Multiple Metabolic Alterations Research Articles

Association of aortic stiffness with abdominal vascular and coronary calcifications in patients with stage 3 and 4 chronic kidney disease

Rationale and objectivesIncreased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC).The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries(CAC). Materials and methodsWe included 87 pacientes with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respecti-vely. For the study of the association between Pvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). ResultsPvc-f and Pvc-f index were 11.3 ± 2.6 and 10.6 m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively.Albuminuria (β = 0.13, p = 0.005) and Kauppila score (β = 0.36, p = 0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (β = 0.39, p = 0.001), DM (β = 0.46, p = 0.01), and smoking (β = 0.53; p = 0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6−6.9; p = 0.001)].The Kauppila score was independently associated with the Agatston score (β = 1.53, p = 0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%.The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04−10.2, p = 0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95%CI: 0.71−0.93, p = 0.001) and 0.81 (95% CI: 0.67–0.96, p = 0.02), respectively. ConclusionsWhen stage 3–4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3–4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

Asociación de la rigidez aórtica con calcificaciones vasculares abdominales y coronarias en pacientes con enfermedad renal crónica estadios 3 y 4

Rationale and objectivesIncreased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC).The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries (CAC). Materials and methodsWe included 87 patients with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respectively. For the study of the association between iPvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). ResultsPvc-f and Pvc-f index were 11.3±2.6m/s and 10.6m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively.Albuminuria (β=0.13, p=0.005) and Kauppila score (β=0.36, p=0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (β=0.39, p=0.001), DM (β=0.46, p=0.01), and smoking (β=0.53; p=0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6–6.9; p=0.001)].The Kauppila score was independently associated with the Agatston score (β=1.53, p=0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%.The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04–10.2, p=0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95% CI: 0.71–0.93, p=0.001) and 0.81 (95% CI: 0.67–0.96, p=0.02), respectively. ConclusionsWhen stage 3–4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3–4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice

Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors.

Virtually all patients with multiple myeloma become unresponsive to treatment with proteasome inhibitors over time. Relapsed/refractory multiple myeloma is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations, diverse proteomic and metabolic alterations, and profound changes of the bone marrow microenvironment. However, the molecular mechanisms that drive resistance to proteasome inhibitors within the context of the bone marrow microenvironment remain elusive. In this review article, we summarize the latest knowledge about the complex interaction of malignant plasma cells with its surrounding microenvironment. We discuss the pivotal role of metabolic reprograming of malignant plasma cells within the tumor microenvironment with a subsequent focus on metabolic rewiring in plasma cells upon treatment with proteasome inhibitors, driving multiple ways of adaptation to the treatment. At the same time, mutual interaction of plasma cells with the surrounding tumor microenvironment drives multiple metabolic alterations in the bone marrow. This provides a tumor-promoting environment, but at the same time may offer novel therapeutic options for the treatment of relapsed/refractory myeloma patients.

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19.

Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8+ T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00430-021-00727-0.

Prevalence of Low Vitamin D Levels and Metabolic Syndrome in Patients Attending Consultation at a Tertiary Level Hospital

Vitamin D is involved in multiple metabolic alterations that affect adiposity, glycemic control and cardiovascular risk factors. Cardiovascular Diseases (CVD) are the leading cause of global mortality.

Abstract 2467: Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis

Abstract Understanding the impact of risk factors on the progression of pancreatic cancer is critical for the development of novel therapeutics. Multiple studies have clearly shown that obesity positively correlates with increased progression of pancreatic adenocarcinoma (PDAC). We have demonstrated that individual adipose derived cytokines (aka adipokines) can elicit either pro-tumorigenic or anti-tumorigenic effects on PDAC progression. We previously demonstrated that adiponectin receptor agonism effectively suppresses pancreatic cancer growth in vitro as well as in vivo, through suppression of MAPK as well as STAT3 pathways. Yet, adiponectin is well known to stimulate the AMPK pathway and therefore we hypothesized that adiponectin agonism could also be affecting metabolic function in PDAC. In our current studies, we defined multiple metabolic alterations in pancreatic cancer cells in response to adiponectin receptor agonism using a seahorse-based assay. Human and murine PDAC cell lines were seeded into XFe96 microplates and subjected to a mitochondrial stress test as well as the glycolysis stress test. Our results demonstrate that adiponectin receptor activation impairs pancreatic cancer mitochondrial function leading to a metabolic switch from mitochondrial respiration to glycolysis. We further demonstrate that this switch is associated with AMPK phosphorylation-mediated inhibition of Acetyl Coenzyme A Carboxylase (ACC), the lipogenic enzyme whose inhibition induces fatty acid breakdown. Thus, our results support a role for adipose-secreted factors to influence the metabolic phenotype of pancreatic cancer. Since metabolic rewiring is often associated with development of chemotherapeutic resistance in cancer, we are currently testing whether dual therapeutic targeting of the mitochondrial respiration, via adiponectin receptor agonism, and glycolysis would provide an efficacious therapeutic. Citation Format: Sharon J. Manley, Jarrid Jack, Joseph Ambrose, Appolinaire A. Olou, Michael N. VanSaun. Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2467.

