Enzyme response to thyrotoxicosis and hypothyroidism in human liver and muscle: comparative aspects

Abstract. 1. Activities of phosphoglucomutase, hexokinase, glucose-6-phosphate dehydrogenase, triosephosphate dehydrogenase, mitochondrial glycerophosphate dehydrogenase, hexosediphosphatase and phosphoenolpyruvate-carboxykinase, of enzymes involved in the citric acid cycle and connected pathways, of hydroxyacyl-CoA dehydrogenase and carnitine acetyltransferase were determined in biopsy specimens of liver and of tibialis anterior muscle from thyrotoxic and hypothyroid patients and from controls. The results are compared with data obtained from liver and red and white muscle of thyrotoxic rats and guinea pigs. 2. Concomitant with diminished glucose tolerance, the glucokinase activity is decreased in thyrotoxic human liver. The decrease of rat liver glucokinase activity as a response to administered thyroid hormones is found to be dose-dependent. A relationship between the diminished glucose tolerance in thyrotoxicosis and the decrease of glucokinase activity is discussed. The increase of hexokinase activity (isozyme II) is the most interesting finding in thyrotoxic human muscle because of its possible significance with respect to the elevated metabolic rate. The activity of triosephosphate dehydrogenase, (NADP) malate dehydrogenase, phosphoenolpyruvate carboxykinase and carnitine acetyltransferase is markedly enhanced in human thyrotoxic liver, whereas that of phosphoglucomutase is diminished. 3. Mitochondrial glycerophosphate dehydrogenase, which is known to be markedly increased in the liver and red muscle of thyrotoxic rats, is not increased in the liver and tibialis anterior muscle of thyrotoxic patients, nor in the liver and white muscle of thyrotoxic guinea pigs. The enzyme responses to thyrotoxicosis in human liver and muscle are more similar to those of the guinea pig than of the rat.     

Intermediary metabolism

Carbohydrate and fat form the immediate and long-term energy stores of the body. Protein constitutes the active (functional) cell mass and is also an energy source but, normally, a relatively minor one. All three macronutrients are interrelated. Proteins are synthesized from amino acids derived from ingested protein. Glucose and fat provide energy via adenosine triphosphate. The brain and red blood cells can only obtain their energy from glucose. Glucose is oxidized via the glycolytic and the tricarboxylic acid (Krebs) cycle pathways. Fatty acids are metabolized by the process of β-oxidation, whereby two carbon fragments are cleaved from the fatty acid chain and enter the Krebs cycle. Amino acids are deaminated to keto acids and the nitrogen moiety excreted in the urine mostly as urea. The keto acids enter the metabolic pathways at various points, mostly in the Krebs cycle. Glucose can be synthesized from lactate, glycerol and amino acids (gluconeogenesis), but not from fatty acids.     

Acetaminophen glucuronide and plasma glucose report identical estimates of gluconeogenesis and glycogenolysis for healthy and prediabetic subjects using the deuterated water method

Plasma glucose ²H‐enrichment in positions 5 (²H5) and 2 (²H2) from deuterated water (²H₂O) provides a measure of the gluconeogenic contribution to endogenous glucose production. Urinary glucuronide analysis can circumvent blood sampling but it is not known if glucuronide and glucose enrichments are equal. Thirteen subjects with impaired fasting glucose/impaired glucose tolerance and 11 subjects with normal fasting glucose and normal glucose tolerance ingested ²H₂O to ～0.5% body water and acetaminophen. Glucose and glucuronide ²H5 and ²H2 were measured by ²H NMR spectroscopy of monoacetone glucose. For normal fasting glucose/normal glucose tolerance, ²H5 was 0.23 ± 0.02% and 0.25 ± 0.02% for glucose and glucuronide, respectively, whereas ²H2 was 0.47 ± 0.01% and 0.49 ± 0.02%, respectively. For impaired fasting glucose/impaired glucose tolerance, ²H5 was 0.22 ± 0.01% and 0.26 ± 0.02% for glucose and glucuronide, respectively, whereas ²H2 was 0.46 ± 0.01% and 0.49 ± 0.02%, respectively. The gluconeogenic contribution to endogenous glucose production measured from glucose and glucuronide were identical for both normal fasting glucose/normal glucose tolerance (48 ± 4 vs. 51 ± 3%) and impaired fasting glucose/impaired glucose tolerance (48 ± 2 vs. 53 ± 3%). Magn Reson Med 70:315–319, 2013. © 2012 Wiley Periodicals, Inc.     

