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Effects of p.o. administered xylitol in cats
Abstract
Xylitol is commonly used as sugar substitute in households. While it has numerous beneficial effects on human health, it is highly toxic to dogs. The goal of this study was to examine whether xylitol has similar deleterious effects, such as hypoglycaemia and acute hepatic failure, on cats. Our research included six healthy middle-aged cats. Xylitol was dissolved in deionized water and administered p.o. at three doses (100, 500 and 1,000 mg/kg body weight). These dosages have been considered toxic and can cause liver failure or even death in dogs. After every xylitol administration, the basic health status and the blood glucose of cats were observed regularly. Additionally, prior to and 6, 24 and 72 hr after xylitol administration, blood samples were taken to check complete blood count, clinical biochemical parameters and enzymes such as ALT, ALKP, GGT, GLDH, bile acids, BUN, creatinine, phosphate, total protein, albumin, sodium and potassium. There were no significant changes (p > .05) in any of the haematological or biochemical parameters. Blood glucose concentrations did not show any significant alterations, except at 1,000 mg/kg dose, where a mild but significant increase was observed, but it was in physiological range. Based on our results, xylitol did not induce toxic effects on cats.
... In contrast to dogs, xylitol is much less toxic to cats. Jerzsele et al. (2018) investigated the effect of xylitol in cats using dosages considered toxic for dogs (100, 500 and 1.000 mg/kg body weight), with the potential to cause liver failure or even death. The authors of this study concluded that xylitol at these doses is not toxic to cats, as it did not change the hematological or biochemical parameters analyzed. ...
... According to these authors, xylitol has been reported as a strong stimulator of insulin release for dogs. The contact of pets such as dogs and cats with xylitol, in general, occurs due to the accidental ingestion of xylitol in products used in the domestic environment (Jerzsele et al. 2018). Symptoms like vomiting, anorexia, jaundice, lethargy and weakness were observed in dogs, resulting in hypoglycemia and acute hepatic necrosis. ...
Xylitol is considered as one of the top relevant biorefinery sugar-derived products due to its interesting properties and its use has already been approved in more than forty countries. This polyol is mainly recognized in the food sector due to its sweetness equivalent to sucrose but with a significantly lower glycemic index. A great variety of products formulated with xylitol can be found in the market, being most industrially applied in chewing gum production. However, xylitol has others interesting properties, with several clinical applications, acting both on the prevention and treatment of diseases, such as cardiovascular diseases, otitis and diabetes. This chapter comprehensively presents the established and in development xylitol applications, from food to medical sector, including recently discovered COVID-19 treatment potential, and chemical industries applications, exploring xylitol-based materials and its use on tissue-engineering. In addition, xylitol safety and side effects are explored, including the main policies regarding its use.KeywordsXylitolFood sectorNutritional propertiesMedical applicationsSafety policies
... This demonstrated that our prepared crystals were nontoxic with LD 50 values > 2000 mg/kg body weight of the animals. The results are in accordance with Jerzsele et al. (2018) and Belsito et al. (2019), who observed that xylitol administration in both cats and mice at dosage levels of 1000 mg kg/kg bw and 2000 mg/kg bw did not adversely affect them. However, these studies were performed with crystals produced from ultrapure D-xylose (via catalytic route) against our crystals produced from a real time lignocellulosic feedstock through microbial fermentation. ...
Xylitol, a five-carbon sugar alcohol, has a steady global market and finds application as a natural sugar substitute in various food and confectionery products. Biocatalytic xylitol production, although touted as a greener alternative to conventional chemical catalysis, suffers from certain challenges, the primary being high cost of production. This study demonstrates a process for food-grade xylitol production from corncob biomass with energy reduction through two major process modifications. A non-conventional fermentation strategy was adopted whereby adjusting aeration without agitation, xylitol with high yield (0.86 ± 0.015 g/g), and productivity (0.74 gL⁻¹h⁻¹) could be produced by a GRAS Pichia caribbica MTCC 5703 strain. Xylitol was recovered from the broth in the form of crystals using a combination of membrane-based filtration and crystallization. The crystals demonstrated ~98 % purity when quantified with ¹H NMR. Oral toxicity analysis of the crystals demonstrated no adverse effect in female Winstar rats (at a loading of 2000 mg/kg body weight of animals). Overall process statistics showed that 0.584 kg of food-grade xylitol crystals could be produced from 3.5 kg of corncob biomass. The two-process modifications during fermentation and xylitol recovery enabled an energy saving of ~20.842 kW/kg of crystals, providing tremendous advantages for biorefinery-based large-scale xylitol production from corncob biomass.
