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Nutrients Oct 2023Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models....
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Topics: Humans; Animals; Mice; Fructose Intolerance; Fructose; Fructose-Bisphosphate Aldolase; Liver Diseases; Digestive System Diseases; Glucose; Mice, Knockout
PubMed: 37892451
DOI: 10.3390/nu15204376 -
Frontiers in Physiology 2017Acute ingestion of alcohol is often accompanied by cardiovascular dysregulation, malaise and even syncope. The full hemodynamic and cutaneous responses to the...
Acute ingestion of alcohol is often accompanied by cardiovascular dysregulation, malaise and even syncope. The full hemodynamic and cutaneous responses to the combination of alcohol and sugar (i.e., alcopops), a common combination in young people, and the mechanisms for the propensity to orthostatic intolerance are not well established. Thus, the purpose of this study was to evaluate the cardiovascular and cutaneous responses to alcopops in young subjects. Cardiovascular and cutaneous responses were assessed in 24 healthy young subjects (12 men, 12 women) sitting comfortably and during prolonged active standing with a 30-min baseline and 130 min following ingestion of 400 mL of either: water, water + 48 g sugar, water + vodka (1.28 mL.kg of body weight, providing 0.4 g alcohol.kg), water + sugar + vodka, according to a randomized cross-over design. Compared to alcohol alone, vodka + sugar induced a lower breath alcohol concentration (BrAC), blood pressure and total peripheral resistance ( < 0.05), a higher cardiac output and heart rate ( < 0.05) both in sitting position and during active standing. In sitting position vodka + sugar consumption also led to a greater increase in skin blood flow and hand temperature ( < 0.05) and a decrease in baroreflex sensitivity ( < 0.05). We observed similar results between men and women both in sitting position and during active standing. Despite lower BrAC, ingestion of alcopops induced acute vasodilation and hypotension in sitting position and an encroach of the hemodynamic reserve during active standing. Even if subjects did not feel any signs of syncope these results could be of clinical importance with higher doses of alcohol or if combined to other hypotensive challenges.
PubMed: 29176950
DOI: 10.3389/fphys.2017.00860 -
Molecular Metabolism Dec 2023Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage...
Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.
OBJECTIVE
Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD.
METHODS
C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls.
RESULTS
After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression.
CONCLUSIONS
Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.
Topics: Animals; Female; Humans; Male; Mice; Ceramides; Ethanol; Fatty Liver; Glucose; Homeostasis; Insulins; Lipid Droplets; Liver Diseases, Alcoholic; Mice, Inbred C57BL; Perilipin-2
PubMed: 37714377
DOI: 10.1016/j.molmet.2023.101804 -
The Yale Journal of Biology and Medicine 1978In normal individuals, the main route for tyrosine degradation is the hepatic pathway tyrosine→4-hydroxyphenylpyruvic acid→homogentisic acid→CO(2). Quantitatively... (Review)
Review
In normal individuals, the main route for tyrosine degradation is the hepatic pathway tyrosine→4-hydroxyphenylpyruvic acid→homogentisic acid→CO(2). Quantitatively minor pathways, in large part extrahepatic, are: tyrosine→tyramine→octopamine and tyrosine→dopa→catecholamines.In cirrhosis, the main hepatic pathway is blocked to varying degrees at the first three stages. This appears to be due to lack of activity of the enzymes tyrosine transaminase, PHPA oxidase, and HGA oxidase, the first step being rate limiting. Hypertyrosinemia and tyrosine intolerance result.With the main hepatic pathway partially blocked, an abnormally large amount of tyrosine passes into the normally minor extrahepatic pathway leading to the false neurotransmitters tyramine and octopamine. Overproduction of these amines ensues and they accumulate in the body fluid.The false neurotransmitters can displace catecholamines from their storage sites in the peripheral and central nervous system, and thereby disrupt adrenergic processes in arterioles, kidneys, and brain. Their accumulation in cirrhotic patients may play a role in the pathogenesis of hepatic encephalopathy, hepatorenal syndrome, and hyperdynamic circulation.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Alkaptonuria; Amino Acid Metabolism, Inborn Errors; Catecholamines; Homogentisic Acid; Humans; Liver Cirrhosis; Male; Middle Aged; Models, Biological; Octopamine; Oxygenases; Phenylketonurias; Tyramine; Tyrosine; Tyrosine Transaminase
PubMed: 36717
DOI: No ID Found -
Biomolecules Mar 2023Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are...
Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4 and Tlr4) that allow ablation of TLR4 only in hepatocytes (Tlr4) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4 × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4 mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4 × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4 × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4 × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.
