IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

Maternal exposure to high-fat diet during pregnancy and lactation predisposes normal weight offspring mice to develop hepatic inflammation and insulin resistance.

Increasing evidence shows a potential link between the perinatal nutrient environment and metabolic outcome in offspring. Here, we investigated the effects of maternal feeding of a high-fat diet (HFD) during the perinatal period on hepatic metabolism and inflammation in male offspring mice at weaning and in early adulthood. Female C57BL/6 J mice were fed HFD or normal chow (NC) for 4 weeks before mating and during pregnancy and lactation. The male offspring mice were weaned onto an NC diet, and metabolic and molecular experiments were performed in early adulthood. At postnatal day 21, male offspring mice from HFD-fed dams (Off-HFD) showed significant increases in whole body fat mass and fasting levels of glucose, insulin, and cholesterol compared to male offspring mice from NC-fed dams (Off-NC). The RT-qPCR analysis showed two- to fivefold increases in hepatic inflammatory markers (MCP-1, IL-1ß, and F4/80) in Off-HFD mice. Hepatic expression of G6Pase and PEPCK was elevated by fivefold in the Off-HFD mice compared to the Off-NC mice. Hepatic expression of GLUT4, IRS-1, and PDK4, as well as lipid metabolic genes, CD36, SREBP1c, and SCD1 were increased in the Off-HFD mice compared to the Off-NC mice. In contrast, CPT1a mRNA levels were reduced by 60% in the Off-HFD mice. At postnatal day 70, despite comparable body weights to the Off-NC mice, Off-HFD mice developed hepatic inflammation with increased expression of MCP-1, CD68, F4/80, and CD36 compared to the Off-NC mice. Despite normal body weight, Off-HFD mice developed insulin resistance with defects in hepatic insulin action and insulin-stimulated glucose uptake in skeletal muscle and brown fat, and these metabolic effects were associated with hepatic inflammation in Off-HFD mice. Our findings indicate hidden, lasting effects of maternal exposure to HFD during pregnancy and lactation on metabolic homeostasis of normal weight offspring mice.

Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study.

BACKGROUND: Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CPRD) database. METHODS: Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2016 (n = 26 806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, gender and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least 1 year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPI prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS: Among cases, 2960 were PFU, 6607 PLU and 17 239 PNU. Among controls, 1091 were PFU, 5058 PLU and 20 657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32-3.91]) and 1.51 (95% CI, [1.44-1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS: Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription.

IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.

Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (MIL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, MIL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (∼60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging MIL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.-Dagdeviren, S., Jung, D. Y., Friedline, R. H., Noh, H. L., Kim, J. H., Patel, P. R., Tsitsilianos, N., Inashima, K., Tran, D. A., Hu, X., Loubato, M. M., Craige, S. M., Kwon, J. Y., Lee, K. W., Kim, J. K. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.

Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (MIL10). After 16 weeks of a high-fat diet (HFD), MIL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10ob/ob) did not affect spontaneous obesity, but MCK-IL10ob/ob mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R-/-) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R-/- mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.

Should patients prescribed long-term low-dose aspirin receive proton pump inhibitors? A systematic review and meta-analysis.

BACKGROUND: Several clinical guidelines recommend the use of proton pump inhibitors (PPIs) in patients taking low-dose aspirin but report no or limited supporting data. We conducted a systematic review and meta-analysis to examine the effects of co-administration of PPIs in patients taking low-dose aspirin on the risks of adverse gastrointestinal (GI) and cardiovascular (CV) events, and on patient adherence to aspirin. METHODS: We searched PUBMED, EMBASE and Cochrane Central Register of Controlled Trials databases for relevant articles published through November 2013. We included randomised controlled trials (RCTs) and observational studies in patients taking low-dose aspirin with and without PPIs. Risk of bias was assessed using the Cochrane Collaboration's tool (for RCTs) and the Newcastle-Ottawa Scale (for observational studies). Pooled risk ratios (RRs) were computed using a random-effects model. RESULTS: We included 13 studies, of which 12 (2 RCTs and 10 observational studies) reported on GI events, and one (cohort study) on both GI bleeding and CV events. No study reported on adherence to aspirin. Co-administration of PPIs in patients receiving low-dose aspirin was associated with risk reductions of 73% (RR 0.27, 95% CI 0.17-0.42) and 50% (RR 0.50, 95% CI 0.32-0.80) in the occurrence of peptic ulcer and GI bleeding respectively. There was evidence of bias in publications reporting on the GI events. CONCLUSIONS: The practice of co-prescribing PPIs in patients taking low-dose aspirin is supported by some data, but the evidence is rather weak. It currently remains unclear whether the benefits of co-administration of PPIs in users of low-dose aspirin outweigh their potential harms.