... The results are in accordance with Park et al. (2015) and Siripurkpong et al. (2014), who observed that xylitol was non-inhibitory to the standard human cell lines. The non-toxicity of xylitol has also been demonstrated by Jerzsele et al. (2018) who reported that xylitol administration in cats, even at a high dosage of 1 g/kg body weight, did not adversely affect them. ...
Xylitol, a commodity chemical, is widely used in nutraceutical and pharmaceutical formulations. Microbial xylitol production is a promising alternative to mitigate current industrial practice issues and offers an environment-friendly sustainable conversion route. This study demonstrates a bioprocess for xylitol production from corncob using a mesophilic yeast Pichia caribbica. Corncob was hydrolyzed by dilute acid and steam explosion to recover fermentable xylose and used as the feed for xylitol production. Activated carbon treatment (3% w/v) completely removed the biomass-derived inhibitors furfural and hydroxymethyl furfural from the liquid hydrolysate. The fermenting yeast Pichia caribbica produced 124.1 ± 0.45 g/L xylitol from the detoxified and concentrated corncob hydrolysate with a high yield of 0.80 ± 0.02 g/g. The crystallized xylitol with 96.5% purity demonstrated no harmful effects on the cell line used as a control for the in-vitro toxicity studies. This proof of concept can be applied to help scale up for bio-refinery-based large-scale production of xylitol from corncob biomass.
... Xylitol toxicity is an important differential for hypoglycemia in the dog that has not been reported in cats. 18 The hypokalemia seen in this patient is also common and can be attributed to the high insulin levels causing intracellular movement of potassium. 19 All of the six prior feline insulinomas were hypoglycemic. ...
Case summary
A 14-year-old male neutered Maine Coon cat presented with a 6-month history of polyphagia and one recent episode of tremors and weakness. Blood work revealed profound hypoglycemia and results of a paired insulin glucose test were consistent with an insulinoma. Abdominal ultrasound revealed a solitary pancreatic mass, and results of a fine-needle aspirate (FNA) gave further support for the location of the neuroendocrine tumor. After unsuccessful medical management of the hypoglycemia, the mass was surgically removed. Immunohistochemistry confirmed that it was an insulinoma. At the time of writing, the patient had been in clinical remission for 9 months.
Relevance and novel information
Feline insulinomas are rare and there is very little information on their behavior, clinical course and histologic characteristics. This is the first reported case of an insulinoma in a Maine Coon cat and the first to describe results of an ultrasound-guided FNA of the mass. In addition, the progression of disease, histopathology and immunohistochemistry results add to the currently minimal database for feline insulinomas.
... In an experimental study, oral doses of 100, 500 or 1000 mg/kg given to cats did not cause signifi cant changes in haematological or biochemical parameters up to 72 hours aft er ingestion. All the cats remained well, with only transient salivation reported (Jerzsele et al, 2018). ...
Xylitol is toxic to dogs, causing hypoglycaemia and, in some cases, liver failure. This sweetener is found in many foods, medicines and confectionary, particularly chewing gums, because it has anticaries properties and a low glycaemic index. The most common source of xylitol poisoning in dogs is chewing gum, in which the xylitol content can vary enormously. In addition, granulated xylitol is available as a sugar substitute for baking. Xylitol-induced hypoglycaemia may be rapid in onset or, as is often the case with chewing gums, delayed for several hours. Elevated liver enzymes may be apparent within a few hours in some cases. Treatment is aimed at monitoring blood glucose and correcting hypoglycaemia, and protecting the liver. Dogs can survive high doses of xylitol with prompt aggressive treatment. In contrast, xylitol-induced hypoglycaemia and liver failure is not seen in cats, rabbits or rodents, but poisoning has been reported in birds.
... In an experimental study, oral doses of 100, 500 or 1000 mg/kg given to cats did not cause signifi cant changes in haematological or biochemical parameters up to 72 hours aft er ingestion. All the cats remained well, with only transient salivation reported (Jerzsele et al, 2018). ...
