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Biomedical subjects

P McLean

Publications and source records attributed to P McLean.

At least 73 records · Page 4Linked to original sources
PubMed1986

Phosphoribosyl pyrophosphate and phosphoribosyl pyrophosphate synthetase in rat mammary gland. Changes in the lactation cycle and effects of diabetes, insulin and phenazine methosulphate.

Changes in the tissue content of phosphoribosyl pyrophosphate (PPRibP), glucose 6-phosphate, ribose 5-phosphate (Rib5P), RNA and DNA, of the activity of PPRibP synthetase (EC 2.7.6.1) and the conversion of [1-14C]- and [6-14C]-glucose into 14CO2 were measured at mid-lactation in the normal and diabetic rat and in pregnancy, lactation and mammary involution in the normal rat. The PPRibP, glucose 6-phosphate and Rib5P contents increase during pregnancy and early lactation to reach a plateau value at mid-lactation, before falling sharply during weaning. The PPRibP content, PPRibP synthetase activity and flux of glucose through the oxidative pentose phosphate pathway (PPP) all change in parallel during the lactation cycle. Similarly, after 3 and 5 days duration of streptozotocin-induced diabetes, ending on day 10 of lactation, there were parallel declines in PPRibP content, PPRibP synthetase and PPP activity. The effect of streptozotocin was prevented by pretreatment with nicotinamide and partially reversed by insulin administration. Addition of insulin to lactating rat mammary-gland slices incubated in vitro significantly raised the PPRibP content (+47%) and the activity of the PPP (+40%); phenazine methosulphate, which gives a 2-fold increase in PPP activity, raised the PPRibP content of lactating mammary gland slices by approx. 3-fold. It is concluded that Rib5P, generated in the oxidative segment of the PPP, is an important determinant of PPRibP synthesis in the lactating rat mammary gland and that insulin plays a central role in the regulation of the bioavailability of this precursor of nucleotide and nucleic acid synthesis.

Animals↗
PubMed1986

Renal hypertrophy in experimental diabetes. Effect of diabetes on the pathways of glucose metabolism: differential response in adult and immature rats.

The effect of short-term diabetes, 5 days after the administration of streptozotocin, on renal growth and the activity of alternative pathways of glucose metabolism was studied in immature (21-day-old) rats and in adult rats. The kidney weight increased by 28% in the adult diabetic rats, but by only 10% in the immature diabetic rats, relative to their age-matched control groups. The flux of glucose via the pentose phosphate pathway was increased 2-3-fold in the adult diabetic rats, but was unchanged in the immature diabetic group. Enzymes of this pathway (glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) increased by 29% and 77% respectively in adult diabetic rats; in the immature group they showed changes of +5% and +28% respectively. The rate of glucose phosphorylation increased significantly in both groups of diabetic rats; only minor changes were observed in oxidation via the tricarboxylic acid cycle. Increases of 40-50% were found in the activity of enzymes involved in UDP-glucose metabolism (phosphoglucomutase, UDPglucose pyrophosphorylase and UDPglucose dehydrogenase) and in lactate dehydrogenase in both young and adult animals. The results suggest a differential renal response to streptozotocin-diabetes according to the stage of renal growth and development, and it is proposed that the difference is related to the developmental emergence of aldose reductase. Enzymes involved in formation of ribose 5-phosphate and NADPH are strikingly increased in the adult diabetic, whereas metabolic functions dependent on a high ambient glucose concentration, e.g. synthesis of glycogen and glucuronate, are similarly affected in adult and immature diabetic groups, both showing certain aspects of 'glucose overutilization'.

Age Factors↗
PubMed1986

Concentration of phosphoribosyl pyrophosphate in the kidney during development and in experimental diabetic hypertrophy.

The effect of developmental growth on the kidney content of phosphoribosyl pyrophosphate PPRibP was studied in rats at ages between the foetal animal and up to 100 days of age. In addition, the effect of short-term diabetes (up to 14 days) on the renal content of PPRibP was studied in immature rats and in adults aged approx. 60 days. The developmental pattern of PPRibP is such that the PPRibP content is lowest in the young rat and increases as the rate of kidney growth slows. In the adult rat, the early kidney hypertrophy of diabetes is accompanied by a fall in PPRibP content and, again, the PPRibP content returns to normal as the rate of kidney hypertrophy diminishes. Induction of diabetes in the immature rat causes a lesser degree of kidney hypertrophy and also a smaller depression of renal PPRibP content. The activity of PPRibP synthetase (EC 2.7.6.1) is not significantly affected by age or diabetes. The changes in PPRibP content are discussed in relation to the generation of ribose 5-phosphate by the pentose phosphate pathway and the utilization of PPRibP for nucleotide synthesis via the 'de novo' and salvage pathways.

