Introduction and Objective: Glucagon promotes hepatic glucose production (HGP) to maintain glucose homeostasis, whereas augmented glucagon action on HGP resulting in hyperglycemia in obesity and type 2 diabetes (T2D). However, the underlying mechanisms of enhanced glucagon action in obesity and T2D are not fully understood. Here we explored the role of carboxy-terminus of Hsc70-interacting protein (CHIP)-regulated Smad3 stability in augmenting glucagon action on HGP in obesity. Methods: In vivo, male mice were subjected to 3 months of high-fat diet (HFD) feeding to induce obesity. To knockdown or overexpress genes in the liver of obese mice, mice injected (retro-orbitally, RO) with adeno-associated virus serotype 8 expressing short hairpin RNAs or target genes, then maintained on HFD feeding for another month. Blood glucose, glucagon tolerance test, and pyruvate tolerance test were performed. In vitro, primary hepatocytes were isolated from mice and treated with transforming growth factor beta 1 (TGF-β1) or glucagon. Small interfering RNAs were used to knockdown genes in primary hepatocytes. HGP and western blot analysis were performed. Results: We found that ablation of hepatic TGF-β1 signaling attenuated glucagon action on HGP in obesity. Glucagon and TGF-β1 synergistically promoted HGP in a Smad3 dependent manner. Glucagon promoted Smad3 protein level, which upregulated the expression of gluconeogenic gene G6pc in a Foxo1-dependent manner. Furthermore, glucagon promoted Smad3 expression via CHIP-mediated ubiquitination. Moreover, CHIP levels decreased in the livers of HFD-induced obese (DIO) mice. Hepatic CHIP knockdown augmented glucagon action on HGP in DIO mice, such effect was abolished by hepatic Smad3 knockdown. Conclusion: These results demonstrated that CHIP-regulated Smad3 stability plays a key role in augmenting glucagon action on HGP in obesity. Targeting CHIP-regulated Smad3 stability is a potential therapeutic strategy to attenuate glucagon stimulated HGP for glycemic control in T2D. Q. Pan: None. S. Guo: None. American Diabetes Association (1-15-CD-09); National Institutes of Health (R01DK124588)
Epistemic Structural Realism (ESR), the view that structure is all we can know about the unobservable world, has been criticized for lacking sufficient metaphysical depth to qualify as a genuine form of realism. This paper defends a refined version of ESR – which I call agnostic ESR – that avoids these objections by committing to knowledge of detectable, concrete structures while maintaining agnosticism about the existence of objects with intrinsic properties. I respond to prominent criticisms, including Newman’s objection, concerns about ESR’s metaphysical clarity, and potential collapse into other views, by showing that agnostic ESR can provide a rigorous account of structural knowledge grounded in empirical science that cannot be defended by advocates of other realist positions. I argue that agnostic ESR is metaphysically robust to deserve the realist label.
Hole pattern seals (HPS) reduce leakage and suppress rotordynamic instability in high performance compressors. Bulk flow modeling of HPS to obtain stiffness, mass, and damping coefficients for the HPS requires a friction factor model. This is typically obtained experimentally in a flat plate tester with flow between a smooth and a roughened flat plate. This paper presents an alternative approach of training an Artificial Neural Network (ANN) in conjunction with Computational Fluid Dynamics (CFD) modeling to predict friction factors and leakage in a round hole pattern seal. CFD is used to predict friction factors for a large number of round hole pattern flat plate tester configurations. The CFD results are validated by comparison with experimental results for gas and liquid flat plat HPS cases. An ANN is trained using this large dataset of CFD friction factor results. The ANN predicted friction factors are shown to accurately predict friction factors as compared with CFD models. These friction factor predictions are then utilized to obtain the Hirs and Moody friction factor coefficients, and subsequently the seal dynamic coefficients.
