Effects of diabetes and starvation on skeletal muscle branched-chain alpha-keto acid dehydrogenase activity

Abstract

The activation state of branched-chain alpha-keto acid dehydrogenase (BCDH) was studied in rat hindlimb muscles during starvation and insulinopenic diabetes, conditions in which circulating branched-chain amino acids (BCAA) are increased and their oxidation is accelerated. Muscle BCDH is predominantly inactive (phosphorylated) in postabsorptive rats but is activated by increased circulating leucine. Diabetes (streptozotocin-induced and spontaneous BB/W) increased circulating BCAA four- to fivefold and BCDH activity approximately threefold. Insulin treatment caused near normalization of circulating BCAA without correcting BCDH activity. Adrenalectomy of diabetics decreased (without normalizing) circulating BCAA and BCDH activation. Starvation caused mild, progressive increases in circulating BCAA and significant activation of BCDH only after 4 days. Leucine infusion activated BCDH in muscle but the activation by leucine was markedly blunted by diabetes. In isolated perfused hindlimbs (control and diabetic) insulin did not affect BCDH significantly; perfusion with leucine activated BCDH, and this response appeared blunted in diabetics. Activation of muscle BCDH may contribute to increased BCAA catabolism in diabetes; the blunted activation response to hyperleucinemia may spare BCAA and contribute to their persistent elevation in plasma.