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M C Sugden

Publications and source records attributed to M C Sugden.

176 records · Page 10Linked to original sources

Regulation of hepatic lipogenesis in starved and diabetic animals by thyroid hormone.

The effects of intragastric feeding with glucose and of the administration of L-triiodothyronine (T3) on in vivo rates of hepatic lipogenesis were investigated in control (fed ad libitum on normal diet), diabetic (fed ad libitum on normal diet), fat-fed (fed ad libitum on high-fat diet), and starved (food removed for 48 h) rats. Two days of T3 treatment increased hepatic lipogenesis in control and fat-fed animals but not in the diabetic or starved animals, although increases in lipogenesis in diabetic animals were observed after 4 days of T3 treatment. Intragastric glucose feeding increased hepatic lipogenesis in the livers of control animals and T3-treated control animals. Such increases are mediated by an increase in the circulating insulin concentration, as increases are not observed in diabetic rats or T3-treated diabetic rats. Glucose feeding failed to increase hepatic lipogenesis in fat-fed rats or starved rats. Insulin injection together with glucose feeding increased lipogenesis in the fat-fed group but not the starved group; i.e., impaired insulin secretion following an oral glucose load may in part explain the lack of response in the fat-fed but not the starved animals. Marked increases in hepatic lipogenesis after glucose feeding were, however, observed if either the starved or the fat-fed animals were treated with T3. The physiological implications of these observations are discussed.

Animals↗

Lipogenesis in response to an oral glucose load in fed and starved rats.

Lipogenesis in livers of fed but not of starved rats is increased after intragastric feeding with glucose. In contrast, lipogenesis in brown adipose tissue increases in both fed and starved animals. These observations suggest that lipogenesis in brown adipose tissue is regulated by mechanisms in addition to, or other than, those operating in liver. The fate of newly synthesized lipid in brown adipose tissue is not known. However, the formation of palmitoyl-carnitine from palmitoyl-CoA and carnitine by mitochondria from brown fat was inhibited by malonyl-CoA. Although inhibition was not 100%, it is implied that mitochondrial uptake of the newly synthesized fat by the carnitine acyltransferase system is restricted under conditions of increased lipogenesis.

Adipose Tissue↗

Carbohydrate metabolism and the glucoreceptor mechanism.

Current views on the recognition of sugars as signals for insulin biosynthesis and release are discussed. Evidence is presented that the initial steps in the metabolism of N-acetyl-glucosamine differ from those in glucose metabolism in that for the former transport into the islet represents the rate-limiting step. Different enzymes phosphorylate these two sugar, but it is suggested that N-acetylglucosamine and glucose enter the beta-cell via the same carrier since 3-O-methylglucose is shown to be a competitive inhibitor of N-acetylglucosamine oxidation. Inhibitory effects on N-acetylglucosamine oxidation are also observed with caffeine, 3-isobutyl-methylxanthine and phloretin. Inhibition of N-acetylglucosamine metabolism is associated with inhibition of N-acetylglucosamine-stimulated insulin release and biosynthesis. Methylxanthines also inhibit uptake of 45Ca2+ by islet mitochondria. The possible physiological role of islet mitochondrial Ca2+ uptake in the regulation of beta-cell cytosolic Ca2+ concentration is discussed.

1-Methyl-3-isobutylxanthine↗

Protein kinase activities in rat pancreatic islets of Langerhans.

1. Protein kinase activities in homogenates of rat islets of Langerhans were studied. 2. On incubation of homogenates with [gamma-32P]ATP, incorporation of 32P into protein occurred: this phosphorylation was neither increased by cyclic AMP nor decreased by the cyclic AMP-dependent protein kinase inhibitor described by Ashby & Walsh [(1972) J. Biol. Chem. 247, 6637--6642]. 3. On incubation of homogenates with [gamma-32P]ATP and histone as exogenous substrate for phosphorylation, incorporation of 32P into protein was stimulated by cyclic AMP (approx. 2.5-fold) and was inhibited by the cyclic AMP-dependent protein kinase inhibitor. In contrast, when casein was used as exogenous substrate, incorporation of 32P into protein was not stimulated by cyclic AMP, nor was it inhibited by the cyclic AMP-dependent protein kinase inhibitor. 4. DEAE-cellulose ion-exchange chromatography resolved four peaks of protein kinase activity. One species was the free catalytic subunit of cyclic AMP-dependent protein kinase, two species corresponded to 'Type I' and 'Type II' cyclic AMP-dependent protein kinase holoenzymes [see Corbin, Keely & Park (1975) J. Biol. Chem. 250, 218--225], and the fourth species was a cyclic AMP-independent protein kinase. 5. Determination of physical and kinetic properties of the protein kinases showed that the properties of the cyclic AMP-dependent activities were similar to those described in other tissues and were clearly distinct from those of the cyclic AMP-independent protein kinase. 6. The cyclic AMP-independent protein kinase had an s20.w of 5.2S, phosphorylated a serine residue(s) in casein and was not inhibited by the cyclic AMP-dependent protein kinase inhibitor. 7. These studies demonstrate the existence in rat islets of Langerhans of multiple forms of cyclic AMP-dependent protein kinase and also the presence of a cyclic AMP-independent protein kinase distinct from the free catalytic subunit of cyclic AMP-dependent protein kinase. The presence of the cyclic AMP-independent protein kinase may account for the observed characteristics of 32P incorporation into endogenous protein in homogenates of rat islets.