Xylitol is a commonly available sugar substitute found in sugar-free chewing gums and as an excipient in some medicines. It is used for its benefits on oral hygiene and its low-calorie content. It is also found in some peanut butters, ice creams and toothpastes, and can be used as a sugar substitute in baking. Xylitol causes hypoglycaemia (due to stimulation of insulin release) and liver failure in dogs, but not in cats, rabbits or rodents. The hypoglycaemia may be rapid in onset but can be delayed if xylitol-containing chewing gum has been ingested. Management of dogs that have ingested xylitol includes gut decontamination, monitoring, correction of hypoglycaemia and liver protectants. Prognosis is good in most cases and death from profound, uncontrolled hypoglycaemia or liver failure is not common.
Background: Cats and dogs presenting with potential poisoning is common in companion animal practice. However, treatment is not always necessary and so individual case assessment is essential to provide appropriate management, rather than having blanket protocols for all poisoning cases.
Aim of the article: This article gives guidance on performing a risk assessment of poisoning cases and discusses some of the common pitfalls in management and the common toxicants involved.
Veterinarians and pharmacists are familiar with the efficacy and safety aspects attributed to active pharmaceutical ingredients included in medicines, but they are rarely concerned with the safety of excipients present in medicines. Although generally recognized as safe, excipients are not chemically inert and may produce adverse events in certain animal populations. This review aims to present excipients of concern to these populations and highlight their relevance for rational veterinary pharmacotherapy.
A comprehensive review of the literature about the existence of adverse reactions in animals caused by pharmaceutical excipients was carried out based on an exploratory study. An overview of the correct conditions of use and safety of these excipients has also been provided, with information about their function, the proportion in which they are included in the different pharmaceutical dosage forms and the usual routes of administration.
We identified 18 excipients considered of concern due to their potential to cause harm to the health of specific animal populations: bentonite, benzalkonium chloride, benzoic acid, benzyl alcohol, ethanol, lactose, mannitol, mineral oil, monosodium glutamate, polyethylene glycol, polysorbate, propylene glycol, sodium benzoate, sodium carboxymethylcellulose, sodium lauryl sulfate, sulfites, polyoxyethylene castor oil derivatives, and xylitol. Among the 135 manuscripts listed, only 24 referred to studies in which the substances were correctly evaluated as excipients.
Based on the information presented in this review, the authors hope to draw the attention of professionals involved in veterinary pharmacotherapy to the existence of excipients of concern in medicines. This information contributes to rational veterinary pharmacotherapy and supports veterinary pharmacovigilance actions. We hope to shed light on the subject and encourage studies and new manuscripts that address the safety of pharmaceutical excipients to the animal population.
An adult dog were evaluated for treatment loss of consciousness, convulsions, and severe tremors after ingestion of xylitol, a sugar alcohol used as a sweetener in various products. Clinical findings were noted as loss of consciousness, convulsions, and severe tremors, while physio-pathological findings included moderately to severely elevated serum activities of liver enzymes, hypoglycaemia and hypophosphatemia. To correct hypoglycaemia, dextrose was administered intravenously and to provide electrolyte homeostasis Izolen P was administered intravenously. Also, Milk Thistle (Silymarin) & Beta Glucan Complex, Hepatiale Forte Advanced (S-adenosylmethionine), Evicap (Vit E) and Asist (acetylcysteine) were used to correct acute liver damage. Values measured after the applied treatments showed that blood glucose levels and liver enzymes returned to normal, and the patient was discharged. Xylitol causes hypoglycaemia and acute liver damage in dogs after ingestion. As a growing number of products contain xylitol, clinicians should be aware that ingestion of xylitol could have life-threatening effects. This case report also carries the distinction of being the first xylitol toxicity reported in dogs in Turkey.
Owners are often not aware that some common household products, medications, and plants are toxic to dogs and cats. Six cases of toxicoses due to ingestion of xylitol, amatoxin-containing mushrooms, anticoagulant rodenticide, zinc, vitamin D, and lily are presented with typical clinical and laboratory data findings. Changes in the laboratory data are explained in the context of the mechanism of action of the toxin and the organ systems affected.
