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Biomedical subjects

A Burchell

Publications and source records attributed to A Burchell.

At least 109 records · Page 6Linked to original sources
PubMed1992

The molecular basis of the type 1 glycogen storage diseases.

Microsomal glucose-6-phosphatase catalyses the last step in liver glucose production. Glucose-6-phosphatase deficiency, now termed type 1 glycogen storage disease, was first described almost 40 years ago but until recently very little was known about the molecular basis of the various type 1 glycogen storage diseases. Recently we have shown that at least six different proteins are needed for normal glucose-6-phosphatase activity in liver. Four of the proteins have been purified and three cloned. Study of the type 1 glycogen storage diseases has stimulated investigations of the mechanisms of small molecule transport across the endoplasmic reticulum membrane and demonstrated the existence of novel endoplasmic reticulum transport proteins for glucose and phosphate.

Animals↗
PubMed1992

Glucose-6-phosphatase in normal adult human intestinal mucosa.

1. The existence of specific glucose-6-phosphatase activity in human intestinal mucosa has been somewhat controversial. 2. We have demonstrated the presence of low levels of specific glucose-6-phosphatase activity in normal human adult intestinal mucosa. Activity was found in oesophagus, stomach, duodenum and colon. 3. Immunoblot analysis using antibodies monospecific for the 36.5 kDa liver glucose-6-phosphatase catalytic subunit demonstrated that intestinal mucosa contains low levels of the glucose-6-phosphatase enzyme protein. 4. The low levels of activity together with problems of proteolysis make human intestinal biopsies unsuitable for use in the diagnosis of type 1 glycogen-storage disease.

Adult↗
PubMed1992

Impairment of the activity of the hepatic microsomal glucose-6-phosphatase system in three preterm infants.

Three preterm infants born at 26-30 weeks' gestation who died between 103 and 266 days after birth were found to have elevated hepatic glycogen levels. Kinetic analysis of the hepatic microsomal glucose-6-phosphatase system demonstrated that one infant had abnormally low levels of activity of the glucose-6-phosphatase enzyme (partial type 1a glycogen storage disease) and two had deficiencies of T2, a microsomal phosphate/pyrophosphate transport protein (type 1c glycogen storage disease). In all three cases glycogen storage disease was not suspected prior to death even though both hypo- and hyperglycaemic episodes were recorded in the first 15 days after birth indicating that they had somewhat disordered blood glucose regulation. In the infant with low glucose-6-phosphatase enzyme activity, abnormal development of the glucose-6-phosphatase enzyme cannot be ruled out. This is the first description of abnormalities in the glucose-6-phosphatase system in preterm infants.

Biopsy↗
PubMed1992

Glycogen storage disease diagnosed in adults.

Glycogen storage diseases are usually identified in childhood. We present the clinical, biochemical and histological features of 10 patients first diagnosed in adult life. Five had glycogen storage disease type 1a, one type 1c, two type IX, and in two patients there were previously unreported abnormalities of hepatic glucose-6-phosphatase system activity. Of the latter, one patient had an inhibitor of liver glucose-6-phosphatase (pseudo-1b glycogen storage disease) the other having abnormal glucose-6-phosphatase activity and microsomal pyrophosphate transport. A glucagon test is suggested as a useful screening procedure. Glycogen storage disease should be considered in adults with symptoms suggesting hypoglycaemia.

Adolescent↗
PubMed1992

Glucose metabolism and hypoglycaemia in SIDS.

Once a child is born its survival depends on the maturation of the blood glucose homeostatic control mechanisms. When this fails or where there is an inborn error of metabolism the infant is susceptible to potentially fatal hypoglycaemic episodes. A variety of environmental stresses, either singly or in combination, such as inappropriate or low caloric intake, acute infections of childhood, endotoxaemia, fever, xenobiotic exposure, oxidative stress or anaphylaxis, can greatly exacerbate the deficiency of the normal homeostatic compensatory mechanism and result in the onset of hypoglycaemia. Various inborn errors have been found in infants who died of SIDS. Our approach to this problem has been to use the six microsomal glucose-6-phosphatase proteins as a model system to study defects in carbohydrate metabolism in cases of SIDS. Initial studies determined the ontogeny of the glucose-6-phosphatase proteins and showed that intact microsomes isolated from unfrozen liver samples can be used to study glucose-6-phosphatase in cases of SIDS that were presumably due to the low concentrations of liver lipid peroxidation. More recently we have used a combination of techniques to demonstrate the abnormalities of glucose-6-phosphatase in cases of SIDS. Classic gross pathology and histology have now clearly defined the various subgroups of sudden and unexpected deaths of infancy. This now enables us to develop new molecular approaches to predict and prevent hypoglycaemia in infants who are at risk of SIDS.

