Glucotoxicity and pancreatic proteomics
4. PERSEPCTIVES AND CONCLUSIONS:
Glucotoxicity is now recognized as playing a central role in the development of diabetes. It has been shown that one of the possible mechanisms responsible for this toxicity may be due to the modulation of expression of several key proteins. Indeed, several studies have shown the down-regulation of proteins involved in insulin secretion, such as glucokinase or Glut2 after long-term ȕ-cell incubation with high glucose concentration [176]. Moreover, several pro-apoptotic proteins have been shown to be up-regulated in response to chronic high glucose concentration [163].
The recent developments of efficient proteomic methods enable specifically studying the effect of glucotoxicity on the partial proteome of a cell, organ or tissue. So far, the large majority of published work that used proteomic analysis to study glucotoxicity has compared 2-DE gel protein expression between glucose-stimulated and glucose non-stimulated samples. This approach enables identifying the differentially expressed proteins after incubation with different glucose concentrations.
Different types of samples have been used to study glucotoxicity. Proteomic studies on diabetic animal models have shown the modulation of expression of several pancreatic islet proteins compared to wild-type mice [168, 171]. However, it was possible to directly link these modifications to the glucotoxicity since diabetic mice carry additional metabolic dysfunctions, such as chronic high concentration of fatty acids [177]. Indeed, the accumulation of high concentration of fatty acids in non-adipose tissues can induce several metabolic disorders. The toxic effects of fatty acids are named lipotoxicity [178]. It is known that lipotoxicity is able to impair ȕ-cell insulin secretion and to favour insulin resistance in different insulin-sensitive tissues [179, 180]. It was also shown that high concentration of glucose is able to increase
the toxic effects of fatty acids. The combined toxic effect of glucose and fatty acids is called glucolipotoxicity [181].
So far, relatively few proteomic studies have directly assessed the effect of glucotoxicity on the specific expression of pancreatic ȕ-cell proteins. However, as shown in this review, the different proteomic studies performed so far, have confirmed the modulation of expression by chronic hyperglycaemia of several proteins. At the biological level the modulation of expression of some of these proteins, such as anti-ROS enzymes, pro-apoptotic proteins or proteins involved in ER-stress, could explain the toxic effect of chronic hyperglycaemia. In ȕ-cells, the down-regulation of specific proteins of the insulin granules has already been linked to strong insulin secretion impairment [182-184].
Most of the proteomic analysis performed to study glucotoxicity has used 2-DE gel comparison to detect differentially expressed proteins. This workflow proved its efficiency, since it was able to identify many proteins for which the expression is regulated by glucose. However, it is known that 2-DE gels are not adapted for the analysis of membrane or membrane-associated proteins which represent an important family of cell proteins [185]. Moreover, comparison of 2-DE-gel is still a fastidious work, even with the development of gel analysis softwares. To overpass these limitations, alternative workflows have been developed. One of them combined the use of SILAC [186] for protein quantitation and 1-DE gels for protein separation.
SILAC strategy consists of cultivating one cell population with a culture medium in which one amino acid is replaced by an isotopic heavy form of the same amino acid.
The other cell population is cultivated with natural amino acids. In the next step, each
cell population can be treated with different stimuli. The two cell populations are then mixed together and separated with gel-based or non gel-based methods. To overpass the poor capacity of 2-DE gels to resolve membrane proteins, 1-DE gels are often used. SILAC coupled to mass spectrometry analysis can be easily applied to study the effect of chronic hyperglycaemia on protein expression, as shown in figure 2.
Proteomic analysis of whole cells does not necessarily enable identifying low abundance proteins. Therefore, it is also sometimes necessary to analyze the proteome of subcellular structures, such as secretory vesicles, mitochondria or nucleus [187]. The analysis of differentially expressed proteins of a specific organelle in response to chronic hyperglycaemia, will certainly allow obtaining new information about the glucotoxicity mechanisms.
Figure 1:
Figure 1: Chemical processes involved in proteins glycation
Figure 2:
Figure 2: Application of the SILAC strategy for the study of INS-1E cell glucotoxicity Glc: glucose.
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