Age Factors↗
PubMed1986

Fluoride uptake and retention at various stages of rat molar enamel development.

Suckling rat pups were given intraperitoneal fluoride injections at selected ages so that we could study fluoride uptake in the enamel of the maxillary first molar at various stages of enamel development. Plasma fluoride levels in six-day-old and 11-day-old pups were monitored following the intraperitoneal injection of fluoride. The findings indicate that: (1) fluoride was more easily taken up and retained during the early stages of enamel formation, but fluoride uptake can occur during all stages of enamel formation; (2) when injections were started early in enamel formation, more fluoride was contained in the enamel of the maxillary first molar at 13 days of age; and (3) the same dose of fluoride per gram body weight resulted in greater exposure to elevated plasma fluoride levels in six-day-old pups than in 11-day-old pups.

Amelogenesis↗
PubMed1986

Maximum flow ratios at mid-vital capacity in young healthy adults.

Upper airway obstruction is usually diagnosed by visual examination of maximum expiratory and inspiratory flow-volume curves and by calculating a ratio of expiratory to inspiratory flow at 50 percent of vital capacity (mid-vital capacity flow ratio); however, reference values of this ratio have not been well established, and considerable variability exists. The purpose of this study was to examine the range of mid-vital capacity flow ratios in a group of healthy subjects and to determine if some of the variability is accounted for by different maximum inspiratory pressures. We measured maximum expiratory and inspiratory flows at 50 percent of vital capacity from the flow-volume curves, and maximum inspiratory pressures in a group of 60 healthy nonsmokers (30 men and 30 women) whose ages ranged from 21 to 40 years. We found that mid-vital capacity flow ratio (mean +/- SD) was 0.72 +/- 0.19 in men and 0.77 +/- 0.18 in women. The coefficient of variation of the mid-vital capacity flow ratio was 28 percent for men and 23 percent for women. The 95 percent confidence limits for the mid-vital capacity flow ratio were 0.65 to 0.79 for men and 0.70 to 0.84 for women. Maximum inspiratory pressures (mean +/- SD) were 129 +/- 30 cm H2O in men and 91 +/- 16 cm H2O in women, not significantly different from previous studies. Normalizing maximum inspiratory flow for maximum inspiratory pressure did not reduce the coefficient of variation, which became 29 percent in men and 30 percent in women. We conclude that the range of mid-vital capacity flow ratios is wide, and it cannot be reduced by standardizing it for maximum inspiratory pressures.

Adult↗
PubMed1986

Effect of aldose reductase inhibitor (sorbinil) on integration of polyol pathway, pentose phosphate pathway, and glycolytic route in diabetic rat lens.

This study examines the effect of an aldose reductase inhibitor (sorbinil) on the flux of specifically labeled glucose through alternative pathways of metabolism in the lens of normal and diabetic rats 1 wk after the induction of diabetes with alloxan. In the diabetic rat lens, there was an apparent increase in the flux of glucose through the pentose phosphate pathway (PPP), as measured by the difference in the yields of 14CO2 from [1-14C]glucose and [6-14C]glucose [C1-C6], this value was 0.087 +/- 0.005 and 0.263 +/- 0.034 mumol X g lens-1 X h (mean + SE of 6 values) for control and diabetic rats, respectively; sorbinil treatment decreased the values to 0.065 +/- 0.008 and 0.171 +/- 0.028, respectively. With glucose tritiated on carbon 2 or 3, it has been shown that the flux of glucose through the polyol route is increased, whereas the flux through the glycolytic pathway is decreased in the diabetic rat lens; both are restored toward normal in the sorbinil-treated diabetic group. These results suggest that the dual effects of diabetes in increasing the lens content of glucose and glucose 6-phosphate and the flux of glucose in the polyol pathway will result in an increased utilization of NADPH and production of NADH, factors favoring the flow of glucose through the PPP and restricting the glycolytic route in the diabetic rat lens. The inhibition of aldose reductase by sorbinil tends to normalize the redox state of the nicotinamide nucleotides, reimposing the NADPH limitation on the PPP and increasing the availability of NAD+ for the glycolytic route.

