Lipotoxicity

Although free fatty acids (FFA), also termed NEFA, acutely increase insulin secretion, chronic FFA overload diminishes beta-cell function. Type 2 diabetes subjects have often increased FFA due to insulin resistance to (adipocyte) lipolysis. It is now clear that high glucose inhibits beta-cell fatty acid oxidation, which may lead to accumulation of long-chain

Lipotoxicity Beta Cell Dysfunction

FIGURE 6 Schematic representation of possible negative influences of hyperglycemia and increased NEFA, and of various modulators involved in insulin resistance such as TNFa and inflammatory mediators on B-cell dysfunction. The pathways possibly involved are alteration in mitochondrial function and potassium channel function and IAPP aggregation and other pathways leading to B-cell apoptosis or altered gene transcription. Abbreviations: IAPP, islet amyloid polypeptide; NEFA, nonesterified fatty acids; TNFa, tumor necrosis factor alpha.

FIGURE 6 Schematic representation of possible negative influences of hyperglycemia and increased NEFA, and of various modulators involved in insulin resistance such as TNFa and inflammatory mediators on B-cell dysfunction. The pathways possibly involved are alteration in mitochondrial function and potassium channel function and IAPP aggregation and other pathways leading to B-cell apoptosis or altered gene transcription. Abbreviations: IAPP, islet amyloid polypeptide; NEFA, nonesterified fatty acids; TNFa, tumor necrosis factor alpha.

coenzyme A (LC-CoA) (58). This has been suggested to interfere with normal potassium channel activity, or to lead to activation of UCP-2, which would lead to uncoupling of oxidative glucose metabolism from ATP formation in the mitochondrion leading to lower ATP. FFA may diminish UCP-2 via augmentation of PPAR-gamma protein, which would lead to activation of UCP-2 (57). However, PPAR-gamma activation has numerous effects, and its overall importance in beta cells is therefore difficult to assess; for example, in animal models PPAR-gamma activation has been reported to enhance FFA oxidation in beta cells, which may in itself protect against lipotoxicity (59).

Yet another mechanism may involve synthesis of ceramide by FFA or generation of nitric oxide. In other tissues (muscle), degradation of ceramide has been shown to prevent FFA-induced insulin resistance almost completely (60); it is therefore conceivable that FFA act via ceramide formation in pancreas beta cells. Ceramide has been shown to inhibit insulin gene expression (61) and has been implied in apoptosis via various pathways. The importance of the insulin receptor signaling on insulin gene expression should not be underestimated, and may well harbor yet other mechanisms of lipotoxicity: via acyl-CoA FFA may inhibit insulin receptor signaling in beta cells via influences on IRS proteins, PI-3-kinase, or further downstream the insulin signaling cascade (62).

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