[Effect of glucocorticoids on potassium and sodium metabolism during the treatment of congenital dysfunction of the adrenal cortex].
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17-Hydroxycorticosteroids↗
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Hypophosphatemia.
Hypophosphatemia is a common laboratory abnormality that occurs in a wide variety of disorders. When severe and prolonged, it may be associated with rhabdomyolysis, brain dysfunction, myocardial failure and certain defects of erythrocyte function and structure. Other disorders ascribed to hypophosphatemia, including platelet dysfunction and thrombocytopenia, liver dysfunction, renal tubular defects, peripheral neuropathy, metabolic acidosis and leukocyte dysfunction are less well documented. In quantitative terms, the most severe phosphate deficiency is seen in patients who consume a phosphate-deficient diet in conjunction with large amounts of phosphate-binding antacids, in persons with severe, chronic alcoholism and in patients with wasting illnesses who are refed with substances containing an inadequate amount of phosphate. When severe hypophosphatemia occurs in such a setting, the clinical effects appear to be much more pronounced. While there have been some advances in our understanding of the pathophysiology of phosphate depletion and hypophosphatemia, much remains to be learned. Treatment of hypophosphatemia is controversial; however, there is little question that it is indicated in alcoholic patients and those with severe phosphate deficiency.
Acidosis↗
Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.
AIMS/HYPOTHESIS: Both insulin resistance and beta-cell dysfunction play a role in the transition from normal glucose tolerance (NGT) to Type 2 diabetes (T2DM) through impaired glucose tolerance (IGT). The aim of the study was to define the level of glycaemia at which beta-cell dysfunction becomes evident in the context of existing insulin resistance. METHODS: Insulin response (OGTT) and insulin sensitivity (euglycaemic insulin clamp) were evaluated in 388 subjects in the San Antonio Metabolism (SAM) study (138 NGT, 49 IGT and 201 T2DM). In all subjects the insulin secretion/insulin resistance index (DeltaI/DeltaG/IR) was calculated as the ratio of the increment in plasma insulin to the increment in plasma glucose during the OGTT divided by insulin resistance, as measured during the clamp. RESULTS: In lean NGTs with a 2-h plasma glucose concentration (2-h PG) between 5.6 and 6.6 and between 6.7 and 7.7 mmol/l, there was a progressive decline in DeltaI/DeltaG/IR compared with NGTs with a 2-h PG less than 5.6 mmol/l. There was a further decline in DeltaI/DeltaG/IR in IGTs with a 2-h PG between 7.8 and 9.3 and between 9.4 and 11.0 mmol/l, and in Type 2 diabetic patients with a 2-h PG greater than 11.1 mmol/l. Lean and obese subjects showed coincident patterns of relation of 2-h PG to DeltaI/DeltaG/IR. CONCLUSION/INTERPRETATION: When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in "normal" glucose tolerant individuals.
Adult↗
Effects of cholestyramine and parenteral nutrition on hepatic metabolism of lidocaine: a study using isolated rat liver perfusion.
BACKGROUND: The effect of an oral bile salt binder, cholestyramine, on parenteral nutrition-related hepatic dysfunction and lidocaine metabolism was studied in rats. METHODS: Rats were randomly assigned to one of three treatment groups: the PN group received infusions of dextrose and amino acids; the PNC group was treated the same as the PN group, but also received oral cholestyramine; CF group animals were fed rat food and water. Lidocaine metabolism was studied in livers isolated from animals after 7 days of parenteral nutrition. RESULTS: No differences in liver function test values of PN and PNC groups were detected compared with group fed rat food. However, lidocaine metabolism was found to be significantly reduced in both the PN and PNC groups. Significant reductions were observed in the hepatic extraction ratio (23% and 15%) and in intrinsic clearance (61% and 53%) in PN and PNC animals, respectively (p < .05). Material balance at steady state showed that recovery of lidocaine was threefold higher in the PN group and twofold higher in the PNC group than the rat food group (p < .05). Metabolite-to-drug ratios were determined for each lidocaine metabolite and this revealed significant reductions in N-dealkylation (64% and 57%) and aryl methyl hydroxylation (92% and 86%) in PN and PNC animals, respectively (p < .05). CONCLUSIONS: Histologic findings suggest that cholestyramine feeding prevented liver dysfunction, possibly through interruption of secondary bile salt reabsorption. However, lidocaine metabolism was still impaired after cholestyramine ingestion; the impairment mechanism remains unknown.
