CARBOHYDRATE METABOLIC DISTURBANCES IN HYPERTHYROIDISM.
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ABSTRACT:
SUBMITTER: Saini JS
PROVIDER: S-EPMC5530406 | biostudies-other | 1996 Jul
REPOSITORIES: biostudies-other
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Project description:Aim. Hyperthyroidism reduces the oxidative capacity of skeletal muscle (SKM) and promotes development of a glycolytic phenotype by altering the expression of metabolic proteins. Our previous results showed that smoothelin-like protein 1 (SMTNL1), a transcriptional coregulator, promotes insulin sensitivity in SKM. Our aim was to elucidate the role of SMTNL1 in SKM under physiological and pathological 3,3′,5-Triiodo-L-thyronine (T3) concentrations. Methods. Human hyper- and euthyroid SKM biopsies were used for microarray analysis and phospho-kinase arrays. Physiological and hyperthyroid concentrations of T3 were applied on differentiated C2C12 cells upon SMTNL1 overexpression to assess the activity and expression level of the element of insulin signaling. Real-time metabolic measurements of oxygen consumption rate and extracellular acidification rate were measured. Results. Expression of genes related to energy production, nucleic acid- and lipid metabolism were changed significantly in hyperthyroid samples. SMTNL1 expression decreased in the hyperthyroid samples and in T3 treated C2C12 cells. SMTNL1 regulated muscle cell differentiation and compensated for the glycolytic shift in SKM triggered by pathological T3 exposure. Moreover, it selectively regulated TR expression at the transcriptional level. T3 excess triggered the development of insulin resistance while overexpression of SMTNL1 induced insulin sensitivity through the inhibition of JNK activity and hampered the non-genomic effects of T3 by decreasing the activity of ERK1/2 through PKC. SMTNL1 overexpression induced GLUT4 expression in hyperthyroid model to restore the normal responsiveness of glucose transport to insulin. SMTNL1 regulated glucose phosphorylation and balances glycolysis and glycogen synthesis via the downregulation of hexokinase II. T3 overload strongly increased the rate of lactate production, while SMTNL1 overexpression antagonizes the T3 effects. Conclusion. These lines of evidence suggest that SMTNL1 potentially prevents hyperthyroidism-induced changes in SKM and it holds great promise as a novel therapeutic target. Smoothelin-like Protein 1 in Hyperthyroidism
2021-10-27 | GSE178996 | GEO
Project description:The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.
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Project description:ObjectiveBrown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status.DesignParticipants with newly diagnosed Graves' disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity.ResultsTwenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean (r = 0.58, P = 0.01) and resting metabolic rate (RMR) (P < 0.01).ConclusionHyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.
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Project description:Metabolic disturbances are among the most common disorders diagnosed in pediatric patients after anti-cancer therapy (ACT). The aim of our study was to evaluate the prevalence of metabolic disturbances among patients after ACT. The study group comprised 44 patients (31 boys) treated for solid tumors and 31 patients in the control group. Body weight, height, body mass index (BMI) values, lipid parameters are expressed in Standard Deviation Score (SDS), based on centile charts. Indicators of risk to atherosclerosis were calculated. Obesity/overweight was observed in one third of the patients. Hypercholesterolemia occurred in half of them, elevated tryglicerides (TG) SDS in 11, and elevated low-density lipoprotein cholesterol (LDL-C) SDS in nine of the patients. Increased levels of both cholesterol SDS and LDL SDS were found in nine patients and four of them also showed elevated levels of TG SDS. There were significant differences in lipid parameters between the sexes. Risk indicators of lipid disorders defined by statistical distances (τ) were determined for the study group and the control group. The sum of the risk ratios of lipid disorders in the study group was 150 times higher than in the control group. Patients after ACT require special monitoring of lipids profiles and thyroid function as they are at higher risk for dyslipidemia and atherosclerosis than healthy people.