Phenolic Diterpenes from Rosemary Suppress cAMP Responsiveness of Gluconeogenic Gene Promoters

The cAMP/protein kinase A/cAMP response element (CRE)‐binding protein pathway is important for various physiological aspects including regulation of gluconeogenic gene expression. Rosemary, a well‐known herb, has been reported to decrease blood glucose levels. We found that methanol extracts of rosemary suppressed forskolin (FSK)‐stimulated luciferase expression under the control of CRE, as well as the promoters for cytosolic phosphoenolpyruvate carboxykinase (PEPCK‐C) and glucose‐6‐phosphatase (G6Pase) catalytic subunit genes in human hepatoma HepG2 cells. Three abietane‐type diterpenes and two flavonoids were isolated from the rosemary extracts. Among these, 7‐O‐methylrosmanol (1) and royleanonic acid (3) effectively suppressed FSK‐induced luciferase expression under the control of the CRE, PEPCK‐C and G6Pase gene promoters. PEPCK‐C and G6Pase, which play a key role in the homeostatic regulation of blood glucose levels, are important for managing type II diabetes mellitus. Therefore, the ability of rosemary and its components to suppress cAMP responsiveness of the PEPCK‐C or G6Pase gene may contribute to its antihyperglycemic activity. Copyright © 2012 John Wiley & Sons, Ltd.     

Contributions of hepatic gluconeogenesis suppression and compensative glycogenolysis on the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, in non-obese type 2 diabetes Goto-Kakizaki rats

Contributions of gluconeogenesis suppression in liver, kidney, and intestine as major gluconeogenic organs to the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, was evaluated in overnight-fasted Goto-Kakizaki (GK) rats. CS-917 decreased plasma glucose by suppressing glucose release and lactate uptake from liver but not from kidney and intestine. These results suggest that hepatic gluconeogenesis suppression predominantly contributes to the glucose-lowering effect of CS-917 in GK rats. Moreover, the mechanism by which CS-917 decreased plasma glucose more in overnight-fasted GK rats than in non-fasted ones was investigated. Lactate uptake from liver was suppressed by 15 mg/kg of CS-917 in both states, but glucose release from liver and plasma glucose were decreased only in the overnight-fasted state. CS-917 at 30 mg/kg decreased hepatic glycogen content in both states and depleted it in the overnight-fasted state. In the non-fasted GK rats, co-administration of CS-917 with CP-91149, a glycogen phosphorylase inhibitor, suppressed hepatic glycogen reduction by CS-917 and decreased plasma glucose more than single administration of CS-917. These results suggest that gluconeogenesis suppression by CS-917 was counteracted by hepatic glycogenolysis especially in the non-fasted state and that combination therapy with CS-917 and CP-91149 is efficacious to decrease plasma glucose in GK rats.     

Untargeted Metabolome Analysis Reveals Reductions in Maternal Hepatic Glucose and Amino Acid Content That Correlate with Fetal Organ Weights in a Mouse Model of Fetal Alcohol Spectrum Disorders

Prenatal alcohol exposure (PAE) causes fetal growth restrictions. A major driver of fetal growth deficits is maternal metabolic disruption; this is under-investigated following PAE. Untargeted metabolomics on the dam and fetus exposed to alcohol (ALC) revealed that the hepatic metabolome of ALC and control (CON) dams were distinct, whereas that of ALC and CON fetuses were similar. Alcohol reduced maternal hepatic glucose content and enriched essential amino acid (AA) catabolites, N-acetylated AA products, urea content, and free fatty acids. These alterations suggest an attempt to minimize the glucose gap by increasing gluconeogenesis using AA and glycerol. In contrast, ALC fetuses had unchanged glucose and AA levels, suggesting an adequate draw of maternal nutrients, despite intensified stress on ALC dams. Maternal metabolites including glycolytic intermediates, AA catabolites, urea, and one-carbon-related metabolites correlated with fetal liver and brain weights, whereas lipid metabolites correlated with fetal body weight, indicating they may be drivers of fetal weight outcomes. Together, these data suggest that ALC alters maternal hepatic metabolic activity to limit glucose availability, thereby switching to alternate energy sources to meet the high-energy demands of pregnancy. Their correlation with fetal phenotypic outcomes indicates the influence of maternal metabolism on fetal growth and development.