Introduction and Objective: Arginine (ARG) is an important amino acid in T2D as a potent insulin secretagogue and precursor for nitric oxide (NO). Citrulline (CIT), the substrate for de novo ARG synthesis, is mostly produced from glutamine (GLN). Here, we aimed to investigate their metabolism in T2D using a novel stable isotope tracer approach. Methods: We studied 42 individuals (21 with T2D, 21 controls). After an overnight fast, we collected blood samples following pulse administration of ARG, CIT, and GLN stable amino acid tracers. Plasma concentrations and isotopic enrichments were measured by LC-MS/MS and lean soft tissue (LST) by DXA. Compartmental analysis was performed to calculate their WBP. Data are mean (SD) or [95% CI] (t-test and ANCOVA by JASP). Results: The cohort was 60% female, mean age 64.4 (7.5) years, and BMI 33.0 (4.3) kg/m2 (all p>0.05). After adjusting for sex and age, T2D group had lower plasma concentrations of ARG (57.7 [48.9, 66.4] vs. 75.8 [66.9, 84.5] µM, p=0.005), CIT (23.4 [18.9, 27.9] vs. 34.4 [29.9, 38.9] µM, p=0.001), and GLN (463.5 [421.1, 506] vs. 561.7 [519, 604.3] µM, p=0.002). In T2D, WBP was lower for CIT (11.8 [10.1, 13.6] vs. 15.5 [13.8, 17.2] µmol/min, p=0.004) but higher for GLN (537 [503, 571] vs. 481.9 [448.3, 515.5] µmol/min, p=0.004) after controlling for age, sex and LST. T2D group also had lower CIT intracellular production (p=0.003), but higher GLN clearance (p=0.001) and intracellular pool size (p=0.007), and a trend towards higher ARG clearance (p=0.06). Conclusion: In T2D, significant dysregulation exists in ARG, CIT and GLN metabolism. We hypothesize that increased muscle GLN synthesis stimulates gluconeogenesis, increases GLN consumption, and contributes to T2D pathogenesis via blunted insulin secretion, sensitivity and incretin response by having less GLN available for CIT production that may affect ARG (and NO) metabolism. Interventions aiming to reduce GLN production but increase CIT availability may be useful in T2D. M. Tosur: None. R. Wierzchowska-McNew: None. M.P. Engelen: None. N.E. Deutz: None. National Institutes of Health (K23-DK129821)(MT)
Insulin resistance (IR) means the failure of cells to respond normally to insulin, commonly associated with obesity and causing various metabolic dysregulations in type 2 diabetes. As a mediator of innate immunity, stimulator of interferon genes (STING) in human subjects is positively correlated with excessive fat deposition and liver inflammation, which both trigger hepatic and systemic IR. Also, STING expression is increased in insulin-responsive tissues in mice fed a high-fat diet (HFD) for 3 months, coupled with the decreased sensitivity of systemic insulin signaling. However, it is unknown about the effect of STING on IR in mice upon prolonged HFD feeding, which reflects the long-term course of human obesity. In this study, wild-type (WT) and STING-disrupted (STgt) male mice were fed an HFD for 3 months and examined for obesity and IR. Some HFD-fed mice were examined for hepatic insulin signaling upon a bolus injection of insulin into the portal vein. Additional STgt and WT mice were fed an HFD for 7 months and examined for obesity and systemic insulin sensitivity. Compared to male 3-m-HFD-WT mice, male 3-m-HFD-STgt mice gained smaller body weights and decreased levels of hepatic steatosis and inflammation, along with increased response to insulin. Consistently, insulin-stimulated Akt phosphorylation in the liver, adipose tissue, and skeletal muscle from male 3-m-HFD-STgt mice were much greater than those in the respective tissues from male 3-m-HFD-WT mice. However, upon prolonged HFD feeding, STgt mice displayed notably increased severity of obesity, hepatic steatosis and inflammation, all of which cause hepatic and systemic IR, relative to WT or STgt mice upon 3-month HFD feeding. These results indicate HFD feeding for 7 months abolishes the protective effect of STING deletion on obesity-associated hepatic steatosis/inflammation, and IR. As such, diets approach is key in managing obesity-induced metabolic diseases. Disclosure X. Guo: None. H. Li: None. C. Wu: None. Funding National Institutes of Health (DK124854)
