Glucose metabolism in perfused skeletal muscle. Effects of starvation, diabetes, fatty acids, acetoacetate, insulin and exercise on glucose uptake and disposition

Abstract

1. The regulation of glucose uptake and disposition in skeletal muscle was studied in the isolated perfused rat hindquarter. 2. Insulin and exercise, induced by sciatic-nerve stimulation, enhanced glucose uptake about tenfold in fed and starved rats, but were without effect in rats with diabetic ketoacidosis. 3. At rest, the oxidation of lactate (0.44,umol/ mi per 30g ofmuscle in fed-rats) was decreased by 75% in both starved and diabetic rats, whereas the release of alanine and lactate (0.41 and 1.35,umol/min per 30g respectively in the fed state) was increased. Glycolysis, defined as the sum of lactate+alanine release and lactate oxidation, was not decreased in either starvation or diabetes. 4. In all groups, exercise tripled 02 consumption (from -8 to -25umol/min per 30g of muscle) and increased the release and oxidation of lactate five-to ten-fold. The differences in lactate release between fed, starved and diabetic rats observed at rest were no longer apparent however, lactate oxidation was still several times greater in the fed group. 5. Perfusion of the hindquarter ofa fed rat with palmitate, octanoate or acetoacetate did not alter glucose uptake or lactate release in either resting or exercising muscle; however, lactate oxidation was significantly inhibited by acetoacetate, which also increased the intracellular concentration of acetyl-CoA. 6. The data suggest that neither glycolysis nor the capacity for glucose transport are inhibited in the perfused hindquarter during starvation or perfusion with fatty acids or ketone bodies. On the other hand, lactate oxidat-ion is inhibited, suggesting diminished activity ofpyruvate dehydrogenase. 7. Differences in the regulation of glucose metabolism in heart and skeletal muscle and the role of the glucose/fatty acid cycle in each tissue are discussed.The present paper deals with the alterations in muscle-glucose metabolism that occur in starvation and diabetes and therole offreefatty acids and ketone bodies in causing these changes. Much of our present knowledge of this subject has been derived from experiments carried out in the perfused rat heart. Using this preparation, Randle et al. (1966) observed an inhibition of the tiptake, phosphorylation and oxidation of glucose and a -block in glycolysis at the level-of phosphofructokitase both in starvation and diabetes. In iddition, they obsrved a similar pattern in hearts perfused with fatty acids and ketone bodies, whichiled themto stggest that the increased utilization of these substrates in starved and diabetic rats might explain the impaired -glucose metabolism in these states. Comparable findings have been observed in diaphragm by some laboratories but not others (see Ruderman et al., 1969).

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

“…One possible factor is the greater enzymic capacity of heart to oxidize lipids (Winder et al, 1974;Holloszy et al, 1973). Another is that the heart is a continuously contracting muscle with a high rate of glycolysis Randle, 1966) compared with perfused skeletal muscle Goodman et al, 1974;Berger et al, 1976) and presumably non-exercising muscle in vivo Wahren et al, 1971). In keeping with this notion, the glucose-fatty acid cycle has been demonstrated in brain , mammary tissue (Hawkins & Williamson, 1972;Williamson et al, 1974;Robinson & Williamson, 1977) and submaxillary glands (Thompson & Williamson, 1975), all of which have high rates of glycolysis and glucose oxidation.…”

“…Initial studies suggested that lipid fuels do not inhibit glucose utilization in incubated or perfused muscle (Beatty & Bocek, 1971;Jefferson et al, 1972;Goodman et al, 1974;Reimer et al, 1975;Berger et al, 1976), with the possible exception of diaphragm (reviewed by Ruderman et al, 1969), but that they inhibit glucose oxidation at the pyruvate dehydrogenase step (Berger et al, 1976;Hagg et al, 1976). More recently, inhibition of glucose utilization and glycolysis by fatty acids and ketone bodies has been demonstrated in rat soleus muscles incubated in vitro (Maizels et al, 1977;Pearce & Connett, 1980); however, contradictory findings have been reported in the isolated perfused, well-oxygenated, rat hindquarter Ruderman et al, 1980;Richter et al, 1982b).…”

Effect of acetoacetate on glucose metabolism in the soleus and extensor digitorum longus muscles of the rat

“…Less clear is whether fatty acids and ketone bodies inhibit glucose uptake-and glycolysis during severe exhaustive exercise. In studies with the perfused rat hindquarter, Berger et al (1976) noted that acetoacetate inhibited glucose oxidation during isometric exercise induced by bilateral sciaticnerve stimulation at a rate of 5 per s. On the other hand, neither glucose uptake nor glycolysis was decreased, although tissue citrate was moderately increased. Whether inhibition ofglycolysis was missed because of a predominance of white muscle in the exercising portion of the hindquarter or because of other metabolic alterations (e.g.…”

“…There is general agreement that they displace glucose as a fuel in voluntary skeletal muscle by inhibiting pyruvate dehydrogenase (see Berger et al, 1976); however, it is not clear whether they also inhibit glucose uptake and glycolysis (reviewed by Ruderman et al, 1969Ruderman et al, , 1977see Berger et al, 1976). The present study suggests that this, in part, may be related to the heterogeneity of muscle fibres in voluntary muscle.…”

Dysregulation of glucose transport in hearts of genetically obese (fa/fa) Rats

“…post-receptor defects) also contributed to insulin resistance [% 9, 10]. In insulinresistant muscles, several such post-receptor defects have been described [4,7,[10][11][12][13][14]. In isolated soleus muscles of the genetically obese Zucker (fa/fa) rat the following post-receptor abnormalities have been shown: (a) increased utilization of endogenous fatty acids inhibitory to glycolysis [7]; (b) decreased uptake of the D-glucose analogue, 2-deoxy-D-glucose (2-DG) [4,7,12].…”