ELECTRON MICROSCOPIC OBSERVATION OF THE INTRANUCLEAR GLYCOGEN OF THE LIVER IN DIABETES MELLITUS.
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Diabetes Mellitus↗
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Pre- to postnatal reduction in ultrasound attenuation coefficient of the liver.
A recent study showed the ultrasound attenuation coefficient of fetal liver between 26 and 40 weeks of gestation to be 26% higher than after birth. To test the hypothesis that ultrasound attenuation is sensitive to fetal liver glycogen concentration, the livers of 24 fetuses were examined at 5 MHz just prior to and just after birth. The mean pre- to post-delivery reduction in attenuation coefficient was 0.08 dB cm-1 MHz-1 +/- 0.02 (SEM), or 17% of the post-delivery mean. This is consistent with the increase in attenuation measured by others in liver homogenate when glycogen was added. An increase in measurement accuracy, correlation with glycogen content, and, possibly, control for biological variability will be required to make predictions in individual cases, as opposed to these averages. A simple test of glycogen content would be of value scientifically and in prenatal and postnatal management.
Female↗
Nuclear magnetic resonance studies of hepatic glucose metabolism in humans.
Nuclear magnetic resonance (NMR) spectroscopy has made noninvasive and repetitive measurements of human hepatic glycogen concentrations possible. Monitoring of liver glycogen in real-time mode has demonstrated that glycogen concentrations decrease linearly and that net hepatic glycogenolysis contributes only about 50 percent to glucose production during the early period of a fast. Following a mixed meal, hepatic glycogen represents approximately 20 percent of the ingested carbohydrates, while only about 10 percent of an intravenous glucose load is retained by the liver as glycogen. During mixed-meal ingestion, poorly controlled type 1 diabetic patients synthesize only about 30 percent of the glycogen stored in livers of nondiabetic humans studied under similar conditions. Reduced net glycogen synthesis can be improved but not normalized by short-term, intensified insulin treatment. A decreased increment in liver glycogen content following meals was also found in patients with maturity-onset diabetes of the young due to glucokinase mutations (MODY-2). In patients with poorly controlled type 2 diabetes, fasting hyperglycemia can be attributed mainly to increased rates of endogenous glucose production, which was found by 13C NMR to be due to increased rates of gluconeogenesis. Metformin treatment improved fasting hyperglycemia in these patients through a reduction in hepatic glucose production, which could be attributed to a decrease in gluconeogenesis. In conclusion, NMR spectroscopy has provided new insights into the pathogenesis of hyperglycemia in type 1, type 2, and MODY diabetes and offers the potential of providing new insights into the mechanism of action of novel antidabetic therapies.
Diabetes Mellitus, Type 1↗
Decreased erythrocyte deformability in glycogen storage disease.
Liver glycogen storage diseases (GSD) are disorders associated with severe dyslipidaemia which can induce cell membrane alterations and possibly reduced cell deformability. Since decreased erythrocyte deformability is known to disturb blood flow in capillaries and may promote ischaemic diseases, this study was designed to investigate erythrocyte deformability using a new filtration system, the Cell Transit Analyser (CTA), and to examine lipid compounds in the blood of 23 patients affected with GSD, aged from 1 to 20 years and 18 controls aged from 1 to 17 years. The patients showed a mixed hyperlipidaemia with predominant hypertriglyceridaemia and an increase in erythrocytes mean transit times (TT) due to the presence of more rigid erythrocytes subpopulations when compared to controls. Thus the erythrocyte rigidity, in addition to the lipid abnormalities must be taken into account for long-term evolution of GSD patients. Moreover this cellular alteration may contribute to shortened erythrocyte survival.
Adolescent↗
Alterations in erythrocyte membrane fluidity and fatty acid composition in glycogen storage disease.