Key Clinical Message
Xylitol and serotonergic compounds are included in the manufacture of numerous over‐the‐counter products. Both compounds have been documented to cause toxicosis in dogs. This report details the first case of simultaneous xylitol toxicosis and serotonin‐like syndrome in a dog, secondary to ingestion of a single over‐the‐counter product.
Objective . To provide a comprehensive overview of published evidence on the impact of erythritol, a noncaloric polyol bulk sweetener, on oral health. Methods . A literature review was conducted regarding the potential effects of erythritol on dental plaque (biofilm), dental caries, and periodontal therapy. The efficacy of erythritol on oral health was compared with xylitol and sorbitol. Results . Erythritol effectively decreased weight of dental plaque and adherence of common streptococcal oral bacteria to tooth surfaces, inhibited growth and activity of associated bacteria like S. mutans , decreased expression of bacterial genes involved in sucrose metabolism, reduced the overall number of dental caries, and served as a suitable matrix for subgingival air-polishing to replace traditional root scaling. Conclusions . Important differences were reported in the effect of individual polyols on oral health. The current review provides evidence demonstrating better efficacy of erythritol compared to sorbitol and xylitol to maintain and improve oral health.
Several foods that are perfectly suitable for human consumption can be toxic to dogs and cats. Food-associated poisoning cases involving the accidental ingestion of chocolate and chocolate-based products, Allium spp. (onion, garlic, leek, and chives), macadamia nuts, Vitis vinifera fruits (grapes, raisins, sultanas, and currants), products sweetened with xylitol, alcoholic beverages, and unbaked bread dough have been reported worldwide in the last decade. The poisoning episodes are generally due to lack of public knowledge of the serious health threat to dogs and cats that can be posed by these products. The present review aims to outline the current knowledge of common food items frequently involved in the poisoning of small animals, particularly dogs, and provides an overview of poisoning episodes reported in the literature.
We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo, we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50-60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1-overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders.
According to world statistics, dogs and cats are the species that owners most frequently seek assistance with potential poisonings, accounting 95–98% of all reported animal cases. Exposures occur more commonly in the summer and in December that is associated with the holiday season. The majority (>90%) of animal poisonings are accidental and acute in nature and occur near or at the animal owner's home. Feeding human foodstuff to pets may also prove dangerous for their health.
The aim of this review was to present common food items that should not be fed (intentionally or unintentionally) to dogs, i.e. chocolate, caffeine, and other methylxanthines, grapes, raisins, onion, garlic, avocado, alcohol, nuts, xylitol contained in chewing gum and candies, etc. Onion and avocado are toxic for cats, too. The clinical effects of individual toxicants and possible therapy are also mentioned. Knowing what human food has the potential to be involved in serious toxicoses should allow veterinarians to better educate their clients on means of preventing pet poisonings.
It can be concluded that the best advice must surely be to give animal fodder or treats specifically developed for their diets.
The Cases of xylitol poisoning in dogs are increasing as a result of ingestion of xylitol-containing products. Eighteen adult, clinically normal Pekingese dogs were orally dosed with 1 or 4 g/kg xylitol in aqueous solution. Blood samples were collected before and after dosing. Plasma insulin concentrations of both treated groups rose sharply from 20 min after xylitol dosing, peaking at 40 min. Hypoglycemia followed the increase in insulin concentration, with blood glucose values started to decrease 30 min after dosing. Other plasma biochemistry changes associated with xylitol administration were increased alanine aminotransferase and aspartate aminotransferase activities, hypophosphatemia, hypokalemia, and hypercalcemia. Plasma sodium and chloride concentrations remained normal. This study established a biochemical basis for diagnosis and treatment of xylitol poisoning in dogs.
