Glyoxalase 1 knockdown induces age‐related β‐cell dysfunction and glucose intolerance in mice

Abstract

Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age-dependent impairment of glucose tolerance and glucose-stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80-positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP-1 and TNF-a), part of the senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 b-cells to MGO confirms its casual role on b-cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.

Methylglyoxal Impairs the Pro-Angiogenic Ability of Mouse Adipose-Derived Stem Cells (mADSCs) via a Senescence-Associated Mechanism

“…Indeed, increased levels of dicarbonyls, observed in diabetes and aging, induce cellular senescence in ECs [ 11 ]. We recently verified the crucial role of a premature β-cell senescent phenotype in vivo in the alteration of glucose homeostasis induced by MGO accumulation [ 12 ]. Senescent ADSCs lose their angiogenic potential and the transplantation of them causes dysfunction in mice [ 22 , 43 , 44 , 45 , 46 ].…”

“…MGO induces cellular dysfunction through several mechanisms including cellular senescence [ 11 ]. We have recently demonstrated that MGO accumulation induces a β-cell senescence-associated pro-inflammatory phenotype that contributes to the establishment of an early phenotype typical of type 2 diabetes mellitus (T2DM) progression [ 12 ].…”

Molecular Assessment of Methylglyoxal-Induced Toxicity and Therapeutic Approaches in Various Diseases: Exploring the Interplay with the Glyoxalase System

“…While acetylation and oxidation do not affect GLO I activity, glutathione acylation emerges as a potent inhibitor [16]. GLO I dons the attire of phosphorylation on Thr107, and TNFα orchestrates its modulation through PKA-induced phosphorylation, resulting in a dramatic ballet of caspase-dependent cell demise accompanied by a dazzling display of reactive oxygen species (ROS) [4,19,20]. These ROS spectacularly inhibit GLO I, ushering in the intracellular buildup of pro-apoptotic AGEs, such as argpyrimidine, and kickstarting a mitochondrialdependent apoptotic pathway [21][22][23][24].…”