Liver glycogen storage diseases (GSD) are disorders associated with severe dyslipidaemia which can induce cell membrane alterations. Reduced erythrocyte membrane fluidity has been associated with ischaemic cardiovascular disease. Our study has been designed to investigate membrane erythrocyte fluidity, and to determine its lipid composition and peroxidation parameters. Membrane erythrocyte fluidity has been studied by electron spin resonance (ESR) with two fatty acid nitroxide probes (5NS and 16NS). Twenty-five GSD cases aged 1-27 years and 15 controls aged 1-28 years were included. The erythrocyte membrane of GSD patients appeared less fluid with the two probes (P < 0.001). The membrane fatty acid pattern explained this reduced fluidity. Patients showed a relative saturated fatty acid (SFA) increase and polyunsaturated fatty acid (PUFA) decrease which induced lower PUFA/SFA ratio than in controls. We have provided evidence that the PUFA decrease was independent of the oxidative process. These findings should be taken into account for the management of the dietary treatment of GSD patients.
Adolescent↗
[Incidence and significance of nuclear glycogen in liver cells].
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Animals↗
Chronic ethanol ingestion and glycogen metabolism in male and female rats.
Chronic ethanol ingestion decreased liver glycogen levels in both male and female rats; however plasma glucose was decreased only in males. The decreased levels of liver glycogen were related to increases of 42% and 122% in glycogen phosphorylase in males and females, respectively. Both a and b forms of phosphorylase were increased, but the b form was increased more than the a form. Phosphorylase phosphatase was found to be increased 75% and 267% in males and females, respectively. Studies using positive and negative phosphorylase effector molecules indicated that ethanol ingestion may have altered the structure of phosphorylase a and that the degree of alteration was sex related.
Alcoholism↗
CHANGES IN SUBSTRATE LEVELS IN LIVER DURING GLYCOGEN SYNTHESIS INDUCED BY LACTATE AND HYDROCORTISONE.
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Carbohydrate Metabolism↗
Studies on the biological control of glycogen metabolism in liver. 3. Subcellular distribution of glycogen metabolizing enzymes.
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Animals↗
Maternal ethanol ingestion: effect on maternal and neonatal glucose balance.
Liver glycogen availability in the newborn is of major importance for the maintenance of postnatal blood glucose levels. This study examined the effect of maternal ethanol ingestion on maternal and neonatal glucose balance in the rat. Female rats were placed on the Lieber-DeCarli liquid ethanol diet, an isocaloric liquid pair-fed diet, or an ad libitum rat chow diet at 3 wk before mating and throughout gestation. Blood and livers were obtained from dams and rat pups on gestational days 21 and 22. The pups were studied up to 6 h in the fasted state and up to 24 h in the fed state. Maternal ethanol ingestion significantly decreased litter size, birth weight, and growth. A significantly higher mortality during the early postnatal period was seen in the prenatal ethanol exposed pups. Ethanol significantly decreased fed maternal liver glycogen stores but not maternal plasma glucose levels. The newborn rats from ethanol ingesting dams also had significantly decreased liver glycogen stores. Despite mobilizing their available glycogen, these prenatal ethanol exposed pups became hypoglycemic by 6 h postnatal. This was more marked in the fasted pups. Ethanol did not affect maternal nor neonatal plasma insulin levels. Thus maternal ethanol ingestion reduces maternal and neonatal liver glycogen stores and leads to postnatal hypoglycemia in the newborn rat.
Animals↗
Donor nutritional status--a determinant of liver preservation injury.
