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The distribution in liver cell fractions of UDPG-glycogen transferase has been studied. In fasting animals which have been refed 6 hours before sacrifice, the distribution of the enzyme in the various cell fractions can be correlated with the glycogen content of each fraction. A purified glycogen fraction has been prepared by differential centrifugation in sucrose gradients. This glycogen fraction contains vesicular structures which resemble those seen in association with glycogen deposits in the intact liver cell. In addition, the glycogen pellet contains UDPG-glycogen transferase in high specific activity. Subfractionation of the glycogen pellet separates the majority of vesicular elements from the bulk of transferase activity and glycogen. The evidence presented suggests that the presence of UPDG-glycogen transferase in the glycogen pellet is to be attributed to its binding to glycogen rather than to its association with the structural elements found in the glycogen fraction.
PMCID: PMC2225075  PMID: 13764028
2.  Ketosis-Onset Diabetes and Ketosis-Prone Diabetes: Same or Not? 
Objective. To compare clinical characteristics, immunological markers, and β-cell functions of 4 subgroups (“Aβ” classification system) of ketosis-onset diabetes and ketosis prone diabetes patients without known diabetes, presenting with ketosis or diabetic ketoacidosis (DKA) and admitted to our department from March 2011 to December 2011 in China, with 50 healthy persons as control group. Results. β-cell functional reserve was preserved in 63.52% of patients. In almost each subgroup (except A−  β− subgroup of ketosis prone group), male patients were more than female ones. The age of the majority of patients in ketosis prone group was older than that of ketosis-onset group, except A−  β− subgroup of ketosis prone group. The durations from the patient first time ketosis or DKA onset to admitting to the hospital have significant difference, which were much longer for the ketosis prone group except the A+ β+ subgroup. BMI has no significant difference among subgroups. FPG of ketosis prone group was lower than that of A−  β+ subgroup and A+ β+ subgroup in ketosis-onset group. A−  β− subgroup and A+ β+ subgroup of ketosis prone group have lower HbA1c than ketosis-onset group. Conclusions. Ketosis-onset diabetes and ketosis prone diabetes do not absolutely have the same clinical characteristics. Each subgroup shows different specialty.
PMCID: PMC3655588  PMID: 23710177
3.  Effects of Intravenous Glucose Load on Insulin Secretion in Patients With Ketosis-Prone Diabetes During Near-Normoglycemia Remission 
Diabetes Care  2010;33(4):854-860.
Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.
Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.
The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.
Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.
PMCID: PMC2845041  PMID: 20067967
4.  Deficient activity of dephosphophosphorylase kinase and accumulation of glycogen in the liver 
Journal of Clinical Investigation  1969;48(4):704-715.
Low activity of phosphorylase and increased concentration of glycogen were found in liver tissue from five children with asymptomatic hepatomegaly. In vitro activation of liver phosphorylase in these patients occurred at the rate of 10% or less of normal. Elimination of the defect by the addition of kinase that activates phosphorylase demonstrated the integrity of the phosphorylase enzyme and the deficient activity of dephophophosphorylase kinase.
On the average, 60% of the phosphorylase enzyme of normal human liver was in the active form. Phosphorylase kinase of rabbit muscle activated phosphorylase of normal human liver to a final value that was significantly higher than the one obtained in the absence of muscle phosphorylase kinase.
The ultrastructural examination of hepatic tissue from the five patients revealed increased amounts of glycogen. There was scarcity of endoplasmic reticulum. There was intercellular glycogen in continuity with the glycogen of the hepatocytes through breaks in their circumference. Lipid droplets with lucid areas in the form of needles and plates contained aggregates of glycogen. There were numerous lysosomes, some containing glycogen. Large vacuoles filled with glycogen and surrounded by a membrane were seen occasionally. The vacuoles might reflect the lysosomal pathway of glycogen degradation, since there was apparent fusion of such autophagic vacuoles with small vesicles resembling primary lysosomes.
PMCID: PMC322275  PMID: 5774108
5.  Effects of Endotoxin on Gluconeogenesis, Glycogen Synthesis, and Liver Glycogen Synthase in Mice 
Infection and Immunity  1973;7(4):642-654.
