Abstract
Pancreatic β-cell failure and death is considered to be one of the main factors responsible for type 2 diabetes. It is caused by, in addition to hyperglycemia, chronic exposure to increased concentrations of fatty acids, mainly saturated fatty acids. Molecular mechanisms of apoptosis induction by saturated fatty acids in β-cells are not completely clear. It has been proposed that kinase signaling could be involved, particularly, c-Jun N-terminal kinase (JNK), protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt kinases and their pathways. In this review, we discuss these kinases and their signaling pathways with respect to their possible role in apoptosis induction by saturated fatty acids in pancreatic β-cells.
Highlights
Increased concentrations of fatty acids (FAs) in blood are known to be one of the main factors responsible for pancreatic β-cell death in type 2 diabetes [1,2,3,4,5]
MKK4 and MKK7 are activated by several MAP kinase kinase kinases (MAP3Ks) as e.g., transforming growth factor-β-activated kinase 1 (TAK1), apoptosis signal-regulating kinase 1 (ASK1), tumor progression locus 2 (TPL2), and mixed-lineage kinases (MLKs) and by some members of the MEKK family
The PKCδ isoform was the first identified member of the novel protein kinase C (PKC) group. This isoform was, of the respective PKC isoforms, the most often found to be connected with the process of apoptosis induction via regulation of its down-stream targets, e.g., Jun N-terminal kinase (JNK)-STAT1 signaling, Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 MAPK kinases [55,56,57,58]
Summary
Increased concentrations of fatty acids (FAs) in blood are known to be one of the main factors responsible for pancreatic β-cell death in type 2 diabetes [1,2,3,4,5]. It was suggested that saturated FAs (e.g., stearic and palmitic acid) induce apoptosis in pancreatic β-cells, whereas the effect of unsaturated FAs (e.g., oleic and palmitoleic acid) on β-cell viability is not entirely clear It seems that at low concentrations they are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs [2,4,5,6,9,13,14,15,16]. Kinase signaling pathways are regulated in response to various extracellular physical (e.g., UV radiation, and temperature) and chemical (many agens) stimuli and in response to various cytokines They can be involved, depending on cell type, in the regulation of many cellular processes such as proliferation, differentiation, inflammatory response, autophagy, senescence, and in apoptosis (reviewed in [25]). We will discuss available data on above-mentioned pathways, from both in vitro as well as in vivo experiments using β-cells of animal (mainly rat and murine) and human origin
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