Blood Glucose↗
PubMed1991

Characterization of glucose-6-phosphatase in hepatocytes. Effects of amiloride and pentamidine.

The hepatic microsomal glucose-6-phosphatase enzyme is situated inside the lumen of the endoplasmic reticulum and, for normal enzyme activity in vivo, three transport systems are needed for the substrate glucose-6-phosphate and the products phosphate and glucose. Previous studies using isolated microsomes showed that the drugs amiloride and pentamidine do not affect the glucose-6-phosphatase enzyme but can activate the glucose-6-phosphate transport system. Here we demonstrate that, very surprisingly, the addition of pentamidine (and to a lesser extent amiloride) to isolated hepatocytes results in an inhibition of the catalytic subunit of glucose-6-phosphatase.

Amiloride↗
PubMed1991

Pentamidine activates T1 the hepatic microsomal glucose 6-phosphate transport protein of the glucose-6-phosphatase system.

The mechanism of activation of hepatic microsomal glucose-6-phosphatase (EC 3.1.3.9) in vitro by pentamidine has been investigated in both intact and fully disrupted microsomes. The major effect of pentamidine is a 4.7-fold reduction in the Km of glucose-6-phosphatase activity in intact diabetic rat liver microsomes. The site of action of pentamidine is T1 the hepatic microsomal glucose 6-phosphate transport protein. The activation of T1 by pentamidine may contribute to the disturbed blood glucose homeostasis seen in many patients after the administration of the drug pentamidine.

Animals↗
PubMed1991

Identification and characterization of a hepatic microsomal glucose transport protein. T3 of the glucose-6-phosphatase system?

A 52 kDa polypeptide in rat liver microsomes was identified as a glucose-binding protein by its ability to weakly bind cytochalasin B and by its cross-reactivity to an antibody raised against the human erythrocyte glucose transport protein. The microsomal glucose binding polypeptide was purified by affinity chromatography and an antibody was raised against it. The inhibitory effect of this antibody on rat microsomal glucose-6-phosphatase activity and on glucose transport out of microsomal vesicles indicates that this protein is a microsomal glucose transport protein.

Animals↗
PubMed1991

Transverse topology of glucose-6-phosphatase in rat hepatic endoplasmic reticulum.

Antibodies raised against purified components of glucose-6-phosphatase were used to study the transmembrane orientation of the complex. Measurements of glucose-6-phosphatase activities and immunoblot analysis of sealed microsomes and detergent-solubilized microsomes after treatment with proteases suggested that most of the catalytic subunit resides within the lumen of the endoplasmic reticulum. In contrast, other components of glucose-6-phosphatase are accessible to the cytoplasm. Treatment of the partially purified glucose-6-phosphatase enzyme with glycopeptide N-glycosidase indicated that the catalytic subunit of the enzyme was a glycoprotein.

Animals↗
PubMed1991

Kinetic and immunologic evidence for the absence of glucose-6-phosphatase in early human chorionic villi and term placenta.

The existence of the enzyme glucose-6-phosphatase (G6Pase) in early and term human placenta was investigated by comparing the characteristics of placental microsomal glucose 6-phosphate (G6P) hydrolytic activity and liver G6Pase. Placental microsomes exhibited similar apparent Km values for G6P and beta-glycerophosphate in intact and deoxycholate-treated microsomes, heat stability at acidic pH, low latency of mannose 6-phosphate hydrolysis, very low activity of pyrophosphate: glucose phosphotransferase, and undetectable [U-14C]G6P transport into the placental microsomes, all of which indicated that specific G6Pase activity does not exist in placenta. Immunological evidence of the absence of both 36.5 kDa and T2 proteins, which represent the G6Pase catalytic protein and the phosphate/pyrophosphate transporter protein, respectively, confirmed that early and term human placenta are devoid of the multicomponent G6Pase enzyme.

Animals↗