This study was undertaken to characterize the nature of carbohydrate loss due to endotoxin poisoning in mice and to elucidate mechanisms responsible for the changes. Female ICR mice, fasted overnight, were injected intraperitoneally with a mean lethal dose of endotoxin extracted from Salmonella typhimurium strain SR-11. Liver glycogen levels, alanine-U-14C and pyruvate-2-14C incorporation into blood glucose and liver glycogen, glucose-U-14C incorporation into liver glycogen, and liver glycogen synthase activities were measured at intervals after treatment. Liver glycogen in fasted mice given endotoxin was diminished significantly as early as 1 h after treatment. Liver glycogen synthase was significantly decreased in poisoned mice at 17 h. The use of actinomycin D showed that the induction of this enzyme due to fasting or hydrocortisone, or both, was inhibited by endotoxin. The incorporation of the 14C-label from alanine-U-14C, pyruvate-2-14C, or glucose-U-14C into blood glucose and liver glycogen was substantially impaired in endotoxemic animals at 12 h. Decreases in incorporation occurred as early as 4 h after treatment. The progressive increase in glycogen synthase activity observed in fasted controls was not seen in endotoxin-poisoned mice. The administration of a glucose or pyruvate load to endotoxin-treated mice did not restore gluconeogenesis, glycogen synthesis, or liver glycogen synthase activity to normal levels. The in vivo activation of glycogen synthase by glucose was significantly reduced in endotoxemic animals. These changes indicate reduced carbohydrate synthesis as a probable cause for rapid sugar loss during endotoxemia in mice.
PMCID: PMC422738  PMID: 4202664
6.  Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib 
The aim of this study was to characterize the frequency and causes of anemia in glycogen storage disease type I.
Hematologic data and iron studies were available from 202 subjects (163 with glycogen storage disease Ia and 39 with glycogen storage disease Ib). Anemia was defined as hemoglobin concentrations less than the 5th percentile for age and gender; severe anemia was defined as presence of a hemoglobin <10 g/dl.
In glycogen storage disease Ia, 68/163 patients were anemic at their last follow-up. Preadolescent patients tended to have milder anemia secondary to iron deficiency, but anemia of chronic disease predominated in adults. Severe anemia was present in 8/163 patients, of whom 75% had hepatic adenomas. The anemia improved or resolved in all 10 subjects who underwent resection of liver lesions. Anemia was present in 72% of patients with glycogen storage disease Ib, and severe anemia occurred in 16/39 patients. Anemia in patients with glycogen storage disease Ib was associated with exacerbations of glycogen storage disease enterocolitis, and there was a significant correlation between C-reactive protein and hemoglobin levels (P = 0.036).
Anemia is a common manifestation of both glycogen storage disease Ia and Ib, although the pathophysiology appears to be different between these conditions. Those with severe anemia and glycogen storage disease Ia likely have hepatic adenomas, whereas glycogen storage disease enterocolitis should be considered in those with glycogen storage disease Ib.
PMCID: PMC3808879  PMID: 22678084
anemia; glycogen storage disease I; hepcidin; inflammatory bowel disease; iron
7.  A metabolic link between mitochondrial ATP synthesis and liver glycogen metabolism: NMR study in rats re-fed with butyrate and/or glucose 
Butyrate, end-product of intestinal fermentation, is known to impair oxidative phosphorylation in rat liver and could disturb glycogen synthesis depending on the ATP supplied by mitochondrial oxidative phosphorylation and cytosolic glycolysis.
In 48 hr-fasting rats, hepatic changes of glycogen and total ATP contents and unidirectional flux of mitochondrial ATP synthesis were evaluated by ex vivo 31P NMR immediately after perfusion and isolation of liver, from 0 to 10 hours after force-feeding with (butyrate 1.90 mg + glucose 14.0 mg.g-1 body weight) or isocaloric glucose (18.2 mg.g-1 bw); measurements reflected in vivo situation at each time of liver excision. The contribution of energetic metabolism to glycogen metabolism was estimated.
A net linear flux of glycogen synthesis (~11.10 ± 0.60 μmol glucosyl units.h-1.g-1 liver wet weight) occurred until the 6th hr post-feeding in both groups, whereas butyrate delayed it until the 8th hr. A linear correlation between total ATP and glycogen contents was obtained (r2 = 0.99) only during net glycogen synthesis. Mitochondrial ATP turnover, calculated after specific inhibition of glycolysis, was stable (~0.70 ± 0.25 μmol.min-1.g-1 liver ww) during the first two hr whatever the force-feeding, and increased transiently about two-fold at the 3rd hr in glucose. Butyrate delayed the transient increase (1.80 ± 0.33 μmol.min-1.g-1 liver ww) to the 6th hr post-feeding. Net glycogenolysis always appeared after the 8th hr, whereas flux of mitochondrial ATP synthesis returned to near basal level (0.91 ± 0.19 μmol.min-1.g-1 liver ww).
