Oral administration of methylglyoxal leads to kidney collagen accumulation in the mouse

doi:10.1016/S0024-3205(98)00336-1

Life Sciences

Volume 63, Issue 9, 24 July 1998, Pages 801-807

https://doi.org/10.1016/S0024-3205(98)00336-1 Get rights and content

Abstract

Methylglyoxal (MG) is a physiological substrate of the glyoxalase system which is impaired in the diabetic state and implicated in the development of diabetic complications. Like other reactive aldehydes in diabetes mellitus (DM) this carbonyl can bind to and modify proteins which may lead to changes of biochemical and biophysical properties of connective tissue proteins, a hallmark of diabetes mellitus. As previous studies on MG effects were confounded by other aldehydes found in DM, we decided to administer MG to 10 healthy, female OF-1 mice for a period of five months, at a level of 50 mg/kg body weight per day using 10 healthy untreated litter mates as controls. The left kidneys were taken for the determination of total kidney collagen, fluorescence, acid solubility of collagen and the right kidneys were used for the determination of glomerular basement membrane thickness. Total kidney collagen was significantly higher in the MG treated mice compared to control mice. Only about half the amount of collagen could be extracted from kidneys of MG treated animals indicating reduced solubility. Fluorescence in proteins from extracted kidneys of MG treated animals was about twice that of untreated animals. Glomerular basement membrane thickness was significantly higher in MG treated animals. Our findings indicate that MG can increase glomerular basement membrane thickness and the suggested underlying mechanism may be decreased solubility by increased cross linking as reflected by elevated protein fluorescence and decreased acid salt extraction. The involvement of MG in the development of diabetic complications postulated by others is herewith clearly supported by our findings.

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Protein glycation in diabetes mellitus
2023, Advances in Clinical Chemistry
Diabetes mellitus is the ninth leading cause of mortality worldwide. It is a complex disease that manifests as chronic hyperglycemia. Glucose exposure causes biochemical changes at the proteome level as reflected in accumulation of glycated proteins. A prominent example is hemoglobin A1c (HbA1c), a glycated protein widely accepted as a diabetic indicator. Another emerging biomarker is glycated albumin which has demonstrated utility in situations where HbA1c cannot be used. Other proteins undergo glycation as well thus impacting cellular function, transport and immune response. Accordingly, these glycated counterparts may serve as predictors for diabetic complications and thus warrant further inquiry. Fortunately, modern proteomics has provided unique analytic capability to enable improved and more comprehensive exploration of glycating agents and glycated proteins. This review broadly covers topics from epidemiology of diabetes to modern analytical tools such as mass spectrometry to facilitate a better understanding of diabetes pathophysiology. This serves as an attempt to connect clinically relevant questions with findings of recent proteomic studies to suggest future avenues of diabetes research.
Habitual intake of dietary methylglyoxal is associated with less low-grade inflammation: the Maastricht Study
2022, American Journal of Clinical Nutrition
Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously and also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown.
We sought to examine the associations of dietary dicarbonyl intake with low-grade inflammation and microvascular function.
In 2792 participants (mean ± SD age: 60 ± 8 y; 50% men; 26% type 2 diabetes) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking FFQ outcome data to our food composition database of the MGO, GO, and 3-DG content of >200 foods. Low-grade inflammation was assessed as six plasma biomarkers, which were compiled in a z score. Microvascular function was assessed as four plasma biomarkers, compiled in a zscore; as diameters and flicker light–induced dilation in retinal microvessels; as heat-induced skin hyperemic response; and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and microvascular function were investigated using linear regression with adjustments for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle and dietary factors.
Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z score for inflammation [standardized β coefficient (STD β): −0.05; 95% CI: −0.09 to −0.01, with strongest inverse associations for hsCRP and TNF-α: both −0.05; −0.10 to −0.01]. In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (STD β: −0.07; 95% CI: −0.12 to −0.01), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes.
Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation of an association between MGO intake and health outcomes in humans and warrants further investigation.
The activity of glyoxylase 1 is regulated by glucose-responsive phosphorylation on Tyr136
2022, Molecular Metabolism
Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that glycates proteins. MG has been linked to the development of diabetic complications: MG is the major precursor of advanced glycation end products (AGEs), a risk marker for diabetic complications in humans. Furthermore, flies and fish with elevated MG develop insulin resistance, obesity, and hyperglycemia. MG is detoxified in large part through the glyoxalase system, whose rate-limiting enzyme is glyoxalase I (Glo1). Hence, we aimed to study how Glo1 activity is regulated.
We studied the regulation and effect of post-translational modifications of Glo1 in tissue culture and in mouse models of diabetes.
We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. We find that Glo1 Y136 phosphorylation responds in a bimodal fashion to glucose levels, increasing in cell culture from 0 mM to 5 mM (physiological) glucose, and then decreasing at higher glucose concentrations, both in cell culture and in mouse models of hyperglycemia.
These data, together with published findings that elevated MG leads to hyperglycemia, suggest the existence of a deleterious positive feedback loop whereby hyperglycemia leads to reduced Glo1 activity, contributing to elevated MG levels, which in turn promote hyperglycemia. Hence, perturbations elevating either glucose or MG have the potential to start an auto-amplifying feedback loop contributing to diabetic complications.
Methylglyoxal influences development of Caenorhabditis elegans via lin-41-dependent pathway
2021, Food and Chemical Toxicology
Methylglyoxal is a highly reactive dicarbonyl compound. It can be obtained either endogenously through biological enzymatic/non-enzymatic pathways or exogenously via the uptake of certain foods and beverages, such as Manuka honey. Studies about its biological properties are quite controversial, though the majority reported a positive association between methylglyoxal and certain pathologies. In this report, we tested if methylglyoxal can alter the development of animals using Caenorhabditis elegans as the in vivo model. Treatment of methylglyoxal at 0.1 and 1 mmol/L for 2 days significantly inhibited the development of Caenorhabditis elegans, particularly targeting the transition from L3 stage. Pharyngeal pumping rate, the food intake marker was also significantly reduced by methylglyoxal at both 0.1 and 1 mmol/L. Additionally, treatment of 0.1 mmol/L methylglyoxal increased, while 1 mmol/L methylglyoxal decreased the nematodes’ average moving speed. The effect of methylglyoxal on development was in part due to the modulation of lin-41, which encodes a homolog of human TRIM71. The mutation of lin-41 could alleviate or abolish the effects of methylglyoxal on growth rate, body size, pumping rate and