Glutamate dehydrogenase, an enzyme central to glutamate metabolism, is deficient in patients with heterogeneous neurological disorders characterized by multiple system atrophy. There is evidence for multiplicity of human glutamate dehydrogenase, which may account for the heterogeneity of the above disorders. However, only one mRNA that is encoded by an intron-containing gene (GLUD1) is presently known. Because blindness due to neuroretinal degeneration can occur in rare forms of multiple system atrophy, we searched for retina-specific GLUD mRNA(s) by screening a lambda gt10 library derived from human retina. A novel cDNA encoded by an X chromosome-linked intronless gene, designated GLUD2, was isolated and characterized. Reverse transcription-polymerase chain reaction analysis of human tissues revealed that the novel cDNA is expressed in human retina, testis, and, at lower levels, brain. In vitro translation of mRNAs derived from GLUD1 and GLUD2 genes generated proteins with distinct electrophoretic characteristics. The retinal cDNA was expressed in the baculovirus heterologous system, producing a protein capable of catalyzing the oxidative deamination of glutamate. The mobility of the expressed protein on SDS-polyacrylamide gel electrophoresis and its catalytic properties were very similar to those of the naturally occurring human brain glutamate dehydrogenases. The novel gene will be useful for understanding the biology of human neural and testicular tissues and in the study of X-linked neurodegenerative disorders.
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Xylitol is a five-carbon sugar alcohol produced from natural resources frequently used as a sugar substitute for humans. We report the development and successful treatment of acute hepatic failure and coagulopathy in a dog after xylitol ingestion. A 9-year-old 4.95 kg (10.9 lb) neutered male Chihuahua was evaluated at a veterinary clinic for vomiting after ingesting 224 g (45 g/kg, 20.5 g/lb) of granulated xylitol. Hypoglycemia developed within 1-2 h, elevated liver values, suggesting the development of acute hepatic failure, within 12 h and coagulopathy less than 24 h after ingestion. Treatment included maropitant, intravenous dextrose, phytonadione, metronidazole, and fresh frozen plasma. N-acetylcysteine (NAC) and S-adensoyl-L-methionine (SAMe) provided hepatic detoxification and support. The dog survived and liver values returned to normal within 1 month post ingestion. No adverse effects to hepatic function have been identified 2 years after acute xylitol toxicity. This paper is one of the few reports of successful management of a dog with hypoglycemia, hepatic failure, and coagulopathy caused by xylitol toxicity. To date, this is the highest published xylitol dose survived by a dog, as well as the only reported case that documents laboratory changes throughout the course of toxicity and includes normal hepatic indices for 7 months following xylitol toxicity. The rapidly expanding use of xylitol in a variety of products intended for human consumption has led to a rise in xylitol toxicity cases reported in dogs, and clinicians should be aware that more dogs may potentially be exposed and develop similar manifestations.
Once thought to cause only hypoglycemia in dogs, this sugar substitute has recently been discovered to also produce acute, possibly life-threatening liver disease and coagulopathy. And the number of reported exposures to xylitol has been increasing.
NAD(H)-glutamate dehydrogenase (GDH; EC 1.4.1.2) is an abundant and ubiquitous enzyme that may exist in different isoenzymic forms. Variation in the composition of the GDH isoenzyme pattern is observed during plant development and specific cell, tissue and organ localization of the different isoforms have been reported. However, the mechanisms involved in the regulation of the isoenzymatic pattern are still obscure. Regulation may be exerted at several levels, i.e. at the level of transcription and translation of the relevant genes, but also when the enzyme is assembled to originate the catalytically active form of the protein. In Arabidopsis thaliana, three genes (GDH1, GDH2 and GDH3) encode three different GDH subunits (b, a and g) that randomly associate to form a complex array of homo- and hetero-hexamers. In order to asses if the different Arabidopsis GDH isoforms may display different structural properties we have investigated their thermal stability. In particular the stability of GDH1 and GDH3 isoenzymes was studied using site-directed mutagenesis in a heterologous yeast expression system. It was established that the carboxyl terminus of the GDH subunit is involved in the stabilization of the oligomeric structure of the enzyme.
Xylitol is a prevalent sugar substitute found in a wide variety of foods, particularly those labeled as "low carb." It is found in many medicines and dental products both for its antibacterial activity and to increase palatability. Originally, this toxin was recognized as a problem in dogs following sugarless gum ingestions. Xylitol is generally nontoxic to mammals except for dogs. In the dog, xylitol induces marked increases in insulin production and occasionally hepatopathy. The clinical syndrome is manifested with signs consistent with profound hypoglycemia, hypokalemia, hypophosphatemia, and acute hepatic failure. Treatment relies upon administration of intravenous glucose, hepatic support, and general supportive care.