In liver transplantation, the quality of the liver is determined by a number of factors including donor nutritional status. Livers from fasted donors appear to tolerate long-term preservation better than livers from fed donors. In this study we repeated earlier results and obtained 31% (4/13) survival after 40-hr preservation of livers from fed donor Brown Norway rats and 67% (8/12) survivors with donor livers from 4-day-fasted rats (P = 0.154). The explanation for this improvement is not known but may be due to inactivation of Kupffer cells due to nutritional depletion of the liver. Kupffer cell activation has been one explanation advanced to explain how cold storage injuries livers during reperfusion (transplantation). In this study, we have measured how donor fasting affects Kupffer cell function (phagocytosis of colloidal carbon) after preservation of the rat liver. In addition, we measured how enhancing liver glycogen by feeding glucose to the rat donors affected outcome and liver functions tested by isolated perfusion after 24- and 40-hr cold storage of the liver. Preservation did not cause inactivation or activation of Kupffer cell phagocytosis of colloidal carbon. In livers with 0-hr preservation, colloidal carbon uptake was 3.1 +/- 0.2 mg/g/hr, after 40-hr preservation uptake was 3.8 mg/g/hr (P < 0.05 vs. 0 hr) (fed) and 2.7 +/- 0.3 mg/g/hr (fasted, P, 0.05 vs. 0-hr and 40-hr-fed). Thus, the improved survival obtained with livers from fasted donors does not appear related to inactivation of Kupffer cell phagocytosis. Although livers from fasted donors showed improved survival, there was extensive hepatocellular injury as indicated by large LDH release from the livers after 40-hr cold storage as tested by isolated perfusion. LDH released into the perfusate increased from 35.8 +/- 10.1 U/L (fed, 40-hr CS) to 301 +/- 65 U/L (fasted, 40-hr CS) after 1-hr reperfusion. AST release showed a similar pattern and bile production was suppressed more in livers from fasted donors than fed donors. Feeding rats glucose elevated liver glycogen and significantly reduced hepatocellular injury as measured by LDH release and AST release in the isolated perfused liver after 40-hr cold storage. Feeding rats glucose (40% in drinking water for 4 days) also improved survival: fed+glucose = 85% survival versus 31% survival with no glucose and fasted+glucose = 92% survival versus 67% survival with no glucose. These results show that both extensive donor fasting and glucose feeding enhanced outcome in orthotopic liver transplantation. This dilemma (both fasting and feeding improved survival) are discussed in terms of how the interactions between Kupffer cells and hepatocytes affect liver viability. Donor fasting is probably impractical clinically as a method to improve the donor liver, but elevating liver glycogen by glucose supplementation is possible and may lead to improved preservation and outcome in liver transplantation.
Animals↗
Gluconeogenesis in lethally X-irradiated rats.
The in vivo incorporation of U-14C-alanine into blood glucose and liver glycogen was measured in rats irradiated with a single whole body lethal dose of X-rays. Changes in gluconeogenic enzyme activities were studied in the liver. Increased incorporation of 14C-alanine into blood glucose and liver glycogen were found after irradiation. Liver phosphoenolpyruvate carboxykinase and glycogenic activity underwent almost parallel changes and were significantly elevated from the 6th to the 48th hour, with resultant accumulation of glycogen. Glucose-6-phosphatase activity was depressed and there was a negative correlation between it and the liver glycogen concentration. Maximum fructose-1,6-diphosphatase activity was found at 48 hours. The results show that glycogen accumulation in the liver and the raised blood glucose level in X-irradiated rats are based on raised gluconeogenesis.
Alanine↗
Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation.
Recent studies have questioned the efficiency with which administered glucose generates hepatic glycogen through the direct nonrecycling route compared with the indirect route from glucose recycled through glycolysis followed by gluconeogenesis. Using fasted and refed rats, we examined the relative access of infused [1-3H]- and [U-14C]glucose by way of these two pathways to liver glycogen and to hepatic glucuronic acid, the latter recovered from the urine as the glucuronide conjugated with administered acetaminophen. In fasted animals and during early refeeding, extensive dilution of administered [3H]- and [14C]glucose recovered in glycogen showed that 60-70% of the labeled glucose had undergone recycling by the indirect route. As refeeding progressed with substantial glycogen deposition, the contribution of the recycling pathway to glycogen and glucuronic acid diminished considerably. Thus, there is a shift in pathways of hepatic glucose utilization as liver glycogen accumulates. Consequently, the ratio of 3H/14C in glucuronic acid was closely correlated with the glycogen content of the liver at sacrifice, indicating that this ratio may prove useful as a noninvasive indicator of liver glycogen concentration. Since glycogen and glucuronic acid are derived by single reactions from UDP-glucose, they should show a common labeling pattern with 3H and 14C under various nutritional conditions. However, detailed analysis of their labeling patterns showed a striking divergence, implying that there must be compartmentation of the UDP-glucose pools leading to each of these end products, either because they are made in separate compartments within the same cell or because each is made in different hepatocyte populations. We favor the former explanation because galactose secreted in glycoproteins shows 3H and 14C labeling patterns similar to those of glucuronic acid conjugated with acetaminophen, and both of these conjugations occur in the endoplasmic reticulum of the liver, whereas most glycogen is present in the cytosol.
