Control of muscle pyruvate oxidation during late pregnancy

Sugden, Mary C.; Holness, Mark J.

doi:10.1016/0014-5793(93)80091-8

Cited by 18 publications

(6 citation statements)

References 46 publications

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“…PDH a activities were measured in extracts of freezeclamped muscles from rats sampled in the basal state (24 h starved) and after 2 h of insulin-stimulation during refeeding ( Figure 4). In order to assess the extent of reversal of PDH inactivation by phosphorylation that is well-established to occur in response to starvation (Caterson et al, 1982;Holness et al, 1989;Sugden and Holness, 1993), PDH a activities have been expressed relative to those pertaining in the fed state in control (virgin) rats.…”

Section: Insulin-sensitive Targets Distal To Glucose Uptake: Glycogenmentioning

confidence: 99%

“…Significant suppression of glucose utilization by oxidative muscles of late (19-20 day) pregnant rats is also associated with hepatic and peripheral insulin resistance (Leturque etal., 1984) and high levels of plasma fatty acids (Leturque et al, 1989;Holness et al, 1991;Sugden and Holness, 1993). The state of insulin resistance induced by late pregnancy is not further enhanced by high-fat feeding (Leturque etal., 1987).Taken together, these findings suggest that an increase in fatty acid oxidation may underlie the suppression of glucose utilization observed in oxidative muscles during pregnancy.…”

Section: Introductionmentioning

confidence: 97%

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The Role of the Glucose/Fatty Acid Cycle in the Selective Modulation of Non-Oxidative and Oxidative Glucose Disposal by Oxidative Muscle in Late Pregnancy

Sugden¹,

Holness²

1994

Biological Chemistry Hoppe-Seyler

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Physiological insulin stimulation (induced by re-feeding) in late (19 to 20 days) pregnancy in the rat led to only partial reversal of starvation-induced increases in circulating fatty acid concentrations. The impaired suppression of adipose tissue lipolysis was associated with a clear attenuation of the activation of PDHa activity in oxidative skeletal muscles (diaphragm, soleus and adductor longus) in response to physiological insulin stimulation. In contrast, effects of late pregnancy to suppress glucose utilization were only modest in oxidative skeletal muscles, where a predominate fate of glucose under physiological insulin stimulation is glycogen formation. The ability of the pregnant rat to sustain glycogen repletion during physiological insulin stimulation was retained. Glucose utilization by the heart, which in virgin rats is particularly sensitive to increases in lipid-fuel supply and oxidation, bore a significant inverse relationship with the plasma fatty acid concentrations in late-pregnant rats. We conclude that an elevation in circulating fatty acid concentrations in late pregnancy provokes changes in glucose utilization by cardiac and skeletal muscle which are consistent with the operation of the glucose-fatty acid cycle. Importantly, these effects pertain under physiological hyperinsulinaemia. The relative insensitivity of glucose utilization by oxidative skeletal muscle to late pregnancy under conditions of physiological insulin stimulation presumably reflects the predominant use of glucose as a substrate for glycogen synthesis rather than as an energy substrate.

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Section: Insulin-sensitive Targets Distal To Glucose Uptake: Glycogenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

The Role of the Glucose/Fatty Acid Cycle in the Selective Modulation of Non-Oxidative and Oxidative Glucose Disposal by Oxidative Muscle in Late Pregnancy

Sugden¹,

Holness²

1994

Biological Chemistry Hoppe-Seyler

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“…6 Previous studies in rats showed that the heart reduces its glucose consumption, by as much as 75% by late pregnancy, and fulfilling its needs instead with fatty acids. 7–9 Recently, cardiac nitric oxide (NO) synthesis and endothelial NO synthase (eNOS) were shown to increase by late pregnancy, which was accompanied by a decrease in glucose uptake and use, and a corresponding increase in fatty acid uptake. 10, 11 The mechanism for this substrate switch, however, has not been explored.…”

Section: Introductionmentioning

confidence: 99%

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Liu

Rowe

Yang

et al. 2017

Circulation Research

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Rationale Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results We use here 13C-glucose, 13C-lactate, and 13C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Conclusions Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.

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“…However, PDHa activities in skeletal muscle in pregnancy in the fed state (i.e. when insulin levels are high) are similar to those of non-pregnant controls[26]. There is thus every indication that even though adipose-tissue lipolysis is resistant to suppression by insulin in the fed state in pregnancy, the oxidation of available FA by muscle is restricted and incoming acyl CoA is esterified rather than oxidized.…”

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confidence: 97%

“…70 microunits/ml) is unable to normalize plasma NEFA concentrations[25]. Enhanced adipose-tissue lipolysis within 6 h of the onset of starvation in pregnancy is associated with significant suppression of skeletalmuscle PDHa activities[26], findings that strongly suggest an accelerated switch to the oxidation of lipid-derived fuels by maternal skeletal muscle at low insulin concentrations. However, PDHa activities in skeletal muscle in pregnancy in the fed state (i.e.…”

mentioning

confidence: 99%