Y. Kashiwaya et al., SUBSTRATE SIGNALING BY INSULIN - A KETONE-BODIES RATIO MIMICS INSULINACTION IN HEART, The American journal of cardiology, 80(3A), 1997, pp. 50-64
The administration of saturating doses of insulin to the glucose perfu
sed, working rat heart acutely increased activity of the glucose trans
porter 4, GLUT 4, in the plasma membrane (equilibrating extracellular
glucose and intracellular [glucose]), activated glycogen synthase (sti
mulating the rate of glycogen synthesis), and increased mitochondrial
acetyl CoA production by the pyruvate dehydrogenase multienzyme comple
x. Unexpectedly, insulin increased cardiac hydraulic work but decrease
d net glycolytic flux and O-2 consumption, improving net cardiac effic
iency by 28%. These improvements in physiologic performance and metabo
lic efficiency resulted from reduction of the mitochondrial free [NAD(
+)]/[NADH] and oxidation of mitochondrial [coenzyme Q]/[coenzyme QH(2)
], increasing the energy of the proton gradient between cytosolic and
mitochondrial phases and leading to a doubling of the cytosolic free [
Sigma ATP]/[Sigma ADP][Sigma P-i]. The acute metabolic effects of insu
lin were qualitatively duplicated by addition of a ratio of 4 mM D-bet
a-hydroxybutyrate and 1 mM acetoacetate, and the increase in the effic
iency was the same as with addition of insulin. Addition of both insul
in and ketones to the glucose perfusate increased the efficiency of ca
rdiac hydraulic work by 35%. The ability of a physiologic ratio Of ket
one bodies to correct most of the metabolic defects of acute insulin d
eficiency suggests therapeutic roles for these natural substrates duri
ng periods of impaired cardiac performance and in insulin-resistant st
ates.