Topics: Animals; Mice; Ethanol; Glucose Intolerance; Hepatocytes; Insulin; Insulin Resistance; Liver; Mice, Inbred C57BL; Toll-Like Receptor 4
PubMed: 36979389
DOI: 10.3390/biom13030454 -
World Journal of Gastroenterology Jul 2014Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders in Western countries. Despite the high prevalence of this disorders, the therapeutic... (Review)
Review
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders in Western countries. Despite the high prevalence of this disorders, the therapeutic management of these patients is often unsatisfactory. A number of factors have been suggested to be involved in the pathogenesis of IBS, including impaired motility and sensitivity, increased permeability, changes in the gut microbiome and alterations in the brain-gut axis. Also food seems to play a critical role: the most of IBS patients report the onset or the exacerbation of their symptoms after the meals. Recently, an increasing attention has been paid to the role of food in IBS. In this review we summarize the most recent evidences about the role of diet on IBS symptoms. A diet restricted in fermentable, poorly absorbed carbohydrates and sugar alcohols has beneficial effects on IBS symptoms. More studies are needed to improve our knowledge about the relationship between food and IBS. However, in the foreseeable future, dietary strategies will represent one of the key tools in the therapeutic management of patients with IBS.
Topics: Animals; Bacteria; Diet, Carbohydrate-Restricted; Diet, Gluten-Free; Dietary Carbohydrates; Feeding Behavior; Fermentation; Food Hypersensitivity; Humans; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Lactose Intolerance; Microbiota; Risk Factors; Treatment Outcome
PubMed: 25083057
DOI: 10.3748/wjg.v20.i27.8837 -
Oncology 2017Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients... (Review)
Review
Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients with PV, treatment with aspirin and hematocrit control with phlebotomy are recommended. In addition, patients with high-risk status or poor hematocrit control benefit from cytoreductive therapy with hydroxyurea, although approximately 1 in 4 patients develops resistance or intolerance. For patients who are resistant to or intolerant of hydroxyurea, studies have shown that ruxolitinib, a Janus kinase 1/2 inhibitor, provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms. For many patients, PV is managed in a community health setting, and it is important that community hematologists, oncologists, and internists are familiar with the contemporary management of PV to improve patient outcomes, including management for patients who present with unique health-care needs. This review provides an overview of current treatment options for patients with PV and discusses challenging circumstances encountered by community providers in the management of PV, including symptom assessment, identification of hydroxyurea resistance/intolerance, pregnancy, elective surgeries, concomitant immunosuppressants, and managing patients in areas with limited access to specialized hematologic care.
Topics: Community Health Centers; Drug Resistance, Neoplasm; Elective Surgical Procedures; Female; Hematocrit; Humans; Hydroxyurea; Immunosuppressive Agents; Interferon-alpha; Nitriles; Polycythemia Vera; Polyethylene Glycols; Pregnancy; Pyrazoles; Pyrimidines; Recombinant Proteins
PubMed: 28095380
DOI: 10.1159/000454953 -
Metacognitive and Meta-Emotional Styles in Patients With Alcohol and the Other Substance Dependence.International Journal of High Risk... Sep 2015Both alcohol and other substances are utilized for emotional and cognitive regulation.
BACKGROUND
Both alcohol and other substances are utilized for emotional and cognitive regulation.
OBJECTIVES
The purpose of the present study was to compare metacognitive styles and distress intolerance in patients with alcohol and other substance dependence.
PATIENTS AND METHODS
According to DSM-IV TR criteria, 45 patients with alcohol dependence (AD), 44 patients with substance dependence (SD), and 43 volunteers without AD or SD (control group) were enrolled. Socio-demographic information form, Distress Tolerance Scale (DTS), and metacognitive questionaire-30 (MCQ-30) were used to evaluate the participants.
RESULTS
Patients with AD had significantly lower "tolerance" subscale and total DTS scores than those with SD and control group (P = 0.008 for SD sample and P = 0.004 for control group). Patients with SD had significantly higher scores in "appraisal" subscale DTS than control group (P = 0.005). Patients of both AD and SD groups had significantly higher scores in "positive beliefs" subscale of MCQ-30 than control group (P = 0.012 for AD group and P = 0. 001 for SD group). There was no significant difference between AD and SD groups in any MCQ-30 subscale and total scores (P = 0.440).
CONCLUSIONS
Metacognitive regulation strategies are more considerable prediction than emotional regulation strategies in SD group than in AD group. Individuals with AD use alcohol as a means of both cognitive and emotional regulation strategy.
PubMed: 26495260
DOI: 10.5812/ijhrba.24553 -
The Cochrane Database of Systematic... Mar 2010Pegloticase is a potential new treatment option for patients with chronic gout intolerant to other urate-lowering therapies. (Review)
Review
BACKGROUND
Pegloticase is a potential new treatment option for patients with chronic gout intolerant to other urate-lowering therapies.
