Nicolò, Antonella (2023) Unraveling the role of methylglyoxal on glucose homeostasis and the pro-angiogenic potential of adsc. [Tesi di dottorato]

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Abstract

Diabetes Mellitus (DM) is a metabolic disease and represents an important risk factor for vascular disease. Tight control of blood glucose levels is a major goal for the treatment of Type 2 DM (T2DM). However, metabolic defects start up before the pathology can be diagnosed. Indeed, lowering blood glucose, only partially reduces the risk of vascular complications. Methylglyoxal (MGO), a highly reactive dycarbonyl, is a major precursor of AGEs. In pathological conditions, as T2DM, hyperglycemia contributes to MGO accumulation, which induces damaging effect on vascular function, insulin sensitivity and β-cell function. Although MGO-adducts have been already observed in the pre-diabetic state of spontaneously diabetic rodents, the role of MGO in the early steps of T2DM pathogenesis has not been defined. Under physiological condition, MGO is detoxified by the glyoxalase system, of which Glyoxalase 1 (Glo1) is the rate limiting enzyme. However, in pathological conditions, such as oxidative stress, inflammation, and senescence Glo1 levels are reduced. Adipose tissue-derived stem cells (ADSCs) have gained big interest in therapeutic applications in regenerative medicine, thanks to their low immunogenicity, self-renewal ability and differentiation into various tissue-specific cells. ADSCs have the potential to secrete paracrine factors that promote angiogenesis; however, in DM this ability is compromised. The aim of this thesis includes the investigation of two aspects: 1. The evaluation of MGO accumulation on glucose homeostasis in mice knock-down for Glyoxalase 1 (Glo1KD) and 2. The evaluation of MGO effect on the ADSCs pro-angiogenic function and the molecular mediators involved. The results obtained in vivo in the first part of the study show that the endogenous accumulation of MGO in Glo1KD mice leads to an age-dependent development of glucose intolerance. This metabolic alteration associates with the presence of insular inflammatory infiltration, the islet expression of markers of senescence, and a senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their wild type (WT) littermates. In vitro, the exposure of INS832/13 β-cells to MGO confirms its casual role on β-cells dysfunction, which can be reverted by senolytic treatment. In the second part of the study, we show that MGO treatment impairs the pro-angiogenic function of mADSCs and induces their senescence. The impaired mADSCs pro-angiogenic function is mediated, at least in part, by the release of soluble factors, which associates with a reduction of p38 MAPK activation in hRECs. These data indicate that MGO is able to induce early phenotypes typical of the progression to T2DM and to reduce the pro-angiogenic ability of mADSCs, paving the way for novel prevention approaches to T2DM, and treatment strategies for the related complications.

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