SUBSTRATE SIGNALING BY INSULIN - A KETONE-BODIES RATIO MIMICS INSULINACTION IN HEART

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.