Amino Acids↗
Early neuroendocrine alterations in female rats following a diet moderately enriched in fat.
1. High-fat diets disrupt metabolic equilibrium and hypothalamic-pituitary-adrenal axis function and may lead to the development of metabolic and endocrine dysfunctions. The early neuroendocrine responses elicited by a combination of short-term metabolic and emotional stressors is not fully elucidated. 2. The purpose of the present study was to determine the impact on female rats, of a short-term enriched in fat diet, combined with an acute stressor. 3. Adult female Wistar rats were fed a fat diet for 7 days and subsequently exposed to 5 min swimming stress. Plasma leptin, insulin, glucose, luteinizing hormone (LH) and corticosterone, along with brain corticosteroid receptors' mRNAs were measured at 1 h post stress. 4. Diet, compared to chow, reduced food intake and body weight gain, increased leptin and LH, and decreased glucose in the periphery. The diet increased plasma corticosterone and reduced GR mRNA in the hippocampus, similarly to swim stress. 5. The diet significantly modified the animals' response to the subsequent swim stress, by blocking further corticosterone rise and GR mRNA reduction. In addition, exposure of diet-fed rats to stress, altered their endocrine response, in terms of leptin and LH. 6. These observations suggest that even short, moderately unbalanced diets can affect peripheral and central components of energy balance, reproduction and stress response.
Animals↗
Lipid metabolism, cerebral metabolic rate, and some related enzyme activities after brain infarction in rats.
Multiple infarcts were produced in cerebral hemispheres of rats by injecting calibrated 50-micron microspheres into the left internal carotid artery, and alterations in lipid and energy metabolism were evaluated 24 hours later in the embolized hemisphere. Total phospholipid content was decreased by 26%, but the different classes of phospholipids were not equally affected. Phosphatidylinositol and phosphatidylserine levels were decreased by about 40% and phosphatidylcholine and phosphatidylethanolamine by 25%, while sphingomyelin level remained unchanged. There was a 3.2-fold increase in total free fatty acid content with a relatively larger rise in polyunsaturated free fatty acids 20:4 and 22:6 (20-fold increase). Determination of enzyme activities showed decreases in Na+,K+-ATPase (-21%) and hexokinase (-14%) but no changes in phosphofructokinase and pyruvate kinase. Study of energy metabolism using the closed system method of Lowry et al showed a significant depression (-36%) of the cerebral metabolic rate. Taken together, these data suggest a relation between lipid alterations and dysfunction of energy metabolism. Phospholipid degradation with subsequent free fatty acid release and alteration in membrane-bound enzymes may have a direct effect on metabolic machinery and may slow cerebral metabolic rate.
Animals↗
[EEG manifestations in metabolic encephalopathy].
Normal brain function depends on normal neuronal metabolism, which is closely related to systemic homeostasis of metabolites, such as glucose, electrolytes, amino acids and ammonia. "Metabolic encephalopathy" indicates diffuse brain dysfunction caused by various systemic derangements. Electroencephalogram (EEG) is widely used to evaluate metabolic encephalopathy since 1937, when Berger first observed slow brain activity induced by hypoglycemia. EEG is most useful in differentiating organic from psychiatric conditions, identifying epileptogenicity, and providing information about the degree of cortical or subcortical dysfunction. In metabolic encephalopathy, EEG evolution generally correlates well with the severity of encephalopathy. However, EEG has little specificity in differentiating etiologies in metabolic encephalopathy. For example, though triphasic waves are most frequently mentioned in hepatic encephalopathy, they can also be seen in uremic encephalopathy, or even in aged psychiatric patients treated with lithium. Spike-and-waves may appear in hyper- or hypo-glycemia, uremic encephalopathy, or vitamin deficiencies, etc. Common principles of EEG changes in metabolic encephalopathy are (1) varied degrees of slowing, (2) assorted mixtures of epileptic discharge, (3) high incidence of triphasic waves, and (4), as a rule, reversibility after treatment of underlying causes. There are some exceptions to the above descriptions in specific metabolic disorders and EEG manifestations are highly individualized.
