Effects in vivo of food deprivation and 3-mercaptopicolinate in the glycogen-storage-disease (gsd/gsd) rat.
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ABSTRACT:
SUBMITTER: Clark DG
PROVIDER: S-EPMC1152812 | biostudies-other | 1985 Nov
REPOSITORIES: biostudies-other
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Project description:In this study we utilized the phosphorylase b kinase-deficient (gsd/gsd) rat as a model of hepatic substrate utilization where there is a constraint on glycogenesis imposed by the maintenance of high glycogen concentrations. Glucose re-feeding of 48 h-starved gsd/gsd rats led to suppression of hepatic glucose output. In contrast with the situation in normal rats, activation of the pyruvate dehydrogenase complex and lipogenesis was observed. It is suggested that impeding glycogenic flux may divert substrate into lipogenesis, possibly via activation of the pyruvate dehydrogenase complex.
| S-EPMC1148646 | biostudies-other
Project description:The effects of food deprivation on body weight, liver weight, hepatic glycogen content, glycogenolytic enzymes and blood metabolites were compared in young and old phosphorylase b kinase-deficient (gsd/gsd) rats. Although the concentration of glycogen in liver from 9-week-old female gsd/gsd rats (730 mumol of glucose equivalents/g wet wt.) was increased by 7-8% during starvation, total hepatic glycogen was decreased by 12% after 24 h without food. In 12-month-old male gsd/gsd rats the concentration of liver glycogen (585 mumol of glucose equiv./g wet wt.) was decreased by 16% and total hepatic glycogen by nearly 40% after food deprivation for 24 h. Phosphorylase b kinase and phosphorylase a were present at approx. 10% of the control activities in 9-week-old gsd/gsd rats, but both enzyme activities were increased more than 3-fold in 12-month-old affected rodents. It is concluded that the age-related ability to mobilize hepatic glycogen appears to result from the augmentation of phosphorylase b kinase during maturation of the gsd/gsd rat.
| S-EPMC1147208 | biostudies-other
Project description:Now 15-year-old girl with glycogen storage disease (GSD) type IIIa (OMIM 232400) developed severe left ventricular obstructive hypertrophy and hepatomegaly while treated with frequent cornstarch meals. Subsequently, she was introduced the ketogenic diet; continuous ketosis has been maintained for over the last 4 years. After the introduction of ketogenic diet, a normalization of the cardiomyopathy and improvement of hepatopathy was achieved, with enhanced overall quality of life.
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Project description:1. The metabolism of hepatic glycogen, labelled with [6-3H]glucose at day 19.5 of gestation and with 14C from [U-14C]galactose at delivery, was followed for 10 h in food-deprived gsd/gsd and control (GSD/GSD) neonatal rats. 2. In the affected pups glycogen was maintained at 12% (w/w) and there was no loss of incorporated radioactivity. 3. The 3H and 14C in glycogen from the controls were both decreased by 80%, but 14C was removed at 0--5 h and [6-3H]glucose at 5--10 h. 4. Blood glucose concentrations in the unaffected neonatal rats fell from 5.3 mM at 20 min to 1.7 mM after 10 h. In the gsd/gsd pups blood glucose concentration was decreased from 2 mM at birth to 0.3 mM at 2.5 h: it was maintained at 0.8 mM between 5 and 10 h. 5. In neonatal rats that had been dead for 10 h, hepatic glycogen was decreased by 34% in the controls and by 22% in the gsd/gsd pups. These results demonstrate that liver from the affected rats contains glycogenolytic activity, but that it is not expressed in living tissue.
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Project description:RATIONALE:Serious neurological concomitants of alcoholism include Wernicke's encephalopathy (WE), Korsakoff's syndrome (KS), and hepatic encephalopathy (HE). OBJECTIVES:This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. METHODS:Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. RESULTS:Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. CONCLUSIONS:These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.
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Project description:Bovine adipose-tissue glycogen metabolism was studied during food deprivation and re-feeding. Changes in the specific activity of adipose-tissue glycogen synthase paralleled changes in tissue glycogen content: both parameters increased during food deprivation and remained so during the first 10 days of re-feeding. The values for the A0.5 (activation constant) for glucose 6-phosphate of the freshly isolated enzyme from adipose tissue from fed and starved steers were 2.9 +/- 0.1 mM and 0.90 +/- 0.05 mM respectively. Additionally, whereas incubation of adipose-tissue extracts from fed steers did not activate endogenous glycogen synthase (through a presumed phosphoprotein phosphatase mechanism), the enzyme from starved or re-fed (up to 3 days re-feeding) steers was reversibly activated as measured by changes in the value for the A0.5 for glucose 6-phosphate. Thus activation of bovine adipose-tissue glycogen synthase during food deprivation appears to be related to expression of glycogen synthase phosphatase activity. These effects of food deprivation on bovine glycogen metabolism contrast markedly with the effects observed in rat adipose tissue.