In liver from 48 hr-starved rats, the energy need for net glycogen synthesis from exogenous glucose corresponds to ~50% of basal mitochondrial ATP turnover. The evidence of a late and transient increase in mitochondrial ATP turnover reflects an energetic need, probably linked to a glycogen cycling. Butyrate, known to reduce oxidative phosphorylation yield and to induce a glucose-sparing effect, delayed the transient increase in mitochondrial ATP turnover and hence energy contribution to glycogen metabolism.
PMCID: PMC3141389  PMID: 21676253
8.  Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats. 
Liver glycogen formation can occur via the direct (glucose----glucose-6-phosphate----glycogen) or indirect (glucose----C3 compounds----glucose-6-phosphate----glycogen) pathways. In the present study we have examined the effect of hyperglycemia on the pathways of hepatic glycogenesis, estimated from liver uridine diphosphoglucose (UDPglucose) specific activities, and on peripheral (muscle) glucose metabolism in awake, unstressed control and 90% pancreatectomized, diabetic rats. Under identical conditions of hyperinsulinemia (approximately 550 microU/ml), 2-h euglycemic (6 mM) and hyperglycemic (+5.5 mM and +11 mM) clamp studies were performed in combination with [3-3H,U-14C]glucose, [6-3H,U-14C]glucose, or [3-3H]glucose and [U-14C]lactate infusions under postabsorptive conditions. Total body glucose uptake and muscle glycogen synthesis were decreased in diabetic vs. control rats during all the clamp studies, whereas glycolytic rates were similar. By contrast, hyperglycemia determined similar rates of liver glycogen synthesis in both groups. Nevertheless, in diabetic rats, the contribution of the direct pathway to hepatic glycogen repletion was severely decreased, whereas the indirect pathway was markedly increased. After hyperglycemia, hepatic glucose-6-phosphate concentrations were increased in both groups, whereas UDPglucose concentrations were reduced only in the control group. These results indicate that in the diabetic state, under hyperinsulinemic conditions, hyperglycemia normally stimulates liver glycogen synthesis through a marked increase in the indirect pathway, which in turn may compensate for the reduction in the direct pathway. The increase in the hepatic concentrations of both glucose-6-phosphate and UDPglucose suggests the presence, in this diabetic rat model, of a compensatory "push" mechanism for liver glycogen repletion.
PMCID: PMC442816  PMID: 1530852
9.  Evaluation of Ischemia-Modified Albumin and C-Reactive Protein in Type 2 Diabetics With and Without Ketosis 
Biomarker Insights  2012;7:19-26.
To investigate whether serum ischemia-modified albumin or C-reactive protein is reliable for predicting type 2 diabetic patients with ketosis.
One hundred and four diabetic patients, 48 with diabetic ketosis, and 33 controls were enrolled in the study. Serum ischemia-modified albumin and C-reactive protein were measured and evaluated for their ability to distinguish diabetic ketosis.
Compared to the controls, the ischemia-modified albumin and C-reactive protein levels were higher in patients with diabetic ketosis and type 2 diabetes at the baseline. The levels of ischemia-modified albumin were higher in patients with type 2 diabetes than in the controls. C-reactive protein and ischemia-modified albumin levels were reduced after insulin treatment. The level of ischemia-modified albumin was an independent risk marker for diabetic ketosis (OR = 1.085, P = 0.008, 95% CI: 1.022–1.152). Receiver operating characteristic curves revealed that the areas under the curve were 0.917 for the modified albumin and 0.357 for C-reactive protein.
This study indicates that ischemia-modified albumin was significantly associated with diabetic ketosis and was more sensitive than C-reactive protein in reflecting diabetic ketosis.
PMCID: PMC3308681  PMID: 22442627
diabetic ketosis; ischemia-modified albumin; C-reactive protein; biomarker
10.  Influence of islet function on typing and prognosis of new-onset diabetes after intensive insulin therapy 
It is difficult in clinical practice to differentiate patients with newly diagnosed diabetes and ketosis. The aim of this study was to investigate the effect of intensive insulin therapy on islet function in patients with new-onset diabetes and concomitant ketosis, and to determine the value of alternation in islet function in the typing of diabetes.
A total of 206 inpatients with new-onset diabetes and ketosis were recruited after intensive insulin therapy and followed for 36 months. Patients were divided into type 1 diabetes group (Group A) and type 2 diabetes group (Group B). Islet function was compared between the 2 groups before and after intensive insulin therapy, and the influence of islet function on the typing of diabetes and the selection of therapeutic strategies is discussed.