Blood Glucose↗
Increased theophylline clearance in a patient with hyperthyroidism.
The association between thyroid disease and asthma is complex. Treatment of asthma in patients with thyroid disease is further complicated by the effects of thyroid dysfunction on drug metabolism. We report a patient with asthma whose calculated theophylline clearance was 0.156 L/kg/h during active Graves' disease which decreased to 0.042 L/kg/h after a euthyroid state was achieved. The potential mechanisms of this interaction are discussed and the effects of thyroid dysfunction on asthma and drug metabolism are reviewed.
Asthma↗
Associations between laboratory parameters and outcome of paraquat poisoning.
Paraquat, a non-selective herbicide, is a known fatal substance in humans, and intentional ingestion of paraquat is increasing among Korean suicides. In 1999, 147 subjects admitted to the Institute of Pesticide Poisoning, Soonchunhyang Chunan Hospital, Korea ingested paraquat. Initial routine laboratory tests were conducted and the outcome of paraquat poisoning was categorized as survivor and fatality. Mean amount (S.D.) of ingestion was 54.5 (104.9) ml, and the overall fatality rate was 44.2%. Abnormal liver function (GOT and GPT), renal dysfunction (BUN and creatinine), metabolic acidosis (pH and PaCO(2)), and abnormal urine analysis (RBC, WBC, and protein) had significant odds ratios (ORs) for paraquat fatality (P<0.05). In multiple logistic regression, subjects with liver or renal dysfunction or metabolic acidosis had significant risks of the fatality. Our results determined that initial routine laboratory parameters could be used to predict the outcome of paraquat poisoning and recommended that evaluation of acid-base status and renal and liver function should be conducted and evaluated before intensive therapy.
Adult↗
Nuclear magnetic resonance as a measure of cerebral metabolism: effects of hypertonic saline resuscitation.
UNLABELLED: Fears of central nervous system dysfunction from acute hypernatremia and hyperosmolarity with hypertonic saline resuscitation are often cited. We used high-energy phosphate nuclear magnetic resonance to investigate resuscitation effects on cerebral metabolism. Rats were instrumented for hemodynamic monitoring and fluid infusion and a phosphorus surface coil placed on their skulls. After shimming, baseline spectra were obtained. Animals were then bled for one hour to a mean arterial pressure (MAP) of 45 mm Hg, followed by resuscitation for one hour to a MAP of 75 mm Hg with lactated Ringer's (LR, n = 17) or 7.5% hypertonic saline (HS, n = 25). Spectra were obtained again and analyzed for the ratio of high-energy phosphocreatine (PCr) to low-energy inorganic phosphate (Pi). Intracellular hydrogen ion concentration [H+] was calculated from the PCr/Pi shift. [table: see text] CONCLUSIONS: (1) Hypertonic saline results in a decreased intracellular pH compared with LR without associated changes in high-energy phosphate metabolism. (2) Decreases in pH may be the result of cell dehydration rather than metabolic dysfunction.
Animals↗
Nuclear receptors and their coregulators in kidney.
Nuclear receptors are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and apoptosis. Dysfunction of nuclear receptor signaling leads to a wide spectra of proliferative, reproductive, and metabolic diseases, including cancers, infertility, obesity, and diabetes. In addition, many proteins have been identified as coregulators which can be recruited by DNA-binding nuclear receptors to affect transcriptional regulation. The cellular level of coregulators is crucial for nuclear receptor-mediated transcription and many coregulators have been shown to be targets for diverse intracellular signaling pathways and posttranslational modifications. This review provides a general overview of the roles and mechanism of action of nuclear receptors and their coregulators. Since progression of renal diseases is almost always associated with inflammatory processes and/or involve metabolic disorders of lipid and glucose, cell proliferation, hypertrophy, apoptosis, and hypertension, the importance of nuclear receptors and their coregulators in these contexts will be addressed.
