Glucolipotoxicity of the pancreatic beta cell - PubMed (original) (raw)

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Glucolipotoxicity of the pancreatic beta cell

Vincent Poitout et al. Biochim Biophys Acta. 2010 Mar.

Abstract

The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway, the metabolic sensor Per-Arnt-Sim kinase (PASK), and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.

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Figures

Figure 1

Figure 1. Effects of glucose on lipid partitioning in the beta cell

In the presence of simultaneously elevated levels of glucose and fatty-acid (FA), the increase in cytosolic malonyl-CoA resulting from glucose metabolism inhibits the enzyme carnitine-palmitoyl transferase-1 (CPT-1). Transport of long-chain acyl-CoA (LC-CoA) in the mitochondria is reduced, and the esterification pathway is preferentially activated, leading to cytosolic accumulation of lipid-derived signaling molecules such as ceramide, diglycerides (DG), phosphatidic acid (PA), phospholipids (PL), and triglycerides (TG).

Figure 2

Figure 2. Working model of the mechanisms of fatty-acid inhibition of insulin gene expression

Several signaling pathways are activated in beta cells in the presence of simultaneously elevated levels of palmitate and glucose. First, de novo ceramide synthesis [17] leads to sustained activation of ERK ½ [82] and exclusion of PDX-1 from the nuclear compartment [18]. Second, palmitate blocks glucose-induction of PASK expression, which results in decreased PDX-1 expression and increased C/EBPβ expression [82]. Third, palmitate decreases MafA expression [18]. These 3 pathways result in decreased binding activities of PDX-1 and MafA on the insulin promoter. In addition, palmitate induces the cleavage of ATF6, which also represses insulin gene transcription (our unpublished data).

Figure 3

Figure 3. Concentrations of unbound fatty acids (FA) in solution as a function of the fatty acid: BSA ratio for a fixed total palmitate concentration of 0.5 mM

Unbound fatty acids were measured using the fluorescent probe ADIFAB [114]. Data are the average of 2 independent experiments. Also represented are the mean ± SD of unbound FA levels measured in human plasma using the same method, from [115].

Figure 4

Figure 4. Hypothetical representation of the progression from beta-cell compensation to failure in the face of obesity-induced insulin resistance, and the role of glucolipotoxicity

According to this hypothesis, the decrease in insulin sensitivity is initially matched by a marked increase in insulin secretion, insulin gene expression, and beta-cell mass. At this stage the beta-cell adapts to nutrient oversupply by switching to preferential utilization of fatty acids, as part of the compensatory response (glucolipoadaptation [2]). In genetically predisposed individuals, the beta cell eventually becomes unable to further compensate and glucolipoadaptation evolves towards glucolipotoxicity, in which excursions of blood glucose levels outside of the normal range become permissive for the detrimental effects of elevated fatty acids. This phase is characterized by an early loss of insulin gene expression, decreased insulin secretion (relative to the degree of insulin resistance), and reduced beta-cell mass. Finally, beta-cell failure occurs when glucose levels are permanently in the hyperglycemic range. At that stage both glucotoxicity and glucolipotoxicity contribute to the continued deterioration of beta-cell function.

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