Health and Utilities in Patients With Gout Under the Care of a Rheumatologist.

OBJECTIVE: To compare limitations in health between Dutch patients with gout and the general population and to determine factors influencing societal and patient values for health as assessed with different utility approaches. METHODS: A cross-sectional study was done among 110 patients with gout under the care of a rheumatologist, with patients completing the EuroQol 5-domain instrument (EQ-5D), the EQ-5D visual analog scale (EQ-5D VAS), and the Short Form 6-dimensions health survey (SF-6D). Scores on EQ-5D domains were compared with age- and sex-matched general population data. Agreement between utility measures was assessed using the intraclass correlation coefficient (ICC). Mixture modeling was used to assess factors associated with the different approaches to assess utility. RESULTS: Compared to the general population, gout patients reported more limitations in mobility (66% versus 12%), self-care (24% versus 8%), daily activities (49% versus 24%), and pain (76% versus 45%), but equal anxiety/depressive symptoms (18% versus 19%). For patients with gout, utilities were reduced: the mean, median, and interquartile range, respectively, were 0.74, 0.81, and 0.69-0.84 for EQ-5D, 0.69, 0.67, and 0.59-0.81 for SF-6D, and 66, 70, and 57-77 for EQ-5D VAS. ICC agreement between each pair of utilities was only moderate (0.52-0.59). Only minor differences were seen in the type of variables associated with each utility approach, with worse Health Assessment Questionnaire scores, cardiovascular disease (CVD), gout concern, and gout pain consistently associated with lower utility. The strength of contribution of these variables, however, differed among the 3 approaches. CONCLUSION: Patients with gout experience substantially impaired health compared to the general population. Although absolute values of utility varied between instruments and perspectives, functional disability, CVD, and higher gout impact contributed to utility independently of which instrument was used.

How to select the right cost-effectiveness model? : A systematic review and stepwise approach for selecting a transferable health economic evaluation model for rheumatoid arthritis.

OBJECTIVE: In the current study, we propose an approach for selection of a model that is transferable to a specific decision-making context (in this case, the Netherlands), using the case of rheumatoid arthritis (RA). The objectives of this study were (a) to perform a systematic literature review to identify existing health economic evaluation models for economic evaluation of disease-modifying antirheumatic drugs (DMARDs) in RA; and (b) to test the appropriateness of a stepwise model-selection process. METHODS: First, we searched Medline and Embase to identify relevant studies in the English language, published between 1 January 2002 and 31 August 2012. From the included studies, all unique models were identified. Second, we applied a multi-step approach to model selection. Models that did not meet all minimal methodological and structural requirements based on the Outcome Measures in Rheumatology (OMERACT) criteria were excluded. Next, models were assessed on the basis of their fit when transferred to the Dutch health care setting. The criteria for model fit were transferability factors, as published by Welte et al., after exclusion of those that were deemed transferable by simple adaptation. Finally, the remaining models underwent a general quality check using the Philips checklist. Models showing good fit and high quality were considered to be transferable to the Dutch health care setting, using simple adaptation. RESULTS: The systematic literature search identified 498 articles, which included 33 unique health economic evaluation models. Only six models passed the minimal methodological and structural requirements. Two of these models had an imperfect transferability fit to the Dutch health care setting, according to the Welte method. The remaining four models were, according to the Philips method, of good quality and were expected to be transferable by a simple adaptation. CONCLUSION: This study introduces a stepwise approach for selecting health economic evaluation models that are transferable by a simple adaptation. The approach seems feasible and can be applied in various therapeutic areas, provided that the minimal methodological and structural requirements are defined accordingly. Availability of health economic evaluation models coupled with structured model selection could improve the efficiency, quality and comparability of health economic research.