Targeting the γ-glutamyl cycle to prevent vascular complications in type 2 diabetes: a translational study seeking mechanistic insights toward personalized medicine
Progetto Vascular complications remain the leading cause of morbidity and mortality in people
with type 2 diabetes (T2D). The 1q25 lead variant rs10911021 (a single nucleotide
polymorphism upstream the GLUL gene which codes for glutamate-ammonia ligase
catalyzing the conversion of glutamic acid to glutamine) was found to be associated
with cardiovascular disease (CVD) in patients with T2D. Later, we found this variant
affected the γ-glutamyl cycle and the glyoxalase system in human umbilical vein
endothelial cells (HUVEC) in which the risk allele was associated with reduced
expression of the GLUL gene. We therefore hypothesized that alterations in the γglutamyl cycle and the glyoxalase system are responsible for accelerating atherosclerosis
and increased cardiovascular risk in subjects carrying the risk variant. However, to date,
the pathways through which these impairments may lead to an increased risk of
cardiovascular disease still need to be elucidated. There is currently a need for
translational studies validating the in vitro findings concerning the molecular pathways
linking genetic variability of GLUL to vascular disease and transferring the actual
knowledge to the patient level.
Therefore, through interconnected basic and clinical research studies, our aim is to
carry out a translational characterization of possible mechanisms underlying the already
proven association between 1q25 polymorphism and vascular disease in people with
T2D. To this aim, we will perform ex vivo experiments on peripheral blood
mononuclear cells (PBMC) of subjects with T2D to assess the impact of the
polymorphism on markers of oxidative stress and endothelial dysfunction. The same
experiments will be done on HUVEC, a cell model used to assess the previous findings
and relevant to further investigate the molecular mechanisms linking the rs10911021
variant to CVD risk in T2D. The impact of the polymorphism on oxidative stress and
endothelial dysfunction will also be investigated in vivo in people with T2D evaluated
in a clinical setting and in relation with clinical and biochemical features. Furthermore,
prompted by previous findings of glutamine reducing MG levels in HUVEC, we will
evaluate whether glutamine influences markers of oxidative stress and endothelial
dysfunction in the same PBMC and HUVEC.
This project will allow us to gain further insights into the mechanisms through which
the GLUL locus specifically influences CVD risk in T2D and to pave the path for
future studies evaluating the γ-glutamyl cycle as novel target for preventive and
personalized therapies