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Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test OGTT and Insulin Tolerance Test ITT
Published on: January 7, 2018
Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice
Immacolata Prevenzano1, Alessia Leone1, Michele Longo1
1URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine - Federico II, University of Naples, Naples, Italy.
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.
Insights
Methylglyoxal (MGO) accumulation impairs glucose tolerance and insulin secretion in type 2 diabetes mellitus (T2DM) by inducing islet inflammation and senescence. Senolytic treatment can reverse this MGO-induced beta-cell dysfunction.
Area of Science:
- Metabolic disease research
- Diabetes pathogenesis
- Cellular senescence
Background:
- Tight glycemic control is crucial for managing type 2 diabetes mellitus (T2DM).
- Factors beyond glycemic control influence T2DM progression.
- Methylglyoxal (MGO) is linked to T2DM complications, but its role in early pathogenesis is unclear.
Purpose of the Study:
- To investigate the role of MGO accumulation in the early pathogenesis of T2DM.
- To determine if MGO induces age-dependent metabolic alterations and pancreatic changes associated with T2DM.
Main Methods:
- Utilized glyoxalase 1 knockdown (Glo1KD) mice to induce MGO accumulation.
- Assessed glucose tolerance and glucose-stimulated insulin secretion in Glo1KD and wild-type (WT) mice.
- Analyzed pancreatic tissue for inflammatory markers, senescence markers, and cytokine expression.
- Exposed INS832/13 beta-cells to MGO in vitro and tested senolytic treatment.
Main Results:
- MGO accumulation in Glo1KD mice led to age-dependent impairment of glucose tolerance and insulin secretion.
- Observed insular inflammation, islet senescence markers, and increased pro-inflammatory cytokines (MCP-1, TNF-α) in Glo1KD mouse pancreata.
- In vitro MGO exposure caused beta-cell dysfunction, which was reversible with senolytic treatment.
Conclusions:
- MGO accumulation can induce early T2DM-like phenotypes, including metabolic dysfunction and pancreatic inflammation/senescence.
- MGO directly contributes to beta-cell dysfunction.
- These findings suggest MGO as a potential therapeutic target for T2DM prevention.
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