Animals↗
The MYC/TXNIP axis mediates NCL-Suppressed CD8+T cell immune response in lung adenocarcinoma.
BACKGROUND: Lung adenocarcinoma is a deadly malignancy with immune evasion playing a key role in tumor progression. Glucose metabolism is crucial for T cell function, and the nucleolar protein NCL may influence T cell glucose metabolism. This study aims to investigate NCL's role in T cell glucose metabolism and immune evasion by lung adenocarcinoma cells. METHODS: Utilizing single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed cell clustering, annotation, and prognosis. In vitro experiments involved manipulating NCL expression in CD8+ T cells to study immune function and glucose metabolism. In vivo studies using an orthotopic transplant mouse model monitored NCL's impact on CD8+ T cell glucose metabolism and anti-tumor immune function. RESULTS: NCL was associated with T cell dysfunction and glucose metabolism. NCL silencing enhanced CD8+ T cell glucose metabolism, cytotoxicity, and infiltration, while NCL overexpression had the opposite effect. NCL overexpression relieved MYC-mediated transcriptional repression of TXNIP, reducing CD8+ T cell glucose metabolism. In vivo, NCL inhibited CD8+ T cell glucose metabolism through the MYC/TXNIP axis, hindering anti-tumor immune function. CONCLUSIONS: NCL overexpression suppresses CD8+ T cell glucose metabolism and anti-tumor immune function, promoting lung adenocarcinoma progression via the MYC/TXNIP axis.
CD8-Positive T-Lymphocytes↗
Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.
BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.
Humans↗
[Significance of ruminal juice examination in the diagnosis of subclinical rumen dysfunction].
The suitability of the metabolic test of rumen liquor for the diagnosis of subclinical rumen dysfunction was tested. The test for the assessment of the metabolic profile of the rumen included: the determination of pH, total titration acidity in clinical units, lactic acid in mg%, fatty acids in mmol 1-1, ammonia N in mg%, urea N in mg% and the number of infusorians in 1 ml of rumen liquor. This test enabled, on the basis of the examination of rumen liquor, to determine not only the kind and form of the disease but also its cause, with an incomplete clinical syndrome. Therapeutic measures, either direct (in the rumen liquor) or indirect (adjusted monodiet) improved the health condition and provided optimum rumen fermentation of permanent character. The resuption of rumen fermentation also enabled an increased production of fatty acids which favourably influenced the content of butterfat in milk.
Animals↗
Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress.
OBJECTIVES: We investigated whether abnormal pteridine metabolism is related to coronary endothelial dysfunction in insulin-resistant subjects. BACKGROUND: Depletion of tetrahydrobiopterin (BH(4)) and elevation of the 7,8-dihydrobiopterin (BH(2)) (activating and inactivating cofactors of nitric oxide synthase [NOS], respectively) contribute to impairment of NO-dependent vasodilation through reduction of NOS activity as well as increased superoxide anion generation in insulin-resistant rats. METHODS: Thirty-six consecutive nondiabetic, normotensive and nonobese subjects with angiographically normal coronary vessels were studied. Traditional coronary risk factors, plasma pteridine levels, activities of erythrocyte dihydropteridine reductase (DHPR), the recycling enzyme that converts BH(2) to BH(4) and lipid peroxide (LPO) levels were measured and coronary endothelial function was assessed with graded infusions of acetylcholine (ACh). RESULTS: When we divided patients into tertiles based on insulin sensitivity, we observed stepwise decreases in the maximal ACh-induced vasodilation and plasma BH(4)/7,8-BH(2) ratio, and increases in coronary LPO production as insulin sensitivity decreased. The ACh-induced vasodilation was positively correlated with insulin sensitivity, BH(4)/7,8-BH(2) ratio and DHPR activity. Furthermore, BH(4)/7,8-BH(2) was inversely correlated with DHPR activity and insulin sensitivity. In multiple stepwise regression analysis, BH(4)/BH(2) was independently related to ACh-induced vasodilation and accounted for 39% of the variance. However, no significant correlation existed between other traditional risk factors and BH(4)/7,8-BH(2). CONCLUSIONS: These results indicate that both abnormal pteridine metabolism and vascular oxidative stress are linked to coronary endothelial dysfunction in the insulin-resistant subjects.
