind covalently to thioredoxin, allowing TXNIP to "sense" oxidative stress(1). Here, we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high-fat diet (HFD). Mice with an exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivity compared to wild-type (WT) controls following an 8-week HFD. HFD-fed TXNIP C247S mouse livers also showed improved insulin signaling. The Transmembrane 7 superfamily member 2 (Tm7sf2) gene encodes for a sterol reductase involved in the process of cholesterol biosynthesis (2). We identified TM7SF2 as a potential mediator of enhanced insulin signaling in HFD-fed TXNIP C247S mouse livers. TM7SF2 increased Akt phosphorylation and suppressed gluconeogenic markers PCK1 and G6Pc specifically under oxidative-stress-induced conditions in HepG2 cells. We also present data suggesting that a heterozygous variant of TXNIP C247 is well-tolerated in humans. Thus, mammals have a single redox-sensitive amino acid in TXNIP that mediates insulin resistance in the setting of a HFD. Our results reveal an evolutionarily conserved mechanism for hepatic insulin resistance in obesity. Hepatic insulin resistance is an important pathophysiology in type 2 diabetes, and the mechanisms by which high-caloric diets induce insulin resistance are unclear. Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein called Thioredoxin-Interacting Protein (TXNIP) to bind covalently to thioredoxin, allowing TXNIP to "sense" oxidative stress. Here, we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high-fat diet (HFD). Mice with an exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivity compared with WT controls following an 8-week HFD. HFD-fed TXNIP C247S mouse livers also showed improved insulin signaling. The Transmembrane 7 Superfamily Member 2 (Tm7sf2) gene encodes for a sterol reductase involved in the process of cholesterol biosynthesis. We identified TM7SF2 as a potential mediator of enhanced insulin signaling in HFD-fed TXNIP C247S mouse livers. TM7SF2 increased Akt phosphorylation and suppressed gluconeogenic markers PCK1 and G6Pc specifically under oxidative stress-induced conditions in HepG2 cells. We also present data suggesting that a heterozygous variant of TXNIP C247 is well tolerated in humans. Thus, mammals have a single redox-sensitive amino acid in TXNIP that mediates insulin resistance in the setting of an HFD. Our results reveal an evolutionarily conserved mechanism for hepatic insulin resistance in obesity.
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
