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 ( Glo1 KD). 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‐α), part of the senescence‐activated secretory profile, in the pancreas from 10‐month‐old Glo1 KD mice, compared with their WT littermates. In vitro exposure of INS832/13 β‐cells to MGO confirms its casual role on β‐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. image Methylglyoxal accumulation promotes a pro‐inflammatory microenvironment in pancreatic islets of mice, leading to an age‐dependent impairment of glucose‐stimulated insulin secretion (GSIS) and glucose tolerance in mice. Glo1KD mice develop an age‐dependent impairment of glucose tolerance and GSIS. Islets from aging Glo1KD mice show increased expression of senescence markers and macrophage infiltration but preserve both their morphology and insulin and glucagon storage. MGO‐induced senescence of β‐cells leads to the release of SASP factors and the GSIS impairment, which are reverted to control by senolytic treatment.