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M C Sugden

Publications and source records attributed to M C Sugden.

At least 55 records · Page 3Linked to original sources
PubMed1997

Molecular mechanisms underlying the long-term impact of dietary fat to increase cardiac pyruvate dehydrogenase kinase: regulation by insulin, cyclic AMP and pyruvate.

Previous studies have demonstrated that pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat cardiac mitochondria is increased @two-fold by providing a high-fat diet for 28 days. The present study sought to establish the factor(s) that might underlie the response of cardiac PDHK to the provision of a high-fat diet. ELISA assays of PDHKII, conducted over a range of PDHK activities, demonstrated that the increase in cardiac PDHK activity was not due to an increase in mitochondrial immunoreactive PDHKII concentration. The pyruvate concentration giving 50% active PDHC (PDHa) in mitochondria incubated with respiratory substrates was unaffected by high-fat feeding, demonstrating a dissociation between increased PDHK activity and altered sensitivity of PDHK to suppression by pyruvate. In cardiac myocytes cultured (25 h) with n-octanoate (1 mm) plus dibutyryl cAMP (50 microM), insulin at 12.5 microU/ml, 25 microU/ml and 75 microU/ml, suppressed PDHK activities in cells prepared from control rats, but insulin at concentrations <100 microU/ml failed to suppress PDHK activities in cardiac myocytes prepared from high-fat-fed rats. In vivo, cardiac insulin sensitivity (assessed by euglycaemic hyperinsulinaemic clamp in combination with 2-[3H] deoxyglucose administration) was suppressed after high-fat feeding. A sustained (24 h) two- to four-fold elevation in plasma insulin concentration (achieved by insulin infusion via osmotic pumps) did not affect PDHK activity in hearts of control rats. In contrast, PDHK activity in hearts of high-fat-fed rats was suppressed to values not significantly different from (insulin-infused) control rats. Basal and agonist-stimulated cAMP concentrations were unaffected by high-fat-feeding or insulin. Furthermore, rates of palmitate oxidation (to CO2) in cardiac myocytes (in the absence or presence of insulin or adrenergic agonists) were not statistically significantly affected by high-fat-feeding. The results indicate that an impaired action of insulin to suppress PDHK participates in the mechanism by which increased PDHK activity is achieved in response to high-fat feeding, but insulin does not act through decreasing cAMP concentrations or suppressing fatty acid oxidation.

Animals↗
PubMed1997

Glucoregulation during progressive starvation in late pregnancy in the rat.

The response of glucose utilization (transport and phosphorylation) by individual skeletal muscles to progressive starvation in late pregnancy in the rat was investigated in relation to changes in whole body glucose turnover. Compared with insulin-stimulated values, the decline in muscle glucose utilization evoked by short-term (6-h) starvation was about twofold greater in pregnancy. Suppression of glucose utilization by slow-twitch muscles was observed as the starvation period was extended from 6 to 24 h only in unmated rats. Extending starvation to 24 h did not further reduce glucose utilization by fast-twitch skeletal muscles in either group. Suppression of whole body glucose disposal was observed between 6 and 24 h of starvation in unmated, but not pregnant, rats. The results demonstrate that metabolic adaptation of almost complete suppression of glucose utilization by slow-twitch muscle, normally elicited only by prolonged (24-h) starvation, is already established after acute (6-h) starvation in late pregnancy. The present study supports the concept of "accelerated starvation" in late pregnancy with respect to muscle glucose utilization after short-term food withdrawal but demonstrates that further glucose conservation cannot be achieved after more prolonged starvation.

Animals↗
PubMed1997

Differential regulation of glycogen synthase by insulin and glucose in vivo in skeletal muscles of the rat.

Glucose 6-phosphate (G-6-P)-independent glycogen synthase (GSa) and glycogen synthase (GS) total activities were measured in muscles from 24-h-starved rats. Intravenous glucose tolerance tests (0.5 g/kg body wt) were used to produce physiological, transient increases in insulin and glucose concentrations. GS activation occurred at approximately 10 min after glucose administration with peak activation at approximately 15 min. GS activation was reversed approximately 15 min after insulin and glucose concentrations had returned to basal. No differences existed between fast- and slow-twitch muscles. Hyperinsulinemia (approximately 160 mU/ml) in the absence of hyperglycemia elicited 1.5-fold activation of GS (P < 0.001) in two of three fast-twitch muscles but did not activate GS in slow-twitch muscles. Glucose infusion (glycemia approximately 8 mM; insulin approximately 40 mU/ml) significantly (P < 0.01) increased the percentage of total GS in the GSa form in four of the five muscles. Hyperglycemia with modest hyperinsulinemia evoked greater enhancement of GSa activity in fast-twitch muscle than insulin alone at a higher concentration (P < 0.01). In summary, hyperinsulinemia without hyperglycemia does not result in maximal activation of GS in fast-twitch muscle, and a rise in glycemia is obligatory for GS activation by insulin in slow-twitch muscle. The data support an important role for glycemia in modulating the response of skeletal muscle GS to insulin and provide further evidence of heterogeneity among skeletal muscle types.

