O-GlcNAc modification, insulin signaling and diabetic complications.

International audienceO-GlcNAc glycosylation (O-GlcNAcylation) corresponds to the addition of N-acetylglucosamine on serine and threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation is a dynamic post-translational modification, analogous to phosphorylation, that regulates the stability, the activity or the subcellular localisation of target proteins. This reversible modification depends on the availability of glucose and therefore constitutes a powerful mechanism by which cellular activities are regulated according to the nutritional environment of the cell. O-GlcNAcylation has been implicated in important human pathologies including Alzheimer disease and type-2 diabetes. Only two enzymes, OGT and O-GlcNAcase, control the O-GlcNAc level on proteins. Therefore, O-GlcNAcylations cannot organize in signaling cascades as observed for phosphorylations. O-GlcNAcylations should rather be considered as a "rheostat" that controls the intensity of the signals traveling through different pathways according to the nutritional status of the cell. Thus, OGT attenuates insulin signal by O-GlcNAcylation of proteins involved in proximal and distal steps in the PI-3 kinase signaling pathway. This negative feedback may be exacerbated when cells are chronically exposed to elevated glucose concentrations and could thereby contribute to alterations in insulin signaling observed in diabetic patients. O-GlcNAcylation also appears to contribute to the deleterious effects of hyperglycaemia on excessive glucose production by the liver and deterioration of β-cell pancreatic function, resulting in worsening of hyperglycaemia (glucotoxicity). Moreover, O-GlcNAcylations directly participate in several diabetic complications. O-GlcNAcylation of eNOS in endothelial cells have been involved in micro- and macrovascular complications. In addition, O-GlcNAcylations activate the expression of profibrotic and antifibrinolytic factors, contributing to vascular and renal dysfunctions

Evidence of pre-prosomatostatin mRNA in human normal and tumoral anterior pituitary gland

Expression of the SRIH gene was investigated in six human normal anterior pituitaries, six GH-, three PRL-, three mixed GH/PRL-secreting and four nonsecreting adenomas. Total cellular RNA and poly(A+) mRNAs were analyzed by dot and Northern blot hybridization to a 3'-end labeled oligonucleotide probe specific for the human pre-proSRIH mRNA. A weak but detectable pre-proSRIH hybridization signal was present in human normal anterior pituitaries and in the four groups of adenomas. The size of this pre-proSRIH mRNA was indistinguishable from that found in our hypothalamic samples and close to that described in the literature. The wide variation of the signal intensity from one case to the other in each group of the different types of normal and tumoral antehypophyseal samples prevented establishment of any correlation between the level of pre-proSRIH mRNA and the nature of the pituitary tissue. The presence of SRIH mRNA in human normal and tumoral anterior pituitary tissues provides a sound basis to substantiate the hypothesis of a SRIH biosynthesis in the human anterior pituitary gland

Low GH hypophyseal adenomas with acromegaly exhibit undetectable levels of messenger RNA of normal GH

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