Integration of Mass Spectrometry Imaging and Machine Learning Visualizes Region-Specific Age-Induced and Drug-Target Metabolic Perturbations in the Brain

Detailed metabolic imaging of specific brain regions in early aging may expose pathophysiological mechanisms and indicate effective neuropharmacological targets in the onset of cognitive decline. Comprehensive imaging of brain aging and drug-target effects is restricted using conventional methodology. We simultaneously visualized multiple metabolic alterations induced by normal aging in specific regions of mouse brains by integrating Fourier-transform ion cyclotron resonance mass spectrometry imaging and combined supervised and unsupervised machine learning models. We examined the interplay between aging and the response to tacrine-induced acetylcholinesterase inhibition, a well-characterized therapeutic treatment against dementia. The dipeptide carnosine (β-alanyl-l-histidine) and the vitamin α-tocopherol were significantly elevated by aging in different brain regions. l-Carnitine and acetylcholine metabolism were found to be major pathways affected by aging and tacrine administration in a brain region-specific manner, indicating altered mitochondrial function and neurotransmission. The highly interconnected hippocampus and retrosplenial cortex displayed different age-induced alterations in lipids and acylcarnitines, reflecting diverse region-specific metabolic effects. The subregional differences observed in the hippocampal formation of several lipid metabolites demonstrate the unique potential of the technique compared to standard mass spectrometry approaches. An age-induced increase of endogenous antioxidants, such as α-tocopherol, in the hippocampus was detected, suggesting an augmentation of neuroprotective mechanisms in early aging. Our comprehensive imaging approach visualized heterogeneous age-induced metabolic perturbations in mitochondrial function, neurotransmission, and lipid signaling, not always attenuated by acetylcholinesterase inhibition.

Reumatoidná artritída a poruchy metabolizmu

Rheumatoid arthritis is a chronic autoimmune inflammatory disease associated with multiple metabolic alterations and increased cardiovascular risk. It is supposed that visceral obesity seems to be a connection between rheumatoid arthritis and cardiovascular diseases. Obesity is not only associated with increased disease activity and worsened quality of life in this group of patients, but also determines the effectiveness of treatment. Biological therapy interferes with metabolic changes, too. Therefore, there is a tendency to select the right anticytokine preparation in the first line of treatment to reduce not only disease activity but also affect aspects of metabolic syndrome and comorbidites, thereby reducing cardiovascular risk and patients mortality. This work offers a basic overview of the associations between rheumatoid arthritis and metabolic disorders, describes the impact of biological therapy on individual components of the metabolic syndrome.

Effects of high-intensity infrasound on liver lipid content of rats

Previous experimental studies show that exposure to noise with high and audible frequencies causes multiple metabolic alterations, such as increased liver glycogen and triglycerides. However, the effect of exposure to sound with lower frequencies, such as high-intensity infrasound (frequency <20 Hz and sound pressure level >90 dB), on the liver lipid content is still unclear. As such, we aimed to study the effect of exposure to high-intensity infrasound of both normal and glucose intolerant rats on the liver lipid content. For this study, 79 wild-type male Wistar rats were randomly divided into two groups: G1, no treatment, and G2, induced glucose intolerance. Each of these two groups was randomly divided in two subgroups: s (animals kept in silence) and i (animals continuously exposed to high-intensity infrasound noise). At three noise-exposure time-points (1, 6 and 12 weeks) the rats were sacrificed, the liver was excised and hepatic lipids extracted. Data analysis was performed using a two-way ANOVA (p = 0.05). No significant effects due to interactions between the several factors exist on the liver lipid content (p=0.077). Moreover, no significant effects due to infrasound exposure (p=0.407) or glucose tolerance status (p=0.938) were observed. Our study shows that continuous exposure to high-intensity infrasound has no influence on the lipid content of the liver of both normal and glucose intolerant animals. This finding reinforces the need for further experimental studies on the physiological effects of infrasound due to its possible hazardous effects on human health.

