Glucose metabolism in the liver activates the transcription of various genes encoding enzymes of glycolysis and lipogenesis and also G6pc (glucose-6-phosphatase). Allosteric mechanisms involving ...glucose 6-phosphate or xylulose 5-phosphate and covalent modification of ChREBP (carbohydrate-response element-binding protein) have been implicated in this mechanism. However, evidence supporting an essential role for a specific metabolite or pathway in hepatocytes remains equivocal. By using diverse substrates and inhibitors and a kinase-deficient bisphosphatase-active variant of the bifunctional enzyme PFK2/FBP2 (6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase), we demonstrate an essential role for fructose 2,6-bisphosphate in the induction of G6pc and other ChREBP target genes by glucose. Selective depletion of fructose 2,6-bisphosphate inhibits glucose-induced recruitment of ChREBP to the G6pc promoter and also induction of G6pc by xylitol and gluconeogenic precursors. The requirement for fructose 2,6-bisphosphate for ChREBP recruitment to the promoter does not exclude the involvement of additional metabolites acting either co-ordinately or at downstream sites. Glucose raises fructose 2,6-bisphosphate levels in hepatocytes by reversing the phosphorylation of PFK2/FBP2 at Ser32, but also independently of Ser32 dephosphorylation. This supports a role for the bifunctional enzyme as the phosphometabolite sensor and for its product, fructose 2,6-bisphosphate, as the metabolic signal for substrate-regulated ChREBP-mediated expression of G6pc and other ChREBP target genes.
Glucose is an essential nutrient for the human body. It is the major energy source for many cells, which depend on the bloodstream for a steady supply. Blood glucose levels, therefore, are carefully ...maintained. The liver plays a central role in this process by balancing the uptake and storage of glucose via glycogenesis and the release of glucose via glycogenolysis and gluconeogenesis. The several substrate cycles in the major metabolic pathways of the liver play key roles in the regulation of glucose production. In this review, we focus on the short and long-term regulation glucose-6-phosphatase and its substrate cycle counterpart, glucokinase. The substrate cycle enzyme glucose-6-phosphatase catalyzes the terminal step in both the gluconeogenic and glycogenolytic pathways and is opposed by the glycolytic enzyme glucokinase. In addition, we include the regulation of GLUT 2, which facilitates the final step in the transport of glucose out of the liver and into the bloodstream.
Data on the epidemiology of aortic stenosis (AS) are primarily derived from single center experiences and administrative claims data that do not delineate by degree of disease severity.
An ...observational cohort study of adults with echocardiographic AS was conducted January 1st, 2013-December 31st, 2019 at an integrated health system. The presence/grade of AS was based on physician interpretation of echocardiograms.
A total of 66,992 echocardiogram reports for 37,228 individuals were identified. The mean ± standard deviation (SD) age was 77.5 ± 10.5, 50.5% (N = 18,816) were women, and 67.2% (N = 25,016) were non-Hispanic whites. The age-standardized AS prevalence increased from 589 (95% Confidence Interval CI 580–598) to 754 (95% CI 744–764) cases per 100,000 during the study period. The age-standardized AS prevalences were similar in magnitude among non-Hispanic whites (820, 95% CI 806–834), non-Hispanic blacks (728, 95% CI 687–769), and Hispanics (789, 95% CI 759–819) and substantially lower for Asian/Pacific Islanders (511, 95% CI 489–533). Finally, the distribution of AS by degree of severity remained relatively unchanged over time.
The population prevalence of AS has grown considerably over a short timeframe although the distribution of AS severity has remained stable.
•The prevalence of aortic stenosis has grown substantially.•The prevalence of aortic stenosis is lower for Asian/Pacific Islanders.•The distribution of aortic stenosis severity has not changed over time.
Language barriers can influence the quality of health care and health outcomes of limited English proficient patients with cancer. The use of medical interpretation services can be a valuable asset ...for improving communications in emergency care settings.
To evaluate whether a mobile translation application increased call frequency to interpreter services among providers in an Urgent Care Center at a comprehensive cancer center and to assess provider satisfaction of the mobile application.
Prospective pre-post nonrandomized intervention of a mobile translation application with access to an over the phone interpreter (OPI) service at the push of a button and poststudy satisfaction survey.
Sixty-five clinicians working at the Urgent Care Center in a cancer center in New York City.
Mean call frequency to OPI services, tested by the nonparametric Wilcoxon Mann Whitney test, and self-reported provider satisfaction descriptives.
The mobile application contributed to increasing the frequency of phone calls to OPI services during the intervention period (mean=12.8; P=0.001) as compared with the preintervention period (mean=4.3), and showed continued use during the postintervention period (mean=5.7). Most clinicians were satisfied with the use of the mobile application and access to the OPI services.
The results suggest that mobile application tools contribute to increasing the use and ease of access to language services. This has the potential to improve the quality of communication between medical providers and limited English proficient patients in the delivery of cancer care in urgent care settings.
