1752-P: Mechanistic Effects of Intermittent Hypoxia ?(IH) on? ß-Cells, Glucose Homeostasis, and Predisposition to Type 2 Diabetes (T2D)

The capacity of pancreatic β-cells to adapt to insulin resistance or stress conditions is the major determinant of developing Type 2 diabetes (T2D). Obstructive sleep apnea (OSA), a prevalent disorder associated with T2D, causes chronic intermittent hypoxia (IH). The mechanisms through which OSA/chronic IH cause abnormalities in glucose levels and T2DM are not known. Mechanistic responses to hypoxia in other tissues involve alterations in AMPK and mTORC1 signaling, but how these alterations affect tissues responsible for glucose homeostasis, including β-cells, is not known. It was hypothesized that IH leads to alterations in glucose homeostasis by inducing β-cell function via upregulation of mTORC1 signaling in β-cells. To examine the role of IH in glucose homeostasis and β-cell function, we used a system to induce IH in both in vivo and in vitro models. The fractional inspired O2 between 21% and 5% in 30 second intervals (~ 60 episodes/hr), for 12hrs/day for 7, 14, and 28-days in C57B6J mice. IH resulted in improved glucose tolerance and insulin sensitivity. Evidence of hypoxia at the β-cell level was seen by an increase in a common target of hypoxia inducible factor (HIF1), adrenomedullin, and an increase of the Hypoxyprobe marker, pimonidazole. At the mechanistic level, β-cells from IH exposed mice and islets exposed to IH in vitro displayed increase in mTORC1 activation, via activation of its downstream target pS6(240). Taken together, the current evidence showed that IH can induce improvements in glucose tolerance and insulin secretion, and this was associated to augmented mTORC1 signaling. Disclosure T.A. Baker: None. R. Andrade Louzada Neto: None. N.M. Punjabi: None. E. Bernal-Mizrachi: None. Funding R01 DK073716/DK/NIDD

Conformation of the N-Terminal Ectodomain Elicits Different Effects on DUOX Function: A Potential Impact on Congenital Hypothyroidism Caused by a H 2 O 2 Production Defect

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New insights in the molecular regulation of the NADPH oxidase 2 activity: Negative modulation by Poldip2

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NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis

International audienceInterstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-β1/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (H 2 O 2­­ )-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis. Our in vivo data (idiopathic pulmonary fibrosis patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1 +/− and DUOX1 −/− ) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H 2 O 2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation. These findings highlight a role for DUOX1-derived H 2 O 2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis

Raptor levels are critical for β-cell adaptation to a high-fat diet in male mice

The essential role of raptor/mTORC1 signaling in β-cell survival and insulin processing has been recently demonstrated using raptor knock-out models. Our aim was to evaluate the role of mTORC1 function in adaptation of β-cells to insulin resistant state. Here, we use mice with heterozygous deletion of raptor in β-cells (βraHet) to assess whether reduced mTORC1 function is critical for β-cell function in normal conditions or during β-cell adaptation to high-fat diet (HFD). Deletion of a raptor allele in β-cells showed no differences at the metabolic level, islets morphology, or β-cell function in mice fed regular chow. Surprisingly, deletion of only one allele of raptor increases apoptosis without altering proliferation rate and is sufficient to impair insulin secretion when fed a HFD. This is accompanied by reduced levels of critical β-cell genes like Ins1, MafA, Ucn3, Glut2, Glp1r, and specially PDX1 suggesting an improper β-cell adaptation to HFD. This study identifies that raptor levels play a key role in maintaining PDX1 levels and β-cell function during the adaptation of β-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and β-cell function during β-cell adaptation to HFD by reduction of the mTORC1-mediated negative feedback and activation of the AKT/FOXA2/PDX1 axis. We suggest that Raptor levels are critical to maintaining PDX1 levels and β-cell function in conditions of insulin resistance in male mice. •The mTOR signaling pathway is deregulated in human diseases such as cancer and diabetes.•The role of partial mTORC1 reduction in β-cells in normal conditions or during β-cell adaptation to insulin resistance remains unanswered.•Mice with heterozygous deletion of raptor in β-cells develop diabetes and failed to.•To adapt to HFD exhibiting decreased expression of critical β-cell genes such as ins1, mafA, ucn3, glut2 and glp1r.•Raptor levels are critical for maintenance of PDX1 levels and β-cell function.•AKT/FOXA2/PDX1 axis plays a role in β-cell adaptation to HFD

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3,5-Diiodothyronine protects against cardiac ischaemia-reperfusion injury in male rats

What is the central question of this study? 3,5-Diiodothyronine (3,5-T2) administration increases resting metabolic rate, prevents or treats liver steatosis in rodent models, and ameliorates insulin resistance: what are its effects on cardiac electrical and contractile properties and autonomic regulation? What is the main finding and its importance? Chronic 3,5-T2 administration has no adverse effects on cardiac function. Remarkably, 3,5-T2 improves the autonomous control of the rat heart and protects against ischaemia-reperfusion injury. The use of 3,5,3'-triiodothyronine (T3) and thyroxine (T4) to treat metabolic diseases has been hindered by potential adverse effects on liver, lipid metabolism and cardiac electrical properties. It is recognized that 3,5-diiodothyronine (3,5-T2) administration increases resting metabolic rate, prevents or treats liver steatosis in rodent models and ameliorates insulin resistance, suggesting 3,5-T2 as a potential therapeutic tool. However, a comprehensive assessment of cardiac electrical and contractile properties has not been made so far. Three-month-old Wistar rats were daily administered vehicle, 3,5-T2 or 3,5-T2+T4 and no signs of atrial or ventricular arrhythmia were detected in non-anaesthetized rats during 90 days. Cardiac function was preserved as heart rate, left ventricle diameter and shortening fraction in 3,5-T2-treated rats compared to vehicle and 3,5-T2+T4 groups. Power spectral analysis indicated an amelioration of the heart rate variability only in 3,5-T2-treated rats. An increased baroreflex sensitivity at rest was observed in both 3,5-T2-treated groups. Finally, 3,5-T2 Langendorff-perfused hearts presented a significant recovery of left ventricular function and remarkably smaller infarction area after ischaemia-reperfusion injury. In conclusion, chronic 3,5-T2 administration ameliorates tonic cardiac autonomic control and confers cardioprotection against ischaemia-reperfusion injury in healthy male rats