Malonyl-CoA Signaling, Lipid Partitioning, and Glucolipotoxicity

Abstract

␤-Cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the ␤-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences ␤-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that ␤-cell "glucotoxicity" is in part indirectly caused by "lipotoxicity," and that ␤-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of ␤-cell "glucolipotoxicity" that implicates alterations in ␤-cell malonyl-CoA concentrations; peroxisome proliferator؊activated receptor-␣ and -␥ and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed. Diabetes 51 (Suppl. 3):S405-S413, 2002

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

“…We propose a model (Fig. 7) in which glucose promotes activity in a beta cell TG-FA cycle by (1) the malonyl-CoA/LC-CoA switch of fatty metabolism from oxidation to esterification [3,13]; (2) providing glycerol-3-phosphate (Gly-3-P) for synthesis of complex glycerolipids; and (3) activation of lipolysis, as demonstrated in this study. NEFA also contribute to activation of the cycle by providing the other substrate (LC-CoA) for condensation with Gly-3-P.…”

“…Obesity-associated type 2 diabetes develops when beta cell compensation processes fail [3,4]. The mechanisms of islet beta cell compensation, however, are poorly understood.…”

“…Particularly unclear is the role of excess circulating NEFA, which frequently coexists with insulin resistance. Acutely elevated NEFA are well known to enhance glucose-stimulated insulin secretion (GSIS) [3,5]; however, some investigators believe that persistently elevated NEFA may be detrimental to beta cell function or viability [6,7]. We have previously utilised the Zucker fa/fa fatty (ZF) rat model of insulin resistance in order to study beta cell compensation [8] and have done so again for the present work, which focuses on the role of NEFA.…”

“…Central to the model is that an increase in glucose, via increasing malonyl-CoA, which inhibits carnitine palmitoyltransferase-1 (CPT1), as was first described by McGarry and Brown [14], switches the partitioning of NEFA in the beta cell away from oxidation towards the accumulation of LC-CoA and fatty acid acylation and esterification products (e.g. diacylglycerol [3,[13][14][15]), which are proposed to have direct regulatory effects on insulin secretion [3,12,13].…”

“…However, little is known about its regulation and which lipolytic enzymes are operative. A question addressed in this study was whether activity of the lipolysis arm of beta cell lipid partitioning might be enhanced in situations of chronically increased malonyl-CoA/LC-CoA signalling as a way of protecting islets from excess lipid accumulation [3,20].…”