In group A, the AUCI, AUCC, HOMA-β cell and HOMA-IR were significantly lower than those in Group B before and after intensive insulin therapy. The sensitivity and accuracy of antibody test were at a low level in Group A. An insulin release test was done after intensive insulin therapy. Results showed that the peaks of insulin and C peptide appeared at 0.5–1 h after glucose administration in Group A, which was earlier than that before therapy, but the maximal levels were no more than 2 times those of baseline levels. In Group B, the peaks appeared at 2 h, and the maximal levels were about 10 times those of baseline levels.
Poor islet function, incomplete recovery of islet function after intensive insulin therapy, and a short “honeymoon” period are characteristics of type 1 diabetes. Detection of diabetes-related antibodies is not reliable.
PMCID: PMC3787858  PMID: 24056309
diabetic ketosis; typing; islet function; honeymoon period
11.  Prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study 
The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies.
In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes.
The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p<0.001), but no significant difference was found compared with the non-ketotic type 2 diabetics (0.73±0.19 mm, p=0.582) after controlling for differences in age and sex. In both the ketosis-onset and the non-ketotic diabetes, the prevalence of carotid atherosclerosis was markedly increased with age (both p<0.001) after controlling for sex, but no sex difference was observed (p=0.479 and p=0.707, respectively) after controlling for age. In the ketosis-onset diabetics, the presence of carotid atherosclerosis was significantly associated with age, hypertension, low-density lipoprotein cholesterol and mean CIMT.
The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.
PMCID: PMC3583071  PMID: 23324539
Ketosis-prone diabetes; Type 2 diabetes; Atherosclerosis; Carotid arteries; Epidemiology
12.  Prevalence of hepatopathy in type 1 diabetic children 
BMC Pediatrics  2012;12:160.
The Prevalence of liver disease among diabetics has been estimated to be between 17% and 100%. Most of these data were obtained from adult studies. The aim of our study was to screen for liver disease among type 1 diabetic children.
Children with type 1 diabetes following in clinic have been examined for existence of liver disease, from November 2008 to November 2009. All were subjected to the following: History, physical examination, liver function tests, fasting lipid profile, HbA1C, and ultrasound of the liver. A hyperechogenic liver and/or hepatomegaly on ultrasound were attributed most likely to excess glycogen or fat in the liver, after negative extensive work-up to rule out other underlying liver disease.
106 children with type 1 diabetes were studied: age ranged between 8 months to 15.5 years, sixty two patients were females. Twenty two patients (21%) were identified to have abnormal findings on ultrasound of the liver: 10 patients had hepatomegaly and 12 had hyperechogenic liver. The group with hyperechogenic liver had poorer glycemic control than patients with normal liver (Mean HbA1c 12.14% Vs 10.7%; P value = 0.09). Hyperechogenic liver resolved in 60% at 6 months follow-up upon achieving better glycemic control.
Hyperechogenic liver and/or hepatomegaly are not uncommon in children with type 1 diabetes and tend to be more prevalent among children with poor glycemic control. Type 1 diabetes related hepatopathy is reversible by optimizing glycemic control. Because of its safety, and reliability, ultrasound can be used to screen for hepatopathy in type 1 diabetic child.
PMCID: PMC3506494  PMID: 23039762
Fatty liver; Hepatomegaly; Hepatic glycogenosis; Type 1 diabetes; Diabetes mellitus; Ultrasound
13.  AB 103. Respiratory pathology in genetic era 
Journal of Thoracic Disease  2012;4(Suppl 1):AB103.
Department of Pathology was founded in 1960. With the establishment of the Institute for Pulmonary Diseases. Laboratories for histology, cytology, immunohistochemistry and autopsy unit are integral part of this department.
Patients and methods
In histopathologic laboratory over 10,000 endoscopical and surgical biopsies, with ex tempore analyzes annually, are technically prepared and processed by using standard as well as special stainings. Over 6000 samples per year obtained by exfoliative cytology: sputum, pleural, pericardial and abdominal effusions, aspiration cytology: transthoracic fine needle aspiration (FNA), and samples obtained during bronchoscopy: lavage, brushes and transbronchial fine needle aspiration biopsy (obtained during endobronchial ultrasound guided (EBUS) FNA) and bronchoalveolar lavages are processed in the laboratory for cytology. May Grunwald Giemsa and Papanicolaou stainings are used for all cytological specimens and in many cases cell blocks are prepared too for ancillary technics. Laboratory for immunohistochemistry disposes of 43 tumor markers for the diagnosis and differentiation of primary and secondary lung tumors, malignant mesothelioma, lymphoma and thymoma and annually performs over 300 analyzes. Over 200 autopsies per year are performed in the autopsy unit. Predominant field of work is thoracic pathology, but we are also dealing with cardiovascular, endocrine, gastrointestinal, hepatobiliary and gynecological pathology.