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Project description:ObjectiveEndogenous subclinical hyperthyroidism (eSCH) is defined by subnormal serum thyroid-stimulating hormone (TSH) level. There is limited evidence of metabolic changes induced by eSCH. The aim of our work was to evaluate changes in BMI and lipid parameters after radioiodine treatment in patients with grade 1 (TSH: 0.1-0.39 mlU/L) and 2 (TSH <0.1 mlU/L) eSCH.DesignA retrospective study was performed on 74 patients with eSCH caused by benign autonomous nodular goiter which was treated with radioiodine.MethodsWe assessed BMI, lipids parameters, and TSH after radioiodine therapy. The 12-month follow-up time point was used to compare the primary outcome variables. TSH was measured by the electrochemiluminescence method.ResultsAfter radioiodine therapy, the absolute and relative increases in BMI at 12 months were significantly higher in the grade 2 group than in the grade 1 group (1.07 ± 0.27 kg/m2 vs. 0.26 ± 0.15 kg/m2, respectively; p = 0.023 and 4.01 ± 0.98% vs. 1.01 ± 0.56%, respectively; p = 0.026). Compared to baseline, significant increases in the levels of total cholesterol and LDL were observed after treatment in the grade 2 eSCH group (16.7 ± 4.5 mg/dL p < 0.01 and 14.3 ± 4.1 mg/dL p < 0.01, respectively) but not in the grade 1 group. In a multivariate model, a negative correlation was observed between pretreatment TSH levels and absolute BMI gain (p < 0.01).ConclusionsAfter correction of eSCH, increases in BMI and LDL levels were observed only in patients with grade 2 eSCH. Pretreatment serum TSH was the main independent factor associated with BMI changes after radioiodine treatment.
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Project description:Lignin biosynthesis begins with the deamination of phenylalanine and tyrosine (Tyr) as a key branch point between primary and secondary metabolism in land plants. Here, we used a systems biology approach to investigate the global metabolic responses to lignin pathway perturbations in the model grass Brachypodium distachyon. We identified the lignin biosynthetic protein families and found that ammonia-lyases (ALs) are among the most abundant proteins in lignifying tissues in grasses. Integrated metabolomic and proteomic data support a link between lignin biosynthesis and primary metabolism mediated by the ammonia released from ALs that is recycled for the synthesis of amino acids via glutamine. RNA interference knockdown of lignin genes confirmed that the route of the canonical pathway using shikimate ester intermediates is not essential for lignin formation in Brachypodium, and there is an alternative pathway from Tyr via sinapic acid for the synthesis of syringyl lignin involving yet uncharacterized enzymatic steps. Our findings support a model in which plant ALs play a central role in coordinating the allocation of carbon for lignin synthesis and the nitrogen available for plant growth. Collectively, these data also emphasize the value of integrative multiomic analyses to advance our understanding of plant metabolism.
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Project description:The purpose of this study was to determine the effects of glucocorticoid-induced metabolic dysfunction in the presence of diet-induced obesity. C57BL/6J adult male lean and diet-induced obese mice were given dexamethasone, and levels of hepatic steatosis, insulin resistance, and lipolysis were determined. Obese mice given dexamethasone had significant, synergistic effects on fasting glucose, insulin resistance, and markers of lipolysis, as well as hepatic steatosis. This was associated with synergistic transactivation of the lipolytic enzyme adipose triglyceride lipase. The combination of chronically elevated glucocorticoids and obesity leads to exacerbations in metabolic dysfunction. Our findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in individuals with obesity.
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Project description:1. Liver from hyper- and hypo-thyroid male fed rats were perfused with whole blood and their metabolism was compared with euthyroid controls. 2. Hyperthyroid livers produced more bile than controls and hypothyroid livers produced less. 3. Glucose output by all livers was similar; glycogen declined only during perfusion of hyperthyroid livers. Lactate uptake increased in hyperthyroid but decreased in hypothyroid livers. These results may be explained by changes in oxidation of carbohydrate rather than in gluconeogenesis. 4. Secretion of triacylglycerol was decreased in hyperthyroid and not changed significantly in hypothyroid livers. 5. Fractional extraction of infused [1-14C]oleate was unaltered. Hyperthyroid livers oxidized more oleate to CO2 and ketone bodies, esterified less and incorporated less into lipoproteins of d less than 1.006. Hypothyroid livers oxidized and esterified oleate to the same extent as controls; their decreased O2 consumption was due to diminished oxidation of other (non-lipid) substrates; 14C-labelled ketone-body formation was increased, but at the expense of 14CO2 production. 6. Lipogenesis (measured with 3H2O) was unaltered in hyperthyroid but was decreased in hypothyroid livers. Incorporation of 3H and 14C into triacylglycerol relative to phospholipid decreased in hyperthyroid and increased in hypothyroid livers. Cholesterol synthesis was similar in all perfusions. 7. During oleate infusion, the cytosolic redox state, as indicated by the perfusate [lactate]/[pyruvate] ratio, was decreased in hyperthyroid and increased in hypothyroid livers. No change in [3-hydroxybutyrate]/[acetoacetate] was detected. 8. The importance of relating the concentration of plasma non-esterified fatty acids to the interpretation of metabolic data obtained under differing thyroid status is emphasized.