Aldehyde Reductase↗
PubMed1985

The insulin-mimetic action of Mn2+: involvement of cyclic nucleotides and insulin in the regulation of hepatic hexokinase and glucokinase.

Manganese causes a significant rise in hepatic glucokinase and hexokinase in 16-day-old suckling rats, and has an insulinomimetic effect in producing a precocious emergence of glucokinase (EC 2.7.1.2) and a rise in the low Km, hexokinases (EC 2.7.1.1) activities. These enzyme changes occur within 6 hr of manganese administration and there are accompanying increases in plasma insulin and hepatic cyclic GMP. That the effect of manganese is at a site other than, or in addition to, insulin secretion is suggested by the significant increases in glucokinase and hexokinase in 16-day-old streptozotocin-diabetic rats; in this group there is also an increase in hepatic cGMP similar in time scale to that of the normal-manganese-treated group. The effects of manganese and insulin were not additive. It is proposed that one site of action of manganese may be at the level of cyclic GMP systems. The results are also discussed in relation to the known action of manganese at the level of the protein phosphatases.

Animals↗
PubMed1985

Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity.

An examination was made of the effect of different periods of experimental diabetes on the activity of the pentose phosphate pathway in rat kidney. A rapid increase in kidney weight, expressed both in absolute terms and in terms of body weight, occurred shortly after the induction of diabetes. The activity of the enzymes of the oxidative segment of the pentose phosphate pathway and the flux of glucose through the pathway were both increased during the first 7 days after induction of diabetes. Thereafter, enzyme activity returned toward control levels, but the increased functional activity of the pathway, as measured using specifically labeled glucose, persisted. In contrast, transketolase was significantly depressed at the time of most rapid kidney growth. A positive correlation was found between the rate of kidney growth and the change in activity of glucose-6-phosphate dehydrogenase and a negative correlation with changes in transketolase activity. The possible roles of the oxidative and nonoxidative segments of the pentose phosphate pathway in the kidney in early diabetes-induced renal hypertrophy are discussed.

Animals↗
PubMed1984

Regulation of glucose metabolism in rat adrenal gland in alloxan-diabetes: the possible role of fructose 2,6-bisphosphate.

The level of fructose 2,6-bisphosphate is markedly decreased in the rat V.renal gland in diabetes, falling to 23% of the control value. There is parallel decrease in the flux of 14C-labelled glucose through the glycolytic route and tricarboxylic acid cycle. Only minimal changes in hexokinase (EC 2.7.1.1.), a 22% decrease in Type I hexokinase of the soluble fraction, were observed, highlighting the probable significant involvement of fructose 2,6-bisphosphate in the regulation of glycolysis in the adrenal. In contrast, there was evidence for a marked rise in the flux of glucose through the pentose phosphate pathway, which may be linked to enhanced corticoid synthesis in the diabetic state.

Adrenal Glands↗
PubMed1984

Fructose 2,6-bisphosphate, sugar phosphates and adenine nucleotides in the regulation of glucose metabolism in the lactating rat mammary gland.

Fructose 2,6-bisphosphate is present in the rat mammary gland, rising from a value of 1.4 nmol/g in pregnancy to 4.3 nmol/g tissue at 14 days lactation; the equivalent values calculated/ml intracellular water are 5.2 and 11.6 nmol, respectively. The tissue content of fructose 6-phosphate, fructose 1,6-bisphosphate, ATP and phosphoenolpyruvate remain relatively constant in the transition from pregnancy to the height of lactation. The changes in AMP, cyclic AMP, and citrate content of the mammary gland during lactation are such as to promote an increase in fructose 2,6-bisphosphate formation and flux through phosphofructokinase.

Adenosine Monophosphate↗
PubMed1984

Regulation of alternative pathways of glucose metabolism in rat heart in alloxan diabetes: changes in the pentose phosphate pathway.

The flux of glucose through the pentose phosphate pathway, important in relation to the provision of ribose 5-phosphate for nucleotide and RNA synthesis, was decreased by 70% in the diabetic rat heart in parallel with a similar decreased flux through the glycolytic route. A common factor linking the decreased flux through these alternative routes is the known fall in cardiac hexokinase; in these experiments there is a 50% decrease in Type II hexokinase (EC 2.7.1.1.) in both soluble and particulate fractions. The level of fructose 2,6-bisphosphate, a regulator of phosphofructokinase activity, is decreased by 20% in the alloxan diabetic rat heart, this may be a significant additional factor in the marked decrease in the flux of glucose through the glycolytic route in the myocardium in diabetes.