Today The Department of Pathology employs 1 biologist, 6 laboratory technicians and 3 autopsy assistants as well as 2 pathologists, 3 cytopathologists and 1 resident. As the Institute for Pulmonary Diseases is university hospital all doctors, 4 PhD and 2 postgraduate students are engaged in the educational work. Teachers participate in undergraduate and postgraduate teaching at Medical Faculty in Novi Sad, Banja Luka and Foca (Serbian Republic). The Department of Pathology from the very beginning enforced specialization in Pathology and sub-specialization in Medical Cytology. In the cooperation with the Center for Continuing Education, several educational seminars in the field of pathology and cytology have been organized.
The future of this department is the automatization and standardization of working processes, control improvement, continuing education of all employees and greater engagement in the field of research. Introducing of genetic and molecular techniques for better diagnosis and individualized therapy is our task in the next few years.
PMCID: PMC3537378
14.  FIH-1/c-Kit Signaling: A Novel Contributor to Corneal Epithelial Glycogen Metabolism 
Corneal epithelial cells have large stores of glycogen, which serve as their primary energy source. Recently, we demonstrated that factor-inhibiting hypoxia-inducible factor 1 (FIH-1) diminished glycogen stores in vitro and in vivo, working through the Akt/Glycogen Synthase Kinase (GSK)-3β pathway. In this study we investigated the relationship between FIH-1 and c-kit as it pertains to limbal and corneal epithelial glycogen stores.
Limbal and corneal epithelia from wild-type FIH-1−/− and KitW/Wv mice were stained with periodic acid Schiff (PAS) to detect glycogen. RNA samples prepared from laser-capture microdissected populations of limbal epithelium were subjected to real-time quantitative PCR to determine c-kit ligand expression. Submerged cultures of primary human corneal epithelial keratinocytes (HCEKs) transduced with FIH-1 were treated with c-kit ligand to establish further a FIH-1/c-kit interaction via Western analysis. Akt phosphorylation was assessed by Western blotting.
The limbal epithelial cells of FIH-1 null mice had an increase in glycogen levels as well as increased c-kit ligand mRNA compared with wild-type controls. Consistent with a FIH-1/c-kit association, the diminished Akt signaling observed in FIH-1-overexpressing HCEKs could be restored by the addition of c-kit ligand. Interestingly, Akt signaling and glycogen content of the corneal epithelium were significantly decreased in c-kit mutant mice.
c-Kit signaling has been shown to affect glucose metabolism via the Akt/GSK-3β pathway. An inverse relationship between FIH-1 and c-kit signaling pathways accounts, in part, for differences in glycogen content between corneal and limbal epithelial cells.
Maintenance of limbal/corneal epithelial glycogen is essential for homeostasis as glycogen is a primary energy source. We demonstrate that FIH-1, a novel hydroxylase, alters c-kit signaling, which results in a negative regulation of glycogen metabolism.
PMCID: PMC3632267  PMID: 23548624
energy metabolism; Akt signaling; keratinocytes
15.  Glycogen hepatopathy in a 13-year-old male with type 1 diabetes 
Annals of Saudi Medicine  2011;31(4):424-427.
Glycogenic hepatopathy (GH ) is a rare cause of serum transaminase elevations in type 1 diabetes mellitus. We describe a 13-year-old male with a history of poorly controlled type 1 diabetes mellitus who presented with hepatomegaly and severe transaminase flares. Liver histology confirmed GH. Treatment consists of improving glycemic control. Hepatomegaly due to excess glycogen storage in poorly controlled type 1 diabetics has been associated with younger patients with poor glycemic control, occurring about 2-4 weeks after starting insulin treatment, and resolving upon glucose stabilization. We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus, The recovery of severe transaminase elevations in this patient illustrates the more benign course of GH, which is a condition with a far better prognosis. Clinician awareness of GH should prevent diagnostic delay and will provide better insight into the prevalence of GH.
PMCID: PMC3156523  PMID: 21727748
16.  Non-invasive measurement of brain glycogen by NMR spectroscopy and its application to the study of brain metabolism 
Journal of neuroscience research  2011;89(12):1905-1912.