Animals↗
PubMed1997

Selective modification of insulin action in adipose tissue by hyperthyroidism.

Adipose-tissue lipolysis (assessed from glycerol release) and glucose uptake were examined in parametrial and mesenteric adipocytes prepared from control or hyperthyroid rats in relation to changes in insulin sensitivity. Basal rates of lipolysis did not differ significantly between adipose-tissue depots. Lipolysis was maximally stimulated by noradrenaline at 1 microM, half-maximal anti-lipolytic effects of insulin were observed at approximately 11 microU/ ml insulin, and half-maximal stimulation of glucose uptake was observed at approximately 16 microU/ml insulin in adipocytes from both depots. Wortmannin caused a dose-dependent inhibition of the anti-lipolytic effect of insulin (150 microU/ml) on noradrenaline-stimulated lipolysis. Half-maximal effects of wortmannin were observed at 20-40 nM. The p70S6K inhibitor rapamycin and the mitogen-activated protein kinase kinase inhibitor PD098059 had no effects on noradrenaline-stimulated lipolysis. Hyperthyroidism increased basal rates of lipolysis and the maximal response of lipolysis to noradrenaline stimulation (3.1-fold, P < 0.001 and 2.1-fold, P < 0.05 respectively) in parametrial adipocytes. Hyperthyroidism markedly blunted the sensitivity of noradrenaline-stimulated lipolysis to half-maximal suppression by insulin in both parametrial and mesenteric adipocyte depots, and noradrenaline-stimulated lipolysis at a maximal insulin concentration remained significantly higher in adipocytes prepared from hyperthyroid rats compared with controls. Hyperthyroidism had no effect on basal and little effect on insulin-stimulated glucose uptake. Tri-iodothyronine administered at a low dose selectively influenced the anti-lipolytic action of insulin in parametrial adipocytes, and led to significantly less marked elevation in plasma non-esterified fatty acid concentrations in vivo. The results demonstrate a selective effect of hyperthyroidism to impair insulin's anti-lipolytic action, and are consistent with the operation of different downstream signalling mechanisms for the effects of insulin on adipocyte glucose transport and lipolysis.

Adipose Tissue↗
PubMed1996

Pyruvate inhibition of pyruvate dehydrogenase kinase. Effects of progressive starvation and hyperthyroidism in vivo, and of dibutyryl cyclic AMP and fatty acids in cultured cardiac myocytes.

Both prolonged starvation and hyperthyroidism evoke stable increases in cardiac pyruvate dehydrogenase kinase (PDHK) activity. Pyruvate inhibits PDHK in rat heart mitochondria with activation of PDHC. The sensitivity of PDHK to inhibition by pyruvate declines after prolonged starvation. In the present study, pyruvate concentrations giving 50% active complex (PDHa) in mitochondria from fed, control and fed, hyperthyroid rats were 0.3 and 0.8 mM, respectively, compared with 1.0 and 2.8 mM, respectively in mitochondria from 24-h-starved and 48-h-starved rats. The results demonstrate that altered pyruvate sensitivity is not of necessity linked with altered PDHK activity. PDHK activities in mitochondria prepared from cardiac myocytes from fed rats were increased after culture for 24 h with dibutyryl cyclic AMP (50 microM) plus n-octanoate (1 mM), with a concomitant decline in sensitivity of PDHK to pyruvate inhibition, suggesting that changes in sensitivity of PDHK to pyruvate inhibition in vivo may be secondary to increased fatty acid supply and cyclic AMP concentrations.

Animals↗
PubMed1996

Regulation of hepatic pyruvate dehydrogenase kinase by insulin and dietary manipulation in vivo. Studies with the euglycaemic-hyperinsulinaemic clamp.

The provision of a high-fat diet (47% of energy as fat) for 28 days led to a significant increase in hepatic pyruvate dehydrogenase kinase activity, together with significant suppression of hepatic pyruvate dehydrogenase (active form). An enhanced hepatic pyruvate dehydrogenase kinase activity continued to be observed at 6 h after the withdrawal of the high-fat diet. Significant suppression of hepatic pyruvate dehydrogenase kinase activity was observed in post-absorptive, high-fat-fed rats after a 2.5 h euglycaemic-hyperinsulinaemic clamp, such that differences in pyruvate dehydrogenase kinase activities between control and high-fat-fed rats were no longer evident. Starvation for 24 h in rats previously maintained on standard diet also evoked a substantial increase in hepatic pyruvate dehydrogenase kinase activity. This latter response was only partially reversed by 2.5 h of euglycaemic hyperinsulinaemia. Suppression of pyruvate dehydrogenase kinase activity by 2.5 h euglycaemic hyperinsulinaemia in high-fat-fed rats was associated with a substantial increase in hepatic pyruvate dehydrogenase activity (active form) whereas no significant increase in hepatic pyruvate dehydrogenase activity (active form) was observed after 2.5 h euglycaemic hyperinsulinaemia in 24 h-starved rats. The results are consistent with the proposition that hepatic pyruvate dehydrogenase kinase responds directly to an increase in lipid oxidation which is facilitated by insulin deficiency or an impaired action of insulin.

