Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defectss is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in β-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a “signal of plenty,” and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the β-cell, integrating the concentrations of all circulating fuel stimuli in the β-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event.
Skip Nav Destination
Article navigation
Original Articles|
March 01 1996
Are the β-Cell Signaling Molecules Malonyl-CoA and Cystolic Long-Chain Acyl-CoA Implicated in Multiple Tissue Defects of Obesity and NIDDM?
Marc Prentki;
Marc Prentki
Diabetes and Metabolism Unit Evans Department of Medicine and Department of Biochemistry, Boston University Medical Center
Boston, Massachusetts
Search for other works by this author on:
Barbara E Corkey
Barbara E Corkey
Molecular Nutrition Unit Department of Nutrition, University of Montreal, Montreal
Canada
Search for other works by this author on:
Address correspondence and reprint requests to Dr. Barbara E. Corkey, Diabetes & Metabolism Unit, E-205, Boston University School of Medicine, 88 E. Newton St., Boston, Massachusetts 02118.
Diabetes 1996;45(3):273–283
Article history
Received:
September 07 1995
Received:
November 16 1995
Accepted:
November 16 1995
PubMed:
8593930
Citation
Marc Prentki, Barbara E Corkey; Are the β-Cell Signaling Molecules Malonyl-CoA and Cystolic Long-Chain Acyl-CoA Implicated in Multiple Tissue Defects of Obesity and NIDDM?. Diabetes 1 March 1996; 45 (3): 273–283. https://doi.org/10.2337/diab.45.3.273
Download citation file:
328
Views