Abstract
Lipotoxicity refers to cellular dysfunctions caused by elevated free fatty acid levels playing a central role in the development and progression of obesity related diseases. Saturated fatty acids cause insulin resistance and reduce insulin production in the pancreatic islets, thereby generating a vicious cycle, which potentially culminates in type 2 diabetes. The underlying endoplasmic reticulum (ER) stress response can lead to even β-cell death (lipoapoptosis). Since improvement of β-cell viability is a promising anti-diabetic strategy, the protective effect of metformin, a known insulin sensitizer was studied in rat insulinoma cells. Assessment of palmitate-induced lipoapoptosis by fluorescent microscopy and by detection of caspase-3 showed a significant decrease in metformin treated cells. Attenuation of β-cell lipotoxicity was also revealed by lower induction/activation of various ER stress markers, e.g. phosphorylation of eukaryotic initiation factor 2α (eIF2α), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1) and induction of CCAAT/enhancer binding protein homologous protein (CHOP). Our results indicate that the β-cell protective activity of metformin in lipotoxicity can be at least partly attributed to suppression of ER stress.
Highlights
Type 2 diabetes is a global epidemic that has been spread in all countries and threatens a continually growing population
Palmitate-induced Apoptosis in RINm5F Cells b-Cell protective effect of metformin was tested by assessing lipoapoptosis in RINm5F rat insulinoma cells
Palmitate treatment did not cause a significant change in b-cell viability within the first 6 h; an accelerating decrease in the number of viable cells was observed in longer incubations and approximately 75% of palmitate-treated cells died within 24 h (Fig. 1)
Summary
Type 2 diabetes is a global epidemic that has been spread in all countries and threatens a continually growing population It is a complex metabolic disorder affecting the complete fuel homeostasis including the storage and mobilization of nutrients as well as the control of plasma lipoprotein and sugar levels. Permanently increased concentrations of glucose and/or FFA turned out to be toxic to b-cells, and the weaker the tissues respond to insulin the less effectively it is counterbalanced. Aggravation of this derangement results in the exhaustion and death of b-cells, and a substantial shrinkage of the compensatory potential, a key event in the progress of the disease [3]
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