Animals↗

Effects of phosphoenolpyruvate, other glycolytic intermediates and methylxanthines on calcium uptake by a mitochondrial fraction from rat pancreatic islets.

45Ca2+-accumulation by a mitochondrial fraction from isolated rat pancreatic islets was stronly stimulated by ATP. The ATP-dependent uptake was inhibited by phosphoenolpyruvate in a dose-dependent manner over a wide variety of conditions. Inhibition by phosphoenolpyruvate was non-completitive with respect to calcium, competitive with respect to magnesium, and antagonised by high Mg-ATP2- concentrations; fructose 1,6-diphosphate also decreased 45Ca2+-uptake. Other glucose metabolites were either less effective or ineffective in diminishing mitochondrial 45Ca2+-accumulation. The ATP-dependent uptake was also inhibited by xanthine derivatives (caffeine and 3-isobutyl-1-methylaxanthine) which potentiate the effects of glucose on insulin secretion. Cyclic AMP had no effect. It is thought that the rate of insulin secretion is a function of the cytosolic calcium concentration in the B-cell. These data show that phosphoenolpyruvate, fructose 1,6-diphosphate and methylxanthines might influence exocytosis by direct effects on mitochondrial calcium accumulation, and thus the intracellular distribution of calcium.

Adenosine Triphosphate↗

Phosphoenolpyruvate in rat pancreatic islets: a possible intracellular trigger of insulin release?

The content of phosphoenolpyruvate (PEP) has been measured in isolated rat islets of Langerhans incubated in vitro. Islet PEP was higher in islets incubated with 16.7 mmol/1 glucose than in islets incubated with zero or 2.8 mmol/1 glucose. Islet PEP content was also increased in islet incubated with 5 mmol/1 D-glyceraldehyde. Mannoheptulose abolished the glucose-induced rise in PEP content but not that elicited by D-glyceraldehyde. These results are consistent with a role for PEP as an intracellular mediator or glucose- and glyceraldehyde-induced insulin release. The kinetics of pyruvate kinase in extracts of rat islets were studied. The maximal extractable activity was considerably higher than known rates of glycolytic flux. The Km values were found to be 0.16 mmol/1 for PEP and 0.5 mmol/1 for ADP. The control of islet PEP content and the possible role of PEP in insulin release are discussed.

Animals↗

Beta-hydroxybutyrate transport in rat brain: developmental and dietary modulations.

Transport of beta-hydroxybutyrate (betaHB) into rat brain was estimated from the early rise in brain/serum 14C ratio after subcutaneous injection of [14C]betaHB. Permeability of the D isomer exceeded that of the L isomer. Permeability of either isomer rose throughout suckling (sevenfold) and declined after weaning to the low, newborn values. This age dependence differed markedly from those of cerebral blood flow and cerebral permeabilities of urea, glucose, valine, leucine, and DMO (5,5-dimethyloxazolidine-2,4-dione). Fat-feeding more than doubled cerebral betaHB permeability without significantly affecting cerebral blood flow or the permeabilities of urea, glucose, and DMO. Temperature dependence of betaHB permeability was similar to that of glucose transport. The age and diet dependence of betaHB were not accounted for in terms of body temperature, capillary surface, capillary porosity, or plasma proton concentration. A modulable betaHB carrier seemed indicated. Utilization of betaHB by the brain was signficantly governed by permeability, hence the increased permeability in ketotoc states should contribute to glucose sparing and eventually to protein sparing.

Age Factors↗

Lipid fuel metabolism after abdominal surgery.

The work investigated fuel interrelationships in surgical patients infused with saline (Group I) or glucose (Group II) (13 patients in each group) on the day of surgery and subsequently maintained solely on saline until the fifth postoperative day. Blood concentrations of non-esterified fatty acids (NEFA) and ketone bodies were markedly increased in response to surgical stress on the day of surgery only in patients who were not administered carbohydrate. Increased concentrations of lactate and glucose were observed on the day of surgery in patients infused with either saline or glucose. As both fatty acid and ketone body concentrations were decreased by glucose infusion, impaired glucose utilization immediately after surgery is not a simple consequence of increased oxidation of lipid fuels. Glucose and lactate concentrations declined after the day of surgery. Despite a progressive fall in plasma non-esterified fatty acid concentrations from the first to fifth post-operative days, blood ketone body concentrations were strikingly elevated in both groups of patients. The findings emphasize the role of the liver in post-operative fatty acid turnover.

Abdomen↗