Glycogen is the reservoir for glucose in the brain. Beyond the general agreement that glycogen serves as an energy source in the central nervous system, its exact role in brain energy metabolism has yet to be elucidated. Experiments performed in cell and tissue culture and animals have shown that glycogen content is affected by several factors including glucose, insulin, neurotransmitters, and neuronal activation. The study of in vivo glycogen metabolism has been hindered by the inability to measure glycogen non-invasively, but in the past several years, the development of a non-invasive localized 13C nuclear magnetic resonance (NMR) spectroscopy method has enabled the study of glycogen metabolism in the conscious human. With this technique, 13C-glucose is administered intravenously and its incorporation into and wash-out from brain glycogen is tracked. One application of this method has been to the study of brain glycogen metabolism in humans during hypoglycemia: data have shown that mobilization of brain glycogen is augmented during hypoglycemia and, after a single episode of hypoglycemia, glycogen synthesis rate is increased, suggesting that glycogen stores rebound to levels greater than baseline. Such studies suggest glycogen may serve as a potential energy reservoir in hypoglycemia and may participate in the brain's adaptation to recurrent hypoglycemia and eventual development of hypoglycemia unawareness. Beyond this focused area of study, 13C NMR spectroscopy has a broad potential for application in the study of brain glycogen metabolism and carries the promise of a better understanding of the role of brain glycogen in diabetes and other conditions.
PMCID: PMC3189435  PMID: 21732401
Brain glycogen; 13C NMR spectroscopy; in vivo glycogen measurement
17.  Glycogene Expression in Conjunctiva of Patients with Dry Eye: Downregulation of Notch Signaling 
Glycoconjugates regulate a variety of biological events in mucosal surfaces, such as differentiation of postmitotic epithelial cells and maintenance of the wet-surfaced phenotype. This study aimed to identify the repertoire of genes (glycogenes) involved in biosynthesis of glycoconjugates in conjunctiva of normal subjects and dry eye patients.
RNA from conjunctival impression cytology samples was amplified and hybridized to a custom-designed glycogene microarray. Intensity data were converted to expression values and analyzed by ANOVA. Microarray data for selected Notch glycogenes were confirmed by quantitative real-time PCR. Notch receptors and ligands were immunolocalized on conjunctival biopsies by confocal microscopy.
By microarray, 424 glycogenes were identified in normal conjunctival epithelium; galectins, glycosyltransferases, mucins, Notch signaling molecules, and proteoglycans were among the most highly expressed. In dry eye, 46 glycogenes were significantly downregulated, and included five members of the Notch signaling pathway (Notch1, -2, -3, Jagged1, Delta1), four Wnt signaling molecules (Wnt4, -5A, Frizzled6, -7), and three heparan sulfate glycotransferases (HS2ST1, HS3ST6, EXTL2). Only interferon-induced transmembrane protein 1 was upregulated. By real-time PCR, expression ratios of Notch1, -3, and Jagged1 in dry eye were 0.43, 0.56 and 0.50, respectively, compared to controls (p<0.05). Notch1, -3, and Jagged1 immunolocalized throughout the conjunctival epithelium, whereas Notch2 and Delta1 were distributed apically.
This study revealed the differential glycogene expression profiles in normal subjects and dry eye patients. Downregulation of Notch signaling in dry eye may result in abnormal differentiation of the conjunctival epithelium and have implications in the pathogenesis of the disease.
PMCID: PMC2693254  PMID: 19011014
conjunctiva; glycogene; dry eye; microarray; Notch signaling
18.  Bronchial needle aspiration in the diagnosis of bronchial carcinoma. 
Thorax  1981;36(7):508-511.
Sixty consecutive patients with central bronchial carcinomas were studied by fibreoptic bronchoscopy. In all forceps biopsy and bronchial needle aspiration were performed, and in 54 bronchial brushings were obtained. The combination of bronchial brushings and forceps biopsy diagnosed bronchial carcinoma of a defined cell type in 80% of patients. Bronchial needle aspiration was the most effective single technique giving a cytological diagnosis in 80% of patients, and when all three techniques were combined the positive rate increased to 92%. No major complications occurred using bronchial needle aspiration. Needle aspiration was particularly helpful when sampling from lesions in the upper lobes where forceps biopsies were technically difficult, from tumours lying submucosally, and from abnormalities caused by extrinsic compression. We conclude that bronchial needle aspiration should be used routinely, together with other sampling techniques, in the diagnosis of central bronchial carcinoma with the fibreoptic bronchoscope.
PMCID: PMC1020432  PMID: 7314024
19.  Molecular Structural Differences between Type-2-Diabetic and Healthy Glycogen 
Biomacromolecules  2011;12(6):1983-1986.