Animals↗
[Metabolic and hematologic changes in the northern red-backed vole Clethrionomys rutilus and the large-toothed red-backed vole Clethrionomys rufocanus during short-term starvation and refeeding].
The effect of starvation has been investigated on the content of glucose and lipids in the blood plasma, on the level of leucocytes in the peripheral blood and on the concentration of total lipids and glycogen in the liver. It was found that in both species of the voles, starvation within 20-22 hours sharply decreases glucose content and increases lipid content of the blood plasma. The liver glycogen becomes almost completely exhausted. These changes are more significant than those observed under similar conditions in laboratory rodents (albino mice and rats). During starvation of the voles, the level of leucocytes drastically decreases, whereas lipid content of the liver significantly increased. These changes are absent in laboratory rodents. The decrease in the content of glucose and in the level of leucocytes in the blood is more significant in C. rufocanus than in C, rutilis. On the contrary, accumulation of the lipids in the liver is more intense in the latter. The recovery of the investigated indices after refeeding is very slow. Possible significance of these re-arrangements for temperature and immune homeostases, as well as for regulation of other functions in the organism, is discussed.
Animals↗
Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration.
The contribution of net hepatic glycogenolysis to overall glucose production during a physiological increment in the plasma glucagon concentration was measured in six healthy subjects (18-24 years, 68-105 kg) after an overnight fast. Glucagon (approximately 3 ng.kg-1.min-1), somatostatin (0.1 microgram.kg-1.min-1), and insulin (0.9 pmol.kg-1.min-1) were infused for 3 h. Liver glycogen concentration was measured at 15-min intervals during this period using 13C-labeled nuclear magnetic resonance spectroscopy, and liver volume was assessed from magnetic resonance images. The rate of net hepatic glycogenolysis was calculated from the decrease in liver glycogen concentration over time, multiplied by the liver volume. The rate of glucose appearance (Ra) was calculated from [3-3H]glucose turnover data using a two-compartment model of glucose kinetics. Plasma glucagon concentration rose from 136 +/- 18 to 304 +/- 57 ng/l and plasma glucose concentration rose from 5.6 +/- 0.1 to 10.4 +/- 0.9 mmol/l on initiation of the infusions. Mean baseline Ra was 11.8 +/- 0.4 mumol.kg-1.min-1, increased rapidly after the beginning of the infusions, reaching its highest value after 20-40 min, and returned to baseline by 140 min. Liver glycogen concentration decreased almost linearly (from 300 +/- 19 mmol/l liver at baseline to 192 +/- 20 mmol/l liver at t = 124 min) during 2 h after the beginning of the infusions, and the calculated mean rate of net hepatic glycogenolysis was 21.7 +/- 3.6 mumol.kg-1.min-1. Mean Ra during the same time period was 22.8 +/- 2.3 mumol.kg-1.min-1. Thus, net hepatic glycogenolysis accounted for 93 +/- 9% of Ra.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
NMR of glycogen in exercise.