Animals↗
PubMed1984

Acetaminophen-induced alterations in blood glucose and blood insulin levels in mice.

Three hours following administration of a toxic dose of the analgesic acetaminophen (500 mg/kg) to mice, blood glucose levels increased to 225 per cent. By six hours blood glucose levels decreased to approximately control values and by 24 hours glucose levels were 45 percent saline-treated control values. Immunoprecipitable blood insulin levels increased dramatically following acetaminophen treatment and were 300 per cent at 3 hours, 1100 per cent at 8 hours and 800 per cent at 24 hours. Saline treatment did not appreciably alter blood insulin levels. These observations indicate that acetaminophen may selectively alter pancreatic beta cells.

Acetaminophen↗
PubMed1983

Two different metabolic responses to ischaemia: inherent variability or artefact?

Guinea pig hearts, perfused with (5-3H) glucose (8 mmol . litre-1) and subjected to 30 min of reduced (6%) coronary flow, exhibited two distinctly different metabolic and electrophysiological responses to ischaemia. In 22 of the 50 hearts studied (Group 1) glucose utilisation declined during ischaemia from 2.5 +/- 0.2 to 1.3 +/- 0.2 mumol . litre-1 . g-1 dry wt. In these hearts, endogenous substrates such as glucogen and triglyceride were mobilised and, although input into glycolysis may have been initially increased through accelerated glycogenolysis, estimated glycolytic flux (1.7 +/- 0.1 mumol hexose . min-1 . g-1 dry wt) remained limited. Instead, there was a large accumulation of the intermediates of glycolysis, an increase in the content of AMP and cAMP and a particularly marked decline in creatine phosphate levels. With subsequent reperfusion, these hearts all fibrillated. In contrast, in the other 28 hearts (Group 2) glucose utilisation (5.1 +/- 0.4 mumol . min-1 . g-1 dry wt) and estimated glycolytic flux (4.1 +/- 0.01 mumol hexose . min-1 . g-1 dry wt) were increased during ischaemia. In these preparations, relatively little glycogen and triglyceride were utilised, and there was less accumulation of glycolytic intermediates. Further, lower levels of AMP and cAMP were observed and creatine phosphate: creatine ratios were better maintained. These hearts did not fibrillate during reperfusion. Thus the variable susceptibility of the myocardium to ischaemic damage, as evidenced by the random incidence of ventricular fibrillation during reperfusion, may have been related to two distinctly different metabolic responses to restricted perfusion.

Adenine Nucleotides↗
PubMed1983

Alternative pathways of glucose utilization in brain: changes in the pattern of glucose utilization and of the response of the pentose phosphate pathway to 5-hydroxytryptamine during aging.

The oxidation of differentially labelled glucose, pyruvate and glutamate in brain slices from rats aged 20 days to 26 months has been studied and the partition of the glucose used into the glycolytic-tricarboxylic acid cycle pathway, the pentose phosphate pathway and the glutamate-GABA shunt has been calculated. Over the time range 4 to 26 months, there is an approximately 20% decrease in the production of CO2 via the glycolytic-tricarboxylic acid cycle route, as there is in the rate of glucose phosphorylation. The glutamate-GABA pathway falls by about 50% over this same time span. The broad activity of the pentose phosphate pathway falls rapidly and cannot be detected in the brains of rats aged 18 months or more, whereas the fully stimulated pathway, i.e. in the presence of the artificial electron acceptor phenazine methosulphate, declines only marginally over this period, falling sharply only after 23 months. The pentose phosphate pathway is stimulated by the presence of 5-hydroxytryptamine and this stimulation appears to increase with age.

Aging↗
PubMed1983

Differential response of liver and kidney adenine nucleotide translocase and pyruvate dehydrogenase activity to alloxan diabetes. The possible regulatory role of long chain acyl CoA.

Adenine nucleotide translocase (EC 3.6.1.3.), pyruvate dehydrogenase (active and total forms, EC 1.2.4.1) and the long chain acyl CoA content were measured in liver and kidney from normal and alloxan-diabetic rats. The long chain acyl CoA content was significantly increased in liver, but not in kidney, in the diabetic group. Adenine nucleotide translocase activity was decreased in liver and raised in the kidney of alloxan-diabetic rats relative to the control group. Pyruvate dehydrogenase (active) was inhibited to a similar degree in both tissues in diabetes. The results are discussed in the light of the possible regulatory role of long chain acyl CoA and the diverse metabolic demands of the two tissues in diabetes.

Acyl Coenzyme A↗