A Potential New Treatment Option for Asthma in the Setting of Obesity or Insulin Resistance?
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ABSTRACT:
SUBMITTER: Forno E
PROVIDER: S-EPMC8017569 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Insulin resistance potentiates the association between obesity and childhood asthma, but this relationship appears inconsistent in relatively small studies of adults. We investigated effect modification in adults using the National Health and Nutrition Examination Survey 2003-2012, a large, nationally representative database.Insulin resistance and a history of physician-diagnosed current asthma were obtained from 12?421 adults, ages 18-85?years. We used logistic regression to determine associations between obesity and current asthma, adjusting for age, sex, race/ethnicity, poverty income ratio and smoking status. An interaction term evaluated effect modification by insulin resistance of the obesity-asthma association.As expected, obesity was positively associated with current asthma. Insulin resistance modified this association, with obesity measured as body mass index, waist circumference or waist-to-height ratio. The relationship between obesity and current asthma was stronger with increasing insulin resistance tertiles (OR 2.05, 95% CI 2.76-3.00; p-value for interaction 0.03). This association was robust to adjustments for other components of the metabolic syndrome (hypertriglyceridaemia, hypertension, hyperglycaemia and systemic inflammation). None of these components were themselves effect modifiers of the obesity-asthma association.In this large, nationally representative sample, insulin resistance modified the association between obesity and current asthma in adults. Targeting insulin resistance may represent a novel therapeutic strategy for obese patients with asthma.
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Project description:Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk-benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future.
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Project description:Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.
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Project description:Obesity is a critical health concern, and identifying new biomarkers has become essential for better understanding the progression to disease such as type 2 diabetes. DNA methylation has become a useful epigenetic biomarker in part due to its susceptibility to disease influence. Detecting methylation changes in blood is important as it is an easily accessible, compared to the insulin responsive tissue skeletal muscle. The aim of our study was to identify methylation changes in whole blood that were strongly associated with obesity associated insulin resistance. Whole blood was obtained from lean (n=10; BMI= 23.6±0.7 kg/m2) and obese (n=10; BMI= 34.4±1.3 kg/m2) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed the next generation technique, reduced representation bisulfite sequencing (RRBS) on isolated genomic DNA. There were 49 significantly altered differentially methylated cytosines (DMCs; q<0.05). Of these, solute carrier family 19 member 1 (SLC19A1) was also identified using a differentially methylated region approach. The sites for this gene were significantly correlated (P<0.05) with body mass index, body fat percent, and the clamp Rd. Moreover, the decrease in SLC19A1 methylation was similar to the change previously found in skeletal muscle. Pyrosequencing confirmed the changes in methylation at Chr.21:46,957,915 in both tissues. These results demonstrate that the methylation status of SLC19A1 provides a new potential epigenetic biomarker for obesity related insulin resistance.
2016-10-01 | GSE85928 | GEO
Project description:Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m2) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m2) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q < 0.05) that were altered in obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5' untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915-46,958,001 in SLC19A1 of -34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0.10 vs. obese 0.18 ± 0.06) and skeletal muscle (lean 0.71 ± 0.10 vs. obese 0.30 ± 0.11). Our findings demonstrate a new potential epigenetic biomarker, SLC19A1, for obesity and its underlying insulin resistance.
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Project description:Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2. We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2.
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Project description:There is mounting evidence that obesity is associated with asthma, both of which are seeing a dramatic increase in prevalence. Not only is obesity a risk factor for the development of asthma but it is also associated with poor asthma control. Asthma phenotypes associated with obesity include early-onset allergic asthma and late-onset non-allergic asthma. The pathogenesis of the linkage is complex; obesity causes a variety of mechanical, metabolic, and immunological changes that can affect the airways. The treatment of asthma in obesity can be challenging, as obesity is associated with poor response to standard controller medications. A tailored approach that involves combining pharmacologic and non-pharmacologic therapies including weight loss, dietary interventions, and exercise, along with identification and treatment of obstructive sleep apnea, should therefore be considered in this population.
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