Role of the Saturated
Nonesterified Fatty Acid Palmitate
in Beta Cell Dysfunction
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Abstract
Sustained elevated levels of saturated free fatty acids,
such as
palmitate, contribute to beta cell dysfunction, a phenomenon aggravated
by high glucose levels. The aim of this study was to investigate the
mechanisms of palmitate-induced beta cell dysfunction and death, combined
or not with high glucose. Protein profiling of INS-1E cells, exposed
to 0.5 mmol/L palmitate and combined or not with 25 mmol/L glucose,
for 24 h was done by 2D-DIGE, both on full cell lysate and on an enriched
endoplasmic reticulum (ER) fraction. Eighty-three differentially expressed
proteins (<i>P</i> < 0.05) were identified by MALDI-TOF/TOF
mass spectrometry and proteomic results were confirmed by functional
assays. 2D-DIGE analysis of whole cell lysates and ER enriched samples
revealed a high number of proteins compared to previous reports. Palmitate
induced beta cell dysfunction and death via ER stress, hampered insulin
maturation, generation of harmful metabolites during triglycerides
synthesis and altered intracellular trafficking. In combination with
high glucose, palmitate induced increased shunting of excess glucose,
increased mitochondrial reactive oxygen species production and an
elevation in many transcription-related proteins. This study contributes
to a better understanding and revealed novel mechanisms of palmitate-induced
beta cell dysfunction and death and may provide new targets for drug
discovery