Objective: To describe a case of xylitol intoxication causing fulminant hepatic failure in a dog.
Case summary: A 2.5-year-old castrated male English Springer Spaniel weighing 26 kg, was presented after ingestion of half of a loaf of bread containing the sweetener xylitol. Toxic effects of the xylitol in this dog included vomiting, mild hypoglycemia and fulminant hepatic failure. Clinical management of acute hepatic failure and subsequent coagulopathy with supportive care and fresh frozen plasma is described. The dog was discharged 3 days after admission after a full clinical recovery.
New or unique information provided: This paper describes the clinical consequence and successful treatment of fulminant hepatic failure in a dog following ingestion of xylitol.
SIR, — The Veterinary Poisons Information Service (London) would like to warn veterinarians urgently about the hazard that xylitol, a sweetening agent, presents to dogs.
It is found in some chewing gums and sweets, but recently has been marketed in the uk as a sugar substitute for use in baking.
Xylitol is known to cause hepatic ATP catabolism by inducing the trapping of Pi in the form of glycerol 3-P as a consequence of an increase in the NADH:NAD+ ratio, resulting from the oxidation of xylitol to D-xylulose. The question was therefore raised whether D-xylulose also depletes hepatic ATP. In isolated rat hepatocytes, 5 mM D-xylulose decreased ATP by 80% within 5 min compared to 40% with 5 mM xylitol. Intracellular Pi decreased by 70% within the same time interval with both compounds, but was restored three-fold faster with D-xylulose. The rate of utilization of D-xylulose reached 5 mumol.min-1.g-1 of cells, as compared with 1.5 for xylitol, indicating that reduction of xylitol into D-xylulose is a rate-limiting step in the metabolism of the polyol. D-Xylulose barely modified the concentration of glycerol 3-P but increased xylulose 5-P from 0.02 to 0.5 mumol/g within 5 min. The main cause of the ATP- and Pi-depleting effects of D-xylulose was found to be an accumulation of sedoheptulose 7-P from a basal value of 0.1 to 5 mumol/g of cells after 10 min. Ribose 5-P increased from 0.03 to 0.5 mumol/g at 5 min. Ribose 1-P also accumulated, albeit outside of the cells. This extracellular accumulation can be explained by the release of intracellular purine nucleoside phosphorylase from damaged hepatocytes acting on inosine that had diffused out of the cells. Smaller increases in the concentrations of sedoheptulose 7-P and pentose phosphates were recorded after incubations of the cells with xylitol.
Sugar alcohols are used in food products, yet their metabolic effects in humans are poorly known. We examined plasma glucose, insulin, and C-peptide responses and changes in carbohydrate and lipid oxidation after the ingestion of 25 g lactitol, xylitol, or glucose. Eight healthy, nonobese men were studied after an overnight fast. After the ingestion of lactitol or xylitol, the rise in plasma glucose, insulin, and C-peptide concentrations was less than after the ingestion of glucose (P < 0.02), with no difference between the two polyols. With the glycemic index of glucose as 100, the indexes of xylitol and lactitol were 7 and -1, respectively. A reactive hypoglycemia was observed 3 h after glucose ingestion, but not after the ingestion of sugar alcohols. There were no significant changes in the carbohydrate or lipid oxidation as determined by indirect calorimetry after the ingestion of sugar alcohols. After glucose ingestion, the rise in carbohydrate oxidation was nearly significant (P = 0.07). In conclusion, lactitol and xylitol cause smaller changes than does glucose in plasma glucose and insulin concentrations and thermogenic response. A small hormonal response and the lack of a thermogenic effect may be beneficial when these sugar alcohols are used in food products. The small glucose and insulin responses also suggest that lactitol and xylitol are suitable components of the diet for diabetic patients.
