Aspects of hormonal regulation of hepatic carbohydrate and lipid metabolism

The liver is a major site in the rat for conversion of dietary carbohydrateinto glycogen and triglyceride. Hepatic rates of fatty acid andglycogen synthesis were measured y vivo in response to meal-feeding(2h/day) by the incorporation of from 3H20. This technique has notbeen applied previously to glycogen synthesis and was validated in controland streptozotocin diabetic rats* Hepatic glycogen recycling was low infed adult rats but was apparently greater in foetal rats. The precursorsource for glycogen synthesis in vivo could not be determined from thedistribution pattern of 3H incorporation. Hepatic glycogen synthesis waselevated in control rats for 5h after feeding. During this phase,glycogen could not have been a net precursor for other synthetic pathways®Hepatic fatty acid synthesis in control rats increased 20-fold 2h afterfeeding. This response was impaired and delayed, but not abolished, bystreptozotocin diabetes (55mg/kg). Insulin pretreatment (30 P.Z.I.)restored the low diabetic rate of lipogenesis to normal by 8h afterfeeding. Streptozotocin reduced the hepatic Vmax activities of glucokinase,ATP-citrate lyase and total acetyl CoA carboxylase. None of theseenzyme activities increased when hepatic fatty acid synthesis was stimulatedby feeding in control rats or by feeding and insulin in diabeticrats. Feeding stimulated active acetyl CoA carboxylase in control, butnot diabetic, rats. The regulation of hepatic fatty acid synthesis byboth acetyl CoA carboxylase and increased substrate concentration isdiscussed.In control rats for the first 5h after feeding, hepatic glycogen couldnot have been a net fatty acid precursor. Thus the inhibition of hepaticfatty acid synthesis in this period by glucagon (Img/kg) could not havebeen directly due to depletion of glycogen® The glucagon inhibition oflipogenesis was abolished by adrenalectomy but not potentiated bycorticotropin-treatment, suggesting a permissive role for glucocorticoidhormones. Adrenalectomy also impaired the inhibition of hepatic pyruvatekinase by glucagon but did not abolish the inactivation of pyruvatekinase by 10 )jM-cyclic AMP in vitro« The involvement of L-type pyruvatekinase in the regulation of hepatic fatty acid synthesis is discussed.The integrated regulation of the hepatic pathways of lipogenesis,glycolysis, gluconeogenesis and ketogenesis is considered

Biomarker predictors of clinical efficacy of the anti-IgE biologic, omalizumab, in severe asthma in adults: results of the SoMOSA study

Background: the anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. Methods: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting β-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Results: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-β-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions: this is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study

The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment.1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting β-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment.191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-β-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. Background Methods Results</p

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study

The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment.1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting β-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment.191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-β-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. Background Methods Results</p