Animals↗
PubMed1996

Increased hepatic pyruvate dehydrogenase kinase activity in fed hyperthyroid rats: studies in vivo and with cultured hepatocytes.

Experimental hyperthyroidism induced by the administration of tri-iodothyronine (T3; 100 micrograms/100 g body wt; 3 days) increased plasma non-esterified fatty acids in the fed state in the rat. At the same time, hepatic PDH kinase responded with a persistent (1.6-fold) increase in activity. The exposure of hepatocytes from fed euthyroid rats to T3 (100 nM) in culture for 21 h increased PDH kinase activity to an extent comparable to that observed in vivo in response to hyperthyroidism. The in vitro increase in PDH kinase activity was suppressed by insulin (100 microU/ml) and by inhibition of mitochondrial fatty acid oxidation. The results demonstrate a direct hepatic action of T3 to increase PDH kinase activity, which is mediated by intramitochondrial fatty acyl-CoA or a product of beta-oxidation, and facilitated by hepatic insulin resistance.

Acyl Coenzyme A↗
PubMed1996

Suboptimal protein nutrition in early life later influences insulin action in pregnant rats.

First-generation rats received either 20% (standard) or 8% (suboptimal) protein nutrition during pregnancy and lactation. Suboptimal protein nutrition led to reduced body weights of the second-generation progeny at day 19 of gestation (10%, p < 0.001) and at weaning (33% reduction, p < 0.001). Control (born of 20% protein-fed dams) and experimental (born of 8% protein-fed dams) offspring received 20% protein diet after weaning and were studied on day 19 of gestation at 9 to 12 weeks after weaning. Basal glucose turnover was lower (29%, p < 0.05) and glucose utilization by fast-twitch muscle, adipose tissue and diaphragm significantly reduced in experimental offspring. Hyperinsulinaemia increased whole-body glucose disposal rate in both control (2.3-fold, p < 0.001) and experimental (3.2-fold, p < 0.001) offspring. Hyperinsulinaemia normalised the suppression of glucose utilization observed in diaphragm, heart and adipose tissue, but not in fast-twitch muscle, where rates remained 30-40% lower in the experimental offspring. Glucose tolerance and insulin secretion after i.v. glucose were unimpaired in the pregnant experimental offspring. A 27% reduction in basal glucose utilization, without impaired growth, was observed for the third-generation fetuses of the experimental offspring. The results demonstrate that growth retardation evoked by suboptimal protein nutrition during early life leads to decreased basal glucose turnover and glucose utilization by a range of maternal tissues and the fetus during a subsequent pregnancy. It is not, however, associated with any major permanent impairment of glucose-stimulated insulin secretion or insulin action during pregnancy.

Adipose Tissue↗
PubMed1995

The long-term regulation of skeletal muscle pyruvate dehydrogenase kinase by dietary lipid is dependent on fatty acid composition.

The provision of a diet high in saturated and monounsaturated fat for 28 days evoked a significant (1.9-fold) increase in pyruvate-dehydrogenase kinase activity measured in isolated mitochondria from representative slow-twitch (oxidative) skeletal muscles (pooled soleus and adductor longus muscles) from adult rats. The increase observed in response to 28 days of high-fat feeding in slow-twitch skeletal muscle mitochondria was similar in magnitude to that observed in heart mitochondria. Pyruvate-dehydrogenase kinase activity was not increased in response to the provision of the high-fat diet in mitochondria prepared from a representative fast-twitch muscle (tibialis anterior), while the increases evoked by 28 days of high-fat feeding in cardiac and slow-twitch skeletal muscle were prevented by the replacement of 7% of the dietary fatty acids with long-chain omega-3 fatty acids from marine oil. Cardiac myocytes prepared from the high-fat-fed rats showed impaired responses of this enzyme to n-octanoate (1 mM) and N6,2-O-dibutyryladenosine 3',5'-monophosphate (50 microM) individually in cultured cardiac myocytes and of glucose uptake to insulin at low concentrations in freshly prepared cardiac myocytes, compared with control rats maintained on standard low-fat/high-carbohydrate diet. These impairments in responses to agonists were substantially improved by the inclusion of long-chain omega-3 fatty acids in the high-fat diet. The results indicate that pyruvate-dehydrogenase kinase activity in oxidative skeletal muscle is a target for longer-term regulation by high-fat feeding and that the fatty acid composition of the diet, rather than the fat content, is a key influence.