Glycolysis, a simple pathway of glucose metabolism, critically regulates insulin secretion and metabolic functions of various cells. Depending on cell types, rates of glycolysis are determined at ...various steps of glycolysis that are subjected to the control of key metabolic and regulatory enzyme(s), which include glucokinase, 6-phosphofructo-1-kinase, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. These enzymes are regulated by both nutritional and hormonal signals at the levels of transcription, translation, and post-translational modifications. In hepatocytes, glycolysis is involved in the control of hepatic glucose production. The latter, when excessive, contributes to hyperglycemia in diabetes. In pancreatic β cells, glycolysis couples glucose-stimulated insulin secretion. Absolute or relatively low levels of circulating insulin causes hyperglycemia. In adipocytes, glycolysis generates metabolites for lipogenesis and channels fatty acids from excessive oxidation to triglyceride synthesis, thereby reducing oxidative stress. With increased proinflammatory status, adipocytes produce pro-hyperglycemic factors and bring about hyperglycemia and insulin resistance. In hypothalamic neurons, glycolysis conveys nutrient sensing that is related to feeding control. Dysregulation of glycolysis occurs in conditions of insulin deficiency or resistance, and is attributable to inappropriate amount and/or activities of metabolic and regulatory enzymes of glycolysis. Targeting key metabolic and regulatory enzymes to enhance glycolysis may offer viable approaches for treatment of diabetes.
PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferator-activated receptor ...γ (PPARγ), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPARγ activation was determined. In wild-type littermate mice, PPARγ activation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPARγ activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3+/− mice. The lack of anti-diabetic effect in PFKFB3+/− mice was associated with the inability of PPARγ activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPARγ activation on stimulating lipid accumulation. Furthermore, PPARγ activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPARγ activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARγ activation.
Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body weight and adiposity in obese mice. ...Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis. Either of the two treatments produces similar increases in rates of fatty acid oxidation in extrahepatic tissues, i.e., skeletal muscle, leading to an elevation of energy expenditure. However, only 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase overexpression causes a suppression of food intake and a decrease in hypothalamic neuropeptide Y expression, contributing to a more pronounced reduction of body weight with this treatment. Furthermore, the two treatments cause differential lipid profiles due to opposite effects on hepatic lipogenesis, associated with distinct phosphorylation states of carbohydrate response element binding protein and AMP-activated protein kinase. The step at which hepatic glycolysis is enhanced dramatically influences overall whole-body energy balance and lipid profiles.
The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) was recently identified as a new intracellular binding partner for glucokinase (GK). Therefore, we ...studied the importance of this interaction for the activity status of GK and glucose metabolism in insulin-producing cells by overexpression of the rat liver and pancreatic islet isoforms of PFK-2/FBPase-2. PFK-2/FBPase-2 overexpression in RINm5F-GK cells significantly increased the GK activity by 78% in cells expressing the islet isoform, by 130% in cells expressing the liver isoform, and by 116% in cells expressing a cAMP-insensitive liver S32A/H258A double mutant isoform. Only in cells overexpressing the wild-type liver PFK-2/FBPase-2 isoform was the increase of GK activity abolished by forskolin, apparently due to the regulatory site for phosphorylation by a cAMP-dependent protein kinase. In cells overexpressing any isoform of the PFK-2/FBPase-2, the increase of the GK enzyme activity was antagonized by treatment with anti-FBPase-2 antibody. Increasing the glucose concentration from 2 to 10 mmol/l had a significant stimulatory effect on the GK activity in RINm5F-GK cells overexpressing any isoform of PFK-2/FBPase-2. The interaction of GK with PFK-2/FBPase-2 takes place at glucose concentrations that are physiologically relevant for the activation of GK and the regulation of glucose-induced insulin secretion. This new mechanism of posttranslational GK regulation may also represent a new site for pharmacotherapeutic intervention in type 2 diabetes treatment.
A classical twin study was performed to assess the relative contributions of genetic and environmental factors to serum levels of calcium, phosphate and magnesium, urinary levels of calcium, sodium ...and potassium, and creatinine clearance. The subjects were 1747 adult female twin pairs: 539 monozygotic and 1208 dizygotic. The intraclass correlations were calculated, and maximum-likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in monozygotic twin pairs. The heritabilities (with 95% confidence intervals) obtained from model fitting were: serum calcium, 33% (21-45%); serum phosphate, 58% (53-62%), serum magnesium, 27% (15-39%); 24 h urinary potassium, 40% (27-51%); 24 h urinary calcium, 52% (41-61%); 24 h urinary sodium, 43% (30-54%); fractional excretion of sodium, 52% (44-59%); serum creatinine, 37% (25-49); calculated creatinine clearance, 63% (54-72%). This study provides evidence for the importance of genetic factors in determining urinary and blood levels of the major electrolytes involved in blood pressure regulation. Identifying heritability is the first step on the way to finding specific genes, which may improve our insight into the pathophysiology of the metabolism of these electrolytes, and thereby improve our understanding of the aetiology of complex diseases such as renal failure and hypertension.
During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific ...overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.
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