OBJECTIVES
To assess safety (adverse events, death) and efficacy (pain, function, frequency of flares, quality of life, uric acid level, radiographic damage) of pegloticase in various doses or as compared to placebo or other interventions for treatment of hyperuricemia in patients with chronic gout.
SEARCH STRATEGY
We searched six databases: The Cochrane Central Register of Controlled Trials (CENTRAL), via The Cochrane Library, OVID MEDLINE, CINAHL (via EBSCOHost), OVID SPORTdiscus, EMBASE and the Science Citation Index (Web of Science).
SELECTION CRITERIA
All published randomized controlled trials (RCTs) or controlled clinical trials that compared various doses of pegloticase alone or pegloticase alone or in combination with other urate-lowering or anti-inflammatory medications to placebo alone or placebo in combination with these medications, in patients with gout.
DATA COLLECTION AND ANALYSIS
Two review authors (AA, JS) independently extracted data from the included trials, including trial and population characteristics, primary and secondary outcomes. For dichotomous and continuous outcomes, we calculated the risk ratio and mean difference, respectively with 95% confidence interval. Major outcomes were: (a)
EFFICACY
frequency of gout flares and change in serum uric acid; and (b) safety: adverse events, serious adverse events, withdrawals and death. Minor/secondary outcomes were pain, patient/physician global assessment, tophus burden, health related quality of life, function and radiographic progression.
MAIN RESULTS
Only one open-label, phase-II RCT (n=41) met the selection criteria that compared various doses of pegloticase without comparison to placebo or another treatment. Patients were randomized to one of the four doses of pegloticase for 12 to 14 weeks - 4mg every 2 weeks, 8mg every 2 weeks, 8mg every 4 weeks and 12mg every 4 weeks. Percent responders (uric acid below 6 mg/dl 80% or more time) in the four dose groups were 56%, 88%, 52% and 62%. Percent time without hyperuricemia (uric acid below 6 mg/dl) was 78%, 92%, 76% and 76% respectively. No between dose differences were noted. Most common adverse events (10% or more patients) included nephrolithiasis, arthralgia, anemia, dyspnea, headache, muscle spasms, nausea and pyrexia. 89% reported one or more gout flares during the study. Pain, patient/physician global, function, quality of life, tophus size/regression and radiographic progression were not reported in this study.
AUTHORS' CONCLUSIONS
There are no published double-blind, placebo-controlled RCTs of pegloticase. More evidence is needed to assess risks/benefits of pegloticase in patients with chronic gout.
Topics: Chronic Disease; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Gout; Humans; Polyethylene Glycols; Randomized Controlled Trials as Topic; Urate Oxidase; Uricosuric Agents
PubMed: 20238366
DOI: 10.1002/14651858.CD008335.pub2 -
European Review For Medical and... 2013Carbohydrate malabsorption is a frequent clinical condition, often associated with abdominal symptoms. Although lactose represents the most commonly malabsorbed sugar,... (Review)
Review
Carbohydrate malabsorption is a frequent clinical condition, often associated with abdominal symptoms. Although lactose represents the most commonly malabsorbed sugar, also other carbohydrates, such as fructose, trehalose and sorbitol may be incorrectly absorbed in the small intestine. Fructose malabsorption seems more common in patients with functional bowel disease, even if randomized and controlled studies on these topic were few and on small samples. Interpretation of breath hydrogen testing is difficult. In particular, neither studies comparing this test with a gold standard, nor validated doses and concentrations to be used, are available. Trehalose malabsorption due to trehalase deficiency represents a very rare condition and available studies do not support its relevance in clinical practice. Sorbitol absorption is dose and concentration related, and depends on the entity of intestinal absorption surface. Nevertheless, the finding of its malabsorption is not expression of a specific cause of intestinal bowel damage. From available data, it is not possible to draw definite conclusions about clinical relevance of fructose, trehalose and sorbitol malabsorption, as well as, about diagnostic accuracy of commonly used tests to detect all these conditions. On the other hand, in patients who refer abdominal discomfort after ingestion of different carbohydrate-containing foods, a small intestinal bacterial overgrowth, should be promptly considered. This is because the large amount of intestinal bacteria may unspecifically ferment sugars, causing an abnormal H2 production and consequently a misleading diagnosis of sugar malabsorption.
Topics: Breath Tests; Carbohydrate Metabolism, Inborn Errors; Diarrhea; Fructose Intolerance; Humans; Intestinal Absorption; Intestinal Mucosa; Malabsorption Syndromes; Predictive Value of Tests; Prognosis; Sorbitol; Trehalase
PubMed: 24443064
DOI: No ID Found