Animals↗
PubMed1995

Interactive effects of insulin and triiodothyronine on pyruvate dehydrogenase kinase activity in cardiac myocytes.

Hyperthyroidism [produced by the administration of 3,5,3'-triiodothyronine (T3) for 3 days to adult rats] increased PDH kinase activities of freshly isolated cardiomyocytes by 1.6-fold. The effects of hyperthyroidism and 48 h-starvation to increase PDH kinase activities were additive. Culture of cardiomyocytes prepared from fed, euthyroid rats for 25 h with T3 (100 nM) increased PDH kinase activities to values comparable in magnitude to those observed in response to experimental hyperthyroidism in vivo. PDH kinase activities in cardiomyocytes from fed, euthyroid rats after culture with n-octanoate (1 mM) or dibutyryl cyclic AMP (DBcAMP)(50 microM) exceeded those of freshly isolated myocytes. DBcAMP and T3 were without further effect in the presence of n-octanoate. The inclusion of insulin (100 microU/ml) alone in the culture medium did not affect PDH kinase activity, but insulin suppressed the effects of T3, DBcAMP and n-octanoate to increase cardiomyocyte PDH kinase activity in culture. PDH kinase activities in cardiomyocytes isolated from starved rats declined after 25 h of culture. This decline was prevented by the inclusion of T3, but not of DBcAMP, in the culture medium. Insulin (100 microU/ml) suppressed the effects of T3 to oppose the loss of cardiomyocyte PDH kinase activity experienced during culture. The results demonstrate that hyperthyroidism leads to a stable increase in the activity of cardiomyocyte PDH kinase, a response that is mimicked by T3 in vitro. Insulin opposes the effects of T3 (and of fatty acids and cyclic AMP) to increase PDH kinase activity in cultured cardiomyocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The pyruvate dehydrogenase complex: nutrient control and the pathogenesis of insulin resistance.

This review examines the molecular mechanisms underlying substrate competition between glucose and lipid in starvation and in insulin-resistant states. We demonstrate that lipid-derived substrates are oxidized in preference to glucose by skeletal muscle in vivo during prolonged starvation. An accelerated and exaggerated lipolytic and ketogenic response to starvation in late pregnancy is associated with more rapid suppression of glucose oxidation by the maternal skeletal-muscle mass. These benign adaptations to changes in lipid availability (which occur secondarily to changes in carbohydrate supply and demand) contrast with the well-documented detrimental effects to health of an inappropriately high supply of dietary lipid. We present results that indicate that the prolonged consumption of a diet high in saturated fat is associated with a stable enhancement of pyruvate dehydrogenase (PDH) kinase activity at least in two oxidative tissues--liver and heart. This long-term enhancement of PDH kinase activity is concomitant with the development of whole-body insulin resistance and adds a new dimension to the potential role of dietary composition in the pathogenesis of insulin resistance.

Animals↗
PubMed1995

Modulation of in vivo insulin action by dietary protein during pregnancy.

Rats were provided with a standard 20% protein diet or an isocaloric 8% protein diet from day 1 of gestation and were studied on day 19 of pregnancy. Fetal numbers per dam were unchanged, but total fetal weight at day 19 of gestation was reduced by 10% (P < 0.001) in the 8% protein group. In the basal state, endogenous glucose production (Ra) and muscle glucose uptake/phosphorylation were not significantly affected by dietary protein content. The glucose infusion rate required to maintain glycemia and Ra during euglycemic-hyperinsulinemic clamp (insulin infusion rate of 4.17 mU.kg-1.min-1) were reduced in the 8% protein group by 17% (P < 0.05) and 76% (P < 0.001), respectively. Suppression of Ra by insulin was not significant in the 20% protein group. Insulin-stimulated glucose disappearance (Rd) was 24% lower (P < 0.001) in the 8% protein group (25.0 +/- 0.8 mg.min-1.kg-1) than in the 20% protein group (32.7 +/- 0.5 mg.min-1.kg-1). The overall increment in muscle glucose utilization index (mean of 6 muscles) elicited by insulin was impaired by 38.1 +/- 4.0%. Insulin suppressed nonesterified fatty acid concentration (NEFA) by 83% (P < 0.001) and plasma triacylglycerol concentration (TAG) by 67% (P < 0.05) in the 20% protein group but evoked only a 43% (P < 0.01) decline in plasma NEFA and did not significantly suppress plasma TAG in the 8% protein group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