| S-EPMC1161756 | biostudies-other
Project description:Background: A deficiency of muscle phosphofructokinase (PFKM) causes a rare metabolic muscle disease, the Tarui disease (Glycogen storage disease type VII, GSD VII) characterized by exercise intolerance with myalgia due to an inability to use glucose as an energy resource. No medical treatment for GSD VII currently exists. The aim of this study was to determine whether a dietary intervention with excessive fat intake would benefit GSD VII. Patient and Methods: A ketogenic diet (KD) intervention implemented as a modified Atkins diet was established for one patient with PFKM deficiency, with a low late lactate response and very high ammonia levels associated with exercise. We recorded the KD intervention for a total of 5 years with clinical and physiotherapeutic evaluations and regular laboratory parameters. Cardiopulmonary exercise testing, including breath gas analysis and venous lactate and ammonia measurements, was performed before KD and at 3, 8 months and 5 years after initiation of KD. Results: During the 5 years on KD, the patient's muscle symptoms had alleviated and exercise tolerance had improved. In exercise testing, venous ammonia had normalized, the lactate profile remained similar, but oxygen uptake and mechanical efficiency had increased and parameters showing ventilation had improved. Conclusions: This study is the first to show a long-term effect of KD in GSD VII with an alleviation of muscle symptoms, beneficial effects on breathing, and improvement in exercise performance and oxygen uptake. Based on these findings, KD can be recommended under medical and nutritional supervision for selected patients with GSD VII, although further research of this rare disease is warranted.
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Project description:Glycogen storage diseases (GSD) encompass a group of rare inherited diseases due dysfunction of glycogen metabolism. Hypoglycemia is the most common primary manifestation of GSD, and disturbances in glucose metabolism can cause neurological damage. The aims of this study were to first investigate the metabolic, genetic, and neurological profiles of children with GSD, and to test the hypothesis whether GSD type I would have greater neurological impact than GSD type IX. A cross-sectional study was conducted with 12 children diagnosed with GSD [Types: Ia (n=5); 1, Ib (n=1); 4, IXa (n=5); and 1, IXb (n=1)]. Genetic testing was conducted for the following genes using multigene panel analysis. The biochemical data and magnetic resonance imaging of the brain presented by the patients were evaluated. The criteria of adequate metabolic control were adopted based on the European Study on Glycogen Storage Disease type I consensus. Pathogenic mutations were identified using multigene panel analyses. The mutations and clinical chronology were related to the disease course and neuroimaging findings. Adequate metabolic control was achieved in 67% of patients (GSD I, 43%; GSD IX, 100%). Fourteen different mutations were detected, and only two co-occurring mutations were observed across families (G6PC c.247C>T and c.1039C>T). Six previously unreported variants were identified (5 PHKA2; 1 PHKB). The proportion of GSD IX was higher in our cohort compared to other studies. Brain imaging abnormalities were more frequent among patients with GSD I, early-symptom onset, longer hospitalization, and inadequate metabolic control. The frequency of mutations was similar to that observed among the North American and European populations. None of the mutations observed in PHKA2 have been described previously. Therefore, current study reports six GSD variants previously unknown, and neurological consequences of GSD I. The principal neurological impact of GSD appeared to be related to inadequate metabolic control, especially hypoglycemia.
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Project description:Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase ? catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, there is over-accumulation of hepatic glycogen and triglycerides that can lead to steatohepatitis and a risk for hepatocellular adenoma or carcinoma. Here, we examined the effects of the commonly used peroxisomal proliferated activated receptor ? agonist, fenofibrate, on liver and kidney autophagy and lipid metabolism in 5-day-old G6pc -/- mice serving as a model of neonatal GSD Ia. Five-day administration of fenofibrate decreased the elevated hepatic and renal triglyceride and hepatic glycogen levels found in control G6pc -/- mice. Fenofibrate also induced autophagy and promoted ?-oxidation of fatty acids and stimulated gene expression of acyl-CoA dehydrogenases in the liver. These findings show that fenofibrate can rapidly decrease hepatic glycogen and triglyceride levels and renal triglyceride levels in neonatal G6pc -/- mice. Moreover, since fenofibrate is an FDA-approved drug that has an excellent safety profile, our findings suggest that fenofibrate could be a potential pharmacological therapy for GSD Ia in neonatal and pediatric patients as well as for adults. These findings may also apply to non-alcoholic fatty liver disease, which shares similar pathological and metabolic changes with GSD Ia.
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Project description:Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease.With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression.
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