Salivary gland metabolism in an animal model of chronic kidney disease

ObjectiveThe aim of this study was to determine the effects of experimental CKD into the metabolism of parotid and submandibular glands of rats. CKD was induced by 5/6 nephrectomy. DesignSerum analyses of BUN (Blood Urea Nitrogen) and creatinine concentrations were performed. Major salivary glands metabolism was investigated in vivo, both at rest and during salivary stimulation conditions by NMR isotopomer analysis, using [U-13C]glucose as metabolic tracer. ResultsCKD increases BUN and serum creatinine concentrations (p < 0.001). Multiple metabolic alterations were detected in the parotid glands of this animal model, including decreased concentrations of alanine (p < 0.05) and creatine (p < 0.05) and increased lactate/alanine ratios (p < 0.05). The salivary stimulus fostered accumulations of acetate at both analyzed glands of the CKD model (p < 0.05), indicative of disruption of the oxidative metabolic process. ConclusionsExperimental CKD induced by 5/6 nephrectomy altered the parotid salivary gland function, since glucose metabolism is clearly affected after stimulation for salivation in this gland.

Nutritional Support in the Patient with Traumatic and Nontraumatic Brain Injury

The multiple metabolic alterations following neurologic injuries create several unique challenges for clinicians providing nutrition support. The hypermetabolic and hypercatabolic state following traumatic brain injury (TBI) has been well studied over the past three decades. This review discusses several unique issues to incorporate into the nutrition support plan for both acute traumatic and nontraumatic brain injuries. The initial energy expenditure assessment varies drastically among the different neurologic injuries, from the lowest with anoxic brain injury and spinal cord injury to the highest with traumatic subdural hemorrhagic injury. Measuring energy expenditure with indirect calorimetry becomes a critical component of the assessment due to wide-ranging metabolic needs and effects from various drug therapies. An excess or a lack of adequate nutrition support clearly results in worse neurologic and nutrition status outcomes. The nutrition status and preexisting comorbidities of the neurologically injured patient further compound the complexity of the nutrition plan. Anticipating and correcting for refeeding syndrome in the malnourished stroke patient or alcoholic hypermetabolic TBI patient avoid further metabolic, cardiac, and ventilator complications. Fluid balance must be continuously monitored and hyperglycemia avoided to prevent cerebral edema. Planning and implementing an aggressive nutrition support regimen inclusive of drug therapy, appropriate fluid status, electrolyte replacement, and close glucose monitoring incorporate the expertise of several health care disciplines to ensure optimal outcomes from the critical care setting. Nutrition support plans become one of the primary focuses during recovery following a neurologic injury. Proper swallow assessments and techniques to recognize dysphagia and avoid aspiration and its complications with pneumonia become paramount during the stroke rehabilitation phase. Due to the variety of acute neurologic injuries, health care providers must address each of the distinctive issues for an individualized nutrition support therapy to ensure optimal outcomes and minimize complications This review contains 1 figure, 4 tables, and 58 references.

Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring.

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Thyroid Function and Obesity

Nowadays, childhood obesity is one of the biggest health emergencies in the developed countries. Obesity leads to multiple metabolic alterations which increase the risk of developing diabetes and cardiovascular diseases. Thyroid function has been often described as altered in obese children, however, it is not clear whether the altered thyroid function is the cause or the consequence of fat excess. On the other hand, thyroid structure seems also to be affected. Nevertheless, both functional and structural alterations seem to improve after weight loss and therefore no treatment is needed.Conflict of interest:None declared.

Multiple Metabolic Alterations Exist in Mutant PI3K Cancers, but Only Glucose Is Essential as a Nutrient Source

Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies.

Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits

Impaired glucose tolerance (IGT) which precedes overt type 2 diabetes (T2DM) for decades is associated with multiple metabolic alterations in insulin sensitive tissues. In an UPLC-qTOF-mass spectrometry-driven non-targeted metabonomics approach we investigated plasma as well as spot urine of 51 non-diabetic, overnight fasted individuals aiming to separate subjects with IGT from controls thereby identify pathways affected by the pre-diabetic metabolic state. We could clearly demonstrate that normal glucose tolerant (NGT) and IGT subjects clustered in two distinct groups independent of the investigated metabonome. These findings reflect considerable differences in individual metabolite fingerprints, both in plasma and urine. Pre-diabetes associated alterations in fatty acid-, tryptophan-, uric acid-, bile acid-, and lysophosphatidylcholine-metabolism, as well as the TCA cycle were identified. Of note, individuals with IGT also showed decreased levels of gut flora-associated metabolites namely hippuric acid, methylxanthine, methyluric acid, and 3-hydroxyhippuric acid. The findings of our non-targeted UPLC-qTOF-MS metabonomics analysis in plasma and spot urine of individuals with IGT vs NGT offers novel insights into the metabolic alterations occurring in the long, asymptomatic period preceding the manifestation of T2DM thereby giving prospects for new intervention targets.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-010-0203-1) contains supplementary material, which is available to authorized users.

Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species

Upon activation by phytohemagglutine (PHA), T-lymphocytes (T-cells) express receptors for growth factors, insulin, IGF-1 and IL2 and become insulin sensitive. Diabetic ketoacidosis (DKA) is associated with in vivo emergence of these growth factor receptors without incubation with PHA. As DKA consists of multiple metabolic alterations, in addition to hyperglycemia, we investigated the in vitro effect of different concentrations of glucose (5, 15, and 30 mM) in isolated CD4 of human T-cells at various time intervals (0, 24, 48, and 72 h). Hyperglycemia, but not euglycemia, resulted in de novo emergence of growth factor receptors in a dose- and time-dependent fashion. The activation was also associated with incremental changes in GLUT 4, IRS-1, proinflammatory cytokines, and oxidative stress components. We propose that activation of T-cells with development of insulin receptors in hyperglycemic conditions may serve as a mechanism for control of glucose entry into these cells, thus, protecting them against glucose toxicity.

Mechanisms of human DNA repair: an update.

The human genome, comprising three billion base pairs coding for 30000-40000 genes, is constantly attacked by endogenous reactive metabolites, therapeutic drugs and a plethora of environmental mutagens that impact its integrity. Thus it is obvious that the stability of the genome must be under continuous surveillance. This is accomplished by DNA repair mechanisms, which have evolved to remove or to tolerate pre-cytotoxic, pre-mutagenic and pre-clastogenic DNA lesions in an error-free, or in some cases, error-prone way. Defects in DNA repair give rise to hypersensitivity to DNA-damaging agents, accumulation of mutations in the genome and finally to the development of cancer and various metabolic disorders. The importance of DNA repair is illustrated by DNA repair deficiency and genomic instability syndromes, which are characterised by increased cancer incidence and multiple metabolic alterations. Up to 130 genes have been identified in humans that are associated with DNA repair. This review is aimed at updating our current knowledge of the various repair pathways by providing an overview of DNA-repair genes and the corresponding proteins, participating either directly in DNA repair, or in checkpoint control and signaling of DNA damage.

Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.

The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH). Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied. Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed. Of the 40 patients with hyperferritinemia, 29 (72%) had biochemical metabolic abnormalities, 18 of the 26 examined (69%) had insulin resistance, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls, 33 of 128 [26%], p < 0.0001), and all had increased liver iron concentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations, the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multiple metabolic alterations (odds ratio = 5.2, 95% CI = 0.95-28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liver iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal transferrin saturation, but only six remained hyperferritinemic after dietary restriction. Increased ferritin with normal transferrin saturation is frequently found in patients with hepatic steatosis, but it reflects iron overload only in those patients in whom it persists despite an appropriate diet. The simultaneous disorder of iron and glucose and/or lipid metabolism, in most of the cases associated with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH.

Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis

OBJECTIVE: The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH). METHODS: Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied. Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed. RESULTS: Of the 40 patients with hyperferritinemia, 29 (72%) had biochemical metabolic abnormalities, 18 of the 26 examined (69%) had insulin resistance, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls, 33 of 128 [26%], p < 0.0001), and all had increased liver iron concentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations, the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multiple metabolic alterations (odds ratio = 5.2, 95% CI = 0.95–28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liver iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal transferrin saturation, but only six remained hyperferritinemic after dietary restriction. CONCLUSION: Increased ferritin with normal transferrin saturation is frequently found in patients with hepatic steatosis, but it reflects iron overload only in those patients in whom it persists despite an appropriate diet. The simultaneous disorder of iron and glucose and/or lipid metabolism, in most of the cases associated with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH.