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-α), 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 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.

Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice / Prevenzano, I.; Leone, A.; Longo, M.; Nicolo, A.; Cabaro, S.; Collina, F.; Panarese, I.; Botti, G.; Formisano, P.; Napoli, R.; Beguinot, F.; Miele, C.; Nigro, C.. - In: EMBO REPORTS. - ISSN 1469-221X. - (2022), p. e52990. [10.15252/embr.202152990]

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

Prevenzano I.;Longo M.;Cabaro S.;Panarese I.;Botti G.;Formisano P.;Napoli R.;Beguinot F.;
2022

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-α), 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 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.
2022
Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice / Prevenzano, I.; Leone, A.; Longo, M.; Nicolo, A.; Cabaro, S.; Collina, F.; Panarese, I.; Botti, G.; Formisano, P.; Napoli, R.; Beguinot, F.; Miele, C.; Nigro, C.. - In: EMBO REPORTS. - ISSN 1469-221X. - (2022), p. e52990. [10.15252/embr.202152990]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/887190
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