Glycogen is a highly branched glucose polymer functioning as a glucose buffer in animals. Multiple-detector size exclusion chromatography and fluorophore-assisted carbohydrate electrophoresis were used to examine the structure of undegraded native liver glycogen (both whole and enzymatically debranched) as a function of molecular size, isolated from the livers of healthy and db/db mice (the latter a type 2 diabetic model). Both the fully branched and debranched levels of glycogen structure showed fundamental differences between glycogen from healthy and db/db mice. Healthy glycogen had a greater population of large particles, with more α particles (tightly linked assemblages of smaller β particles) than glycogen from db/db mice. These structural differences suggest a new understanding of type 2 diabetes.
PMCID: PMC3113368  PMID: 21591708
20.  Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis. 
Journal of Clinical Investigation  1981;68(1):240-252.
The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.
PMCID: PMC370791  PMID: 7251861
21.  Dysregulation of Multiple Facets of Glycogen Metabolism in a Murine Model of Pompe Disease 
PLoS ONE  2013;8(2):e56181.
Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1 to 2 years of age to a slower progressive course that causes significant morbidity and early mortality in children and adults. The aim of this study is to better understand the biochemical consequences of glycogen accumulation in the Pompe mouse. We evaluated glycogen metabolism in heart, triceps, quadriceps, and liver from wild type and several strains of GAA−/− mice. Unexpectedly, we observed that lysosomal glycogen storage correlated with a robust increase in factors that normally promote glycogen biosynthesis. The GAA−/− mouse strains were found to have elevated glycogen synthase (GS), glycogenin, hexokinase, and glucose-6-phosphate (G-6-P, the allosteric activator of GS). Treating GAA−/− mice with recombinant human GAA (rhGAA) led to a dramatic reduction in the levels of glycogen, GS, glycogenin, and G-6-P. Lysosomal glycogen storage also correlated with a dysregulation of phosphorylase, which normally breaks down cytoplasmic glycogen. Analysis of phosphorylase activity confirmed a previous report that, although phosphorylase protein levels are identical in muscle lysates from wild type and GAA−/− mice, phosphorylase activity is suppressed in the GAA−/− mice in the absence of AMP. This reduction in phosphorylase activity likely exacerbates lysosomal glycogen accumulation. If the dysregulation in glycogen metabolism observed in the mouse model of Pompe disease also occurs in Pompe patients, it may contribute to the observed broad spectrum of disease severity.
PMCID: PMC3572993  PMID: 23457523
22.  Pseudoglandular formations in clot sections from fine needle aspirates--an artefact caused by bubble formation during aspiration. 
Journal of Clinical Pathology  1999;52(7):532-534.
AIMS: To report the occurrence of an uncommon artefact producing pseudoglandular formations in clot sections from haemorrhagic fine needle aspirations. METHODS: All available histological material from 610 fine needle aspirations by pathologists (23 g needle) over a five year period was reviewed. The frequency and associations of the pseudoglandular artefact was assessed. RESULTS: Clot sections were prepared in 41 of the 610 cases (7%). Bubbles were present in the clots in 22 of these cases (54%), and in three cases (7%) these were lined by lymphocytes creating pseudoglandular formations. These were two lymph node aspirates and one thyroid aspirate. In four further cases lesser numbers of cells partly lined some of the bubbles; these were lymphocytes, macrophages, or in one case, thyroid epithelial cells. CONCLUSIONS: When clot sections are prepared in cases of haemorrhagic fine needle aspiration, bubbles are often produced during suction; these can on occasion become lined by lymphocytes or other cells, leading to pseudoglandular formations. Recognition of this artefact will prevent unnecessary further investigation of their nature.
PMCID: PMC501498  PMID: 10605409
23.  Field Study of Dairy Cows with Reduced Appetite in Early Lactation: Clinical Examinations, Blood and Rumen Fluid Analyses 
Acta Veterinaria Scandinavica  2001;42(2):219-228.
