ARE THE BETA-CELL SIGNALING MOLECULES MALONYL-COA AND CYTOSOLIC LONG-CHAIN ACYL-COA IMPLICATED IN MULTIPLE TISSUE DEFECTS OF OBESITY AND NIDDM

Widely held theories of the pathogenesis of obesity-associated NIDDM h ave implicated apparently incompatible events as seminal: 1) insulin r esistance in muscle, 2) abnormal secretion of insulin, and 3) increase s in intraabdominal fat. Altered circulating or tissue lipids are char acteristic features of obesity and NIDDM. The etiology of these defect s is not known. In this perspective, we propose that the same metaboli c events, elevated malonyl-CoA. and long-chain acyl-CoA (LC-CoA), in v arious tissues mediate, in part, the pleiotropic alterations character istic of obesity and NIDDM. We review the evidence in support of the e merging concept that malonyl-CoA and LC-CoA. act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion. me suggest that acetyl-CoA. carboxylase, which synt hesizes malonyl-CoA, a ''signal of plenty,'' and carnitine palmitoyl t ransferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tis sue. The target effecters of LC-CoA may include protein kinase C subty pes, complex Lipid formation, genes encoding metabolic enzymes or tran sduction factors, and protein acylation. We support the concept that o nly under conditions in which both glucose and lipids are plentiful wi ll the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormal ities in the metabolism of malonyl-CoA and LC-CoA contribute to altere d insulin release and sensitivity, it offers a novel explanation for t he presence of variable combinations of these defects in individuals w ith differing genetic backgrounds and for the fact that it has been di fficult to determine whether one or the other is the primary event.