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Project description:Hyperthyroidism triggers a glycolytic shift in skeletal muscle (SKM) by altering the expression of metabolic proteins, which is often accompanied by peripheral insulin resistance. Our previous results show that smoothelin-like protein 1 (SMTNL1), a transcriptional co-regulator, promotes insulin sensitivity in SKM. Our aim was to elucidate the role of SMTNL1 in SKM under physiological and pathological 3,3',5-Triiodo-L-thyronine (T3) concentrations. Human hyper- and euthyroid SKM biopsies were used for microarray analysis and proteome profiler arrays. Expression of genes related to energy production, nucleic acid- and lipid metabolism was changed significantly in hyperthyroid samples. The phosphorylation levels and activity of AMPKα2 and JNK were increased by 15% and 23%, respectively, in the hyperthyroid samples compared to control. Moreover, SMTNL1 expression showed a 6-fold decrease in the hyperthyroid samples and in T3-treated C2C12 cells. Physiological and supraphysiological concentrations of T3 were applied on differentiated C2C12 cells upon SMTNL1 overexpression to assess the activity and expression level of the elements of thyroid hormone signaling, insulin signaling and glucose metabolism. Our results demonstrate that SMTNL1 selectively regulated TRα expression. Overexpression of SMTNL1 induced insulin sensitivity through the inhibition of JNK activity by 40% and hampered the non-genomic effects of T3 by decreasing the activity of ERK1/2 through PKCδ. SMTNL1 overexpression reduced IRS1 Ser307 and Ser612 phosphorylation by 52% and 53%, respectively, in hyperthyroid model to restore the normal responsiveness of glucose transport to insulin. SMTNL1 regulated glucose phosphorylation and balances glycolysis and glycogen synthesis via the downregulation of hexokinase II by 1.3-fold. Additionally, mitochondrial respiration and glycolysis were measured by SeaHorse analysis to determine cellular metabolic function/phenotype of our model system in real-time. T3 overload strongly increased the rate of acidification and a shift to glycolysis, while SMTNL1 overexpression antagonizes the T3 effects. These lines of evidence suggest that SMTNL1 potentially prevents hyperthyroidism-induced changes in SKM, and it holds great promise as a novel therapeutic target in insulin resistance.
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Project description:BackgroundPositive psychosocial factors can play an important role in the development of cardiovascular disease (CVD). Among them, psychological resilience (PR) is defined as the capacity of responding positively to stressful events. Our aim was to assess whether PR is associated with CVD or metabolic disturbances through a systematic review.MethodsWe gathered articles from PubMed, Web of Science, PsycInfo, and Google Scholar up to October 28, 2021. We included articles that were in English, were observational, and had PR examined as exposure. The CVD outcomes were either clinical or metabolic outcomes (i.e., dyslipidemia, obesity, metabolic syndrome, hypertension, and diabetes).ResultsOur literature search identified 3,800 studies, of which 17 met the inclusion criteria. Of them, seven were longitudinal and 10 cross-sectional, and 13 were on adults and four on children. The exposure assessment was heterogeneous, i.e., 12 studies used different kinds of self-administered questionnaires and five used interviews with a psychologist. Regarding outcomes, five studies investigated CVD, seven obesity, one metabolic syndrome, two hypertension, four dyslipidemia, and four diabetes. In longitudinal studies, PR was found to have an inverse association with included outcomes in five studies from the Swedish military conscription cohort but had no association with CVD in a study on African-American women and was associated with slower progression of diabetes in a general population. The cross-sectional studies showed that the prevalence of disease was not associated with PR in many cases but the progression of disease was associated with PR.ConclusionPR seems to have a possibly favorable association with CVD and metabolic disturbances that differs according to the type of outcome and population. Our study limitations are given by the small number of studies available and the heterogeneity in PR measurement.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=237109], identifier [CRD42021237109].
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