The endoplasmic reticulum (ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response (UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases (PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress.

Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake.DOI: http://dx.doi.org/10.7554/eLife.18313.001

Summary Background Limited studies associate changes in microbiota composition and metabolites among children and adolescents with obesity. Decreases in compositional diversity, increases in the proportion of Firmicutes and Bacteroidetes (F/B ratio) and increases in short‐chain fatty acids (SCFAs) have been proposed as contributing factors in the pathophysiology of obesity. Objectives The aim of the current study was to characterize the faecal microbiota composition, diversity, F/B ratio and SCFA levels in different weight categories (lean, overweight, obesity classes 1‐3) of children ages 5 to 12 years. Methods We collected and processed 83 samples from different weight categories (27.7% lean, 11% overweight, 15%, 17% and 17% of obesity classes 1, 2, and 3, respectively). Microbiota content was determined by sequencing the V4 region of the 16S rRNA gene, and SCFA content was analyzed. Results Microbiota compositions showed no significant differences in diversity or F/B ratios between weight categories. However, a relative abundance of Proteobacteria and lack of Verrucomicrobia were demonstrated when comparing severe obesity to the leaner groups. Faecal butyrate, propionate and isopentanoate concentrations increased progressively with weight category demonstrating significance in the class 3 obesity group. Conclusions Our results show that severe childhood obesity in our study population was associated with changes in gut microbiome composition correlated to previously reported cardiometabolic disease states in obesity. Increased SCFA levels correlate with obesity‐related microbiome metabolic function without a reduction in diversity characterized at a phyla level. Further characterization of these specimens at a species level and longitudinal studies are needed to elucidate these relationships.

The vast majority of patients with type 2 diabetes continue metformin after insulin initiation, consistent with guidelines. Other antihyperglycemics are frequently continued along with insulin, and further research is needed to determine which, if any, patients may benefit from this.

Immunosuppressive therapy is well recognized as increasing the risk of lymphoma. Mycosis fungoides is a rare cutaneous form of T-cell lymphoma with a largely unknown etiology and not typically associated with immunosuppression. In this article, we describe our encounter with a 24-year-old male with Crohn’s disease in remission on immunotherapy, specifically dual therapy with azathioprine and infliximab, presenting with a facial rash found to be consistent with mycosis fungoides on biopsy. The patient’s rash resolved with treatment of topical steroids. In addition, the decision was made to discontinue his azathioprine to minimize his risks of developing future malignancies.

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