Abstract:
:Fatty acids (FAs) and other lipid molecules are important for many cellular functions, including vesicle exocytosis. For the pancreatic beta-cell, while the presence of some FAs is essential for glucose-stimulated insulin secretion, FAs have enormous capacity to amplify glucose-stimulated insulin secretion, which is particularly operative in situations of beta-cell compensation for insulin resistance. In this review, we propose that FAs do this via three interdependent processes, which we have assigned to a "trident model" of beta-cell lipid signaling. The first two arms of the model implicate intracellular metabolism of FAs, whereas the third is related to membrane free fatty acid receptor (FFAR) activation. The first arm involves the AMP-activated protein kinase/malonyl-CoA/long-chain acyl-CoA (LC-CoA) signaling network in which glucose, together with other anaplerotic fuels, increases cytosolic malonyl-CoA, which inhibits FA partitioning into oxidation, thus increasing the availability of LC-CoA for signaling purposes. The second involves glucose-responsive triglyceride (TG)/free fatty acid (FFA) cycling. In this pathway, glucose promotes LC-CoA esterification to complex lipids such as TG and diacylglycerol, concomitant with glucose stimulation of lipolysis of the esterification products, with renewal of the intracellular FFA pool for reactivation to LC-CoA. The third arm involves FFA stimulation of the G-protein-coupled receptor GPR40/FFAR1, which results in enhancement of glucose-stimulated accumulation of cytosolic Ca2+ and consequently insulin secretion. It is possible that FFA released by the lipolysis arm of TG/FFA cycling is partly "secreted" and, via an autocrine/paracrine mechanism, is additive to exogenous FFAs in activating the FFAR1 pathway. Glucose-stimulated release of arachidonic acid from phospholipids by calcium-independent phospholipase A2 and/or from TG/FFA cycling may also be involved. Improved knowledge of lipid signaling in the beta-cell will allow a better understanding of the mechanisms of beta-cell compensation and failure in diabetes.
journal_name
Diabetesjournal_title
Diabetesauthors
Nolan CJ,Madiraju MS,Delghingaro-Augusto V,Peyot ML,Prentki Mdoi
10.2337/db06-s003subject
Has Abstractpub_date
2006-12-01 00:00:00pages
S16-23eissn
0012-1797issn
1939-327Xpii
55/Supplement_2/S16journal_volume
55 Suppl 2pub_type
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