Natural-abundance 13C NMR spectroscopy is a non-invasive technique that enables in vivo assessments of muscle and/or liver glycogen concentrations. Over the last several years, 13C NMR has been developed and used to obtain information about human glycogen metabolism with diet and exercise. Since NMR is non-invasive, more data points are available over a specified time course, dramatically improving the time resolution. This improved time resolution has enabled the documentation of subtleties of muscle glycogen re-synthesis following severe glycogen depletion that were not previously observed. Muscle and liver glycogen concentrations have been tracked in several different human populations under conditions that include: (1) muscle glycogen recovery from intense localized exercise with normal insulin and with insulin suppressed; (2) muscle glycogen recovery in an insulin-resistant population; (3) muscle glycogen depletion during prolonged low-intensity exercise; (4) effect of a mixed meal on postprandial muscle and liver glycogen synthesis. The present review focuses on basic 13C NMR and gives results from selected studies.
Exercise↗
Failure of autoresuscitation in weanling mice: significance of cardiac glycogen and heart rate regulation.
"Autoresuscitation" (AR) is the spontaneous recovery from hypoxic apnea by gasping. We examined aspects of heart function in two situations: 1) the maturationally acquired failure of AR that is characteristic of SWR, but not BALB/c, weanling mice and 2) AR failure in BALB/c mice induced by repeated exposures to anoxia. We determined maturational changes in heart and liver glycogen. Unlike liver glycogen levels, heart glycogen levels in SWR mice differed from those in BALB/c mice. They were consistently much lower throughout maturation and reached a nadir during the brief period when SWR weanling mice are vulnerable to AR failure. Also, rate of cardiac glycogen utilization in vulnerable SWR mice was lower than that of same-aged BALB/c mice and was nil during the latter one-half of the gasping stage when heart function is critical for AR success. Therefore, because glycogen utilization reflects cardiac work, heart failure could explain AR failure in SWR weanlings. Additionally, the increase in hypoxic heart rate that occurs with maturation is developmentally delayed in SWR mice, and this may contribute to their AR failure. Cardiac glycogen was not fully depleted in BALB/c mice during repeated anoxic exposures, indicating other reasons for AR failure. We view these findings as a potential model for the age-related peak in incidence of sudden infant death syndrome.
Age Factors↗
Metabolic and hormonal responses to exercise in the anti-obese Lou/C rats.
OBJECTIVE: Lou/C rats are a substrain of Wistar rats that exhibit a spontaneous low caloric intake and no development of obesity with age. Recently, we reported that Lou/C rats, compared to equally food-restricted Wistar counterparts, show lower resting levels of plasma glucose, epinephrine and liver glycogen. To further explore this metabolic particularity, we used exercise (swimming 60 min) as a situation of high-energy demand, to test the ability of Lou/C rats to maintain euglycemia. DESIGN: Male Lou/C rats (14-week-old) were compared to age-matched male Wistar rats fed either ad libitum (WAL) or Wistar rats whose food was chronically restricted (WFR) to the same caloric intake as the Lou/C rats. RESULTS: In spite of low liver glycogen stores ( approximately 50% of normal values), Lou/C rats were able to maintain euglycemia during exercise even though liver glycogen breakdown was blunted. The decreased use of glycogen during exercise in Lou/C rats was associated with a reduced epinephrine response compared to WFR animals. By contrast, WFR were also able to maintain euglycemia during exercise but at the expense of a significant (P<0.01) decrease in liver and muscle glycogen content. Plasma free fatty acid and glycerol concentrations were increased (P<0.01) similarly in all three groups during exercise. In a separate experiment conducted in isolated hepatocytes from 24 h fasted Lou/C and Wistar rats, it was found that gluconeogenic flux from glycerol was found to be significantly (P<0.01) higher in Lou/C than in Wistar rats (5.4+/-0.2 vs 3.7+/-0.1 micromol/min/g dry cells). Resting and exercising plasma leptin levels were also significantly (P<0.05) lower in Lou/C than in the two other groups. CONCLUSION: It is concluded that Lou/C rats have the particularity to rely spontaneously less on their liver glycogen stores to meet their energy demands during exercise while maintaining euglycemia.
3-Hydroxybutyric Acid↗