Abstract
BackgroundLong-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucose-stimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods.ResultsPalmitate-treated human islets showed decline in beta-cell function starting from day two. Affymetrix Human Transcriptome Array 2.0 identified 903 differentially expressed genes (DEGs). Mapping of the genes onto pathways using KEGG pathway enrichment analysis predicted four islet biology-related pathways enriched prior but not after the decline of islet function and three pathways enriched both prior and after the decline of islet function. DEGs from these pathways were analyzed at the transcript level. The results propose that in palmitate-treated human islets, at early time points, protective events, including up-regulation of metallothioneins, tRNA synthetases and fatty acid-metabolising proteins, dominate over deleterious events, including inhibition of fatty acid detoxification enzymes, which contributes to the enhanced GSIS. After prolonged exposure of islets to palmitate, the protective events are outweighed by the deleterious events, which leads to impaired GSIS.ConclusionsThe study identifies temporal order between different cellular events, which either promote or protect from beta-cell failure. The sequence of these events should be considered when developing strategies for prevention and treatment of the disease.
Highlights
Long-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM)
In many of these individuals initial hyperinsulinemia is followed by later reduction of insulin secretion and development of type 2 diabetes mellitus (T2DM) [2, 3]
glucosestimulated insulin secretion (GSIS) and insulin content of human islets exposed to palmitate GSIS and insulin content was determined in isolated human islets exposed to palmitate for 0, 4 and 12 h and 1, 2 and 7 days
Summary
Long-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucosestimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods. Elevated levels of circulating free fatty acids is one of the major factors implicated in alteration of insulin secretion in obese individuals [1] In many of these individuals initial hyperinsulinemia is followed by later reduction of insulin secretion and development of type 2 diabetes mellitus (T2DM) [2, 3]. It is desirable to identify such early mechanisms in order to prevent or reverse the disease by intervening at early stages when beta-cell function is not yet lost and intracellular changes have not passed a point of no return
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