Although reactive oxygen species (ROS) have been implicated in the etiology of alcohol-induced liver disease, neither their relative contribution to cell death nor the cellular mechanisms mediating their formation are known. The purpose of this study was to test the hypothesis that acute and chronic ethanol exposure enhances the mitochondrial generation of ROS in fresh, isolated hepatocytes. Acute ethanol exposure stimulated ROS production, increased the cellular NADH/NAD+ ratio, and decreased hepatocyte viability slightly, which was prevented by pretreatment with 4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase. Similarly, xylitol, an NADH-generating compound, enhanced hepatocyte ROS production and decreased viability. Incubation with pyruvate, an NADH-oxidizing compound, and cyanamide, an inhibitor of aldehyde dehydrogenase, significantly decreased ROS levels in acute ethanol-treated hepatocytes. Chronic ethanol consumption produced a sixfold increase in hepatocyte ROS production compared with levels measured in controls. Hepatocytes from ethanol-fed rats were less viable compared with controls, e.g., viability was 68% +/- 2% (ethanol) versus 83% +/- 1% (control) after 60 minutes of incubation. Antimycin A increased ROS production and decreased cell viability; however, the toxic effect of antimycin A was more pronounced in ethanol-fed hepatocytes. These results suggest that acute and chronic ethanol exposure exacerbates mitochondrial ROS production, contributing to cell death.
Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8--25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells.
A 9-mo-old neutered male Labrador Retriever developed severe hypoglycemia, collapse, and seizures after consuming a large quantity of sugar-free gum sweetened with the sugar-alcohol xylitol. The dog was treated with i.v. boluses and continuous infusion of dextrose; its condition improved rapidly, but the dog remained mildly hypoglycemic for 11 hours before recovering fully. In humans, xylitol has little to no effect on plasma insulin or glucose levels, but in dogs xylitol is a strong promoter of insulin release and can cause severe hypoglycemia with ataxia, collapse and seizures. With the increased appearance of xylitol-sweetened products in the US, xylitol toxicosis in dogs may become more common.
1. Loading the isolated perfused liver from well-fed rats with xylitol (20mm) caused a depletion of adenine nucleotides and P(i) and an accumulation of alpha-glycerophosphate. The ATP content fell to 66% of the control value after 10min and to 32% after 80min. The ADP and AMP contents also fell. After 80min 63% of the total adenine nucleotides and 59% of the P(i) had been lost. 2. The alpha-glycerophosphate content rose from 0.13 to 4.74mumol/g at 10min and reached 8.02mumol/g at 40min. 3. Xylitol was rapidly metabolized, the main products being glucose, lactate and pyruvate. 4. The [lactate]/[pyruvate] ratio in the presence of xylitol rose to 30-40. 5. On perfusion of livers from starved animals the main product of xylitol metabolism was glucose and the mean ratio xylitol removed/glucose formed was 1.29 (corrected for endogenous glucose and lactate production). This is close to the predicted value of 1.2. 6. Evidence is presented indicating that the loss of adenine nucleotides caused by xylitol is not due to the increased ATP consumption but to the accumulation of alpha-glycerophosphate and depletion of P(i). 7. The loss of adenine nucleotides accounts for the hyperuricaemia which can occur after xylitol infusion in man. 8. The relevance of the findings to the clinical use of xylitol as an energy source is discussed.
This study was performed to determine the effect of a drinking water additive on reducing plaque and calculus accumulation in cats. A two-period, parallel crossover design was used with each period consisting of a 56-day test phase. Results demonstrated that the addition of xylitol to the drinking water was effective in reducing plaque and calculus accumulation in cats.
8 adult dogs were evaluated for treatment of lethargy and vomiting after ingestion of xylitol, a sugar alcohol used as a sweetener in various products.
In addition to vomiting and lethargy, 5 of the dogs had widespread petechial, ecchymotic, or gastrointestinal tract hemorrhages. Common clinicopathologic findings included moderately to severely high serum activities of liver enzymes, hyperbilirubinemia, hypoglycemia, hyperphosphatemia, prolonged clotting times, and thrombocytopenia. Necropsies were performed on 3 dogs and severe hepatic necrosis was found in 2. In the third dog, histologic examination revealed severe hepatocyte loss or atrophy with lobular collapse.
Treatments varied among dogs and included IV administration of fluids; plasma transfusions; and, if indicated, administration of dextrose. Three dogs were euthanatized, 2 dogs died, 2 dogs made a complete recovery, and 1 dog was recovering but was lost to follow-up.
Although xylitol causes hypoglycemia in dogs, hepatic failure after ingestion has not previously been reported. Because an increasing number of consumer products contain xylitol, clinicians should be aware that ingestion of xylitol can have serious, life-threatening effects.
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