Acetylcholine↗
Metabolic syndrome and the risk of placental dysfunction.
BACKGROUND: Placental dysfunction (PD), which may manifest partly as the hypertensive disorders of pregnancy and abruption or infarction of the placenta, occurs more commonly in women with obesity, chronic hypertension, diabetes mellitus, and dyslipidemia-each a major feature of the metabolic syndrome. However, the relationship between the metabolic syndrome and the future risk of PD or fetal demise is unknown. METHODS: We completed a retrospective cohort study of 1.03 million women who had a first documented delivery in the province of Ontario between 1990 and 2002. Using linked administrative databases, we categorized women as having zero, one, two, or three to four features of the metabolic syndrome up to 24 months before their index delivery hospitalization. Women were considered to have placental dysfunction if they had a diagnosis of preeclampsia, gestational hypertension, placental abruption, or placental infarction during their first hospitalization for delivery in the period of study. RESULTS: At the time of delivery, 75 380 women (7.3%) were diagnosed as having PD. There was a progressive increase in the risk of PD in women with one (adjusted odds ratio [OR] 3.1; 95% confidence interval [CI] 3.0-3.1), two (OR 5.5; 95% CI 5.2-5.8), or three to four (OR 7.7; 95% CI 6.7-8.9) features of the metabolic syndrome, compared with none. A similar gradient effect was seen for the combined outcome of PD with poor fetal growth, or of PD with concomitant fetal death. CONCLUSIONS: Women who exhibit features of the metabolic syndrome before pregnancy have a higher graded risk of PD and fetal demise. Studies are needed to determine whether modifying a woman's metabolic profile before pregnancy, through modest caloric restriction and increased physical activity, can lower her future risk of PD.
Abruptio Placentae↗
Glucose metabolism in psychiatric disorders: how can we facilitate comparisons among studies?
Positron emission tomography (PET) offers a possibility to study brain function and its relationship to psychiatric disorders. Clinical studies have demonstrated that several psychiatric diseases are coupled with changes in brain glucose metabolism. Schizophrenia seems to involve a lower metabolism in wide areas of the brain--both cortical and subcortical structures. Depression probably involves dysfunction of the metabolism in dorsolateral prefrontal cortex. Obsessive compulsive disorder, panic disorder, anorexia nervosa and the experience of anxiety may involve increased metabolic rates. The results from the different studies do not allow quantitative comparisons or detailed analyses because of large differences in experimental and clinical methodology. The term Good Clinical PET Practice (GCPP) is suggested to encourage standardization in clinical investigations. GCPP includes standardization of both experimental factors (lumped constant, arterialization, purity of tracer, regions of interest, relative rates) and clinical factors (state of the subject, wakefulness, anxiety, gender, course of the disease) in PET performance.
Brain↗
Noninfectious environmental agents associated with myopathies.
Increasing attention is being focused on environmental agents as possible factors in the etiology of certain connective tissue disorders. As our awareness in this area increases, the number and diversity of these agents is expanding yearly and now includes, in addition to infectious agents, a variety of foods and dietary supplements, drugs, occupational and other toxic exposures, biologics, and medical devices. Some of these agents have been associated with the development of muscle disease through mechanisms that involve alterations in the vascular supply to muscle, depletion of electrolytes, direct toxic effects on mitochondria or other metabolic processes, or activation of the immune system. Individual host susceptibility factors, including preexisting organ dysfunction and particular metabolizer or immunogenetic phenotypes, also appear to be important for development of the clinical syndromes identified as environmentally associated myopathies. Although data in this area are limited, they suggest that when susceptible individuals are exposed to selected agents, physiologic alterations occur that lead to myopathy. Physician awareness of chemicals implicated with myopathy and dissection of their pathogenetic mechanisms through human and animal studies may aid in the identification of additional toxic agents, minimize new cases in the future, and lead to a better understanding of the idiopathic myopathies.
Drug-Related Side Effects and Adverse Reactions↗