The study included 125 cows with reduced appetite and with clinical signs interpreted by the owner as indicating bovine ketosis 6 to 75 days postpartum. Almost all of the cows were given concentrates 2 to 3 times daily. With a practitioners view to treatment and prophylaxis the cows were divided into 5 diagnostic groups on the basis of thorough clinical examination, milk ketotest, decreased protozoal activity and concentrations, increased methylene blue reduction time, and increased liver parameters: ketosis (n = 32), indigestion (n = 26), combined ketosis and indigestion (n = 29), liver disease combined with ketosis, indigestion, or both (n = 15), and no specific diagnosis (n = 17). Three cows with traumatic reticuloperitonitis and 3 with abomasal displacement were not grouped. Nonparametric methods were used when groups were compared. Aspartate aminotransferase, glutamate dehydrogenase, gamma-glutamyl transferase and total bilirubin were elevated in the group with liver disease. Free fatty acids were significantly elevated in cows with ketosis, compared with cows with indigestion. Activity and concentrations of large and small protozoas were reduced, and methylene blue reduction time was increased in cows with indigestion. The rumen fluid pH was the same for groups of cows with and without indigestion. Prolonged reduced appetite before examination could have led to misclassification. Without careful interpretation of the milk ketotest, many cases with additional diagnoses would have been reported as primary ketosis. Thorough clinical examination together with feasible rumen fluid examination and economically reasonable blood biochemistry did not uncover the reason(s) for reduced appetite in 14% of the cows. More powerful diagnostic methods are needed.
PMCID: PMC2202315  PMID: 11503366
bovine ketosis; indigestion; rumen acidosis; dairy cattle
24.  Glycogen in Leukocytes from Bovine Blood and Milk 
Glycogen content was determined quantitatively by the Anthrone reagent method in leukocytes obtained from blood and milk of five cows. Distribution of glycogen in leukocytes was studied by microscopic examination of slides stained by Periodic acid-Schiff (PAS) reaction. Blood glucose concentrations were investigated in these animals by standard procedures. In two of five cows both blood glucose levels and blood leukocyte glycogen levels on the same day were determined for six consecutive days. One hundred and two blood leukocyte samples from five cows had a mean glycogen content of 1.32 ± 0.04 (S.E.) mg/109 WBC, and 6.11 ± 0.17 (S.E.) mg/109 PMNs. Leukocyte preparations from 80 samples of milk comprising 97 to 98% PMNs contained 3.81 ± 0.18 (S.E.) mg glycogen/109 milk leukocytes. In PAS preparations of blood and milk leukocytes glycogen was found almost exclusively in PMNs. Glycogen granules, present frequently in PMNs and occasionally in monocytes and large lymphocytes from blood, were not observed in those from milk. The glycogen level in milk leukocytes was significantly lower (P = <0.01) than that of the blood PMNs in every cow, and the overall mean difference between levels for milk leukocytes and blood PMNs was highly significant (P = <0.001). Mean blood glucose concentration in the five cows was 44.46 ± 0.66 (S.E.) mg%. There was no significant relationship between blood glucose and blood leukocyte glycogen levels in the five corresponding cows; nor between blood glucose and blood PMN glycogen levels on the same day in either of two cows investigated. Leukocyte preparations from milk samples obtained on the second day following intramammary infusion of endotoxin consistently contained markedly less glycogen than the leukocyte preparations from first day post-infusion samples.
These tended to level off and became intermediate between first and second day levels. It is postulated that the poor phagocytic competence of leukocytes from bovine mammary glands compared to their counterparts in blood observed by various workers may be due partially to low energy reserves in these cells.
PMCID: PMC1319724  PMID: 4119673
25.  In Vivo Assessment of Antihyperglycemic and Antioxidant Activity from Oil of Seeds of Brassica Nigra in Streptozotocin Induced Diabetic Rats 
Advanced Pharmaceutical Bulletin  2013;3(2):359-365.
Purpose: This study was made to investigate the antihyperglycemic and antioxidant potential of oil of seeds of Brassica nigra (BNO) in streptozotocin -nicotinamide (STZ) induced type 2 diabetic rats. Methods: BNO was orally administered to diabetic rats to study its effect in both acute and chronic antihyperglycemic study. The body weight, oral glucose tolerance test and biochemical parameters viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin and antioxidant parameters were estimated for all treated groups and compared against diabetic control group. Results: Administration of BNO at a dose 500 mg/kg and 1000 mg/kg body weight p.o. to STZ diabetic rats showed reduction in blood glucose level from 335 mg/dl to 280 mg/dl at 4th h and from 330 mg/dl to 265 mg/dl respectively which was found significant (p<0.01) as compared with diabetic control. BNO (500 mg/kg and 1000 mg/kg) and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-nicotinamide induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin level and decrease in glycosylated hemoglobin in test groups as compared to control group. In vivo antioxidant studies on STZ-nicotinamide induced diabetic rat’s revealed decreased malondialdehyde (MDA) and increased reduced glutathione (GSH). Conclusion: Thus the results showed that the oil of seeds of Brassica nigra has significant antihyperglycemic and antioxidant activity.
PMCID: PMC3848242  PMID: 24312861
Brassica nigra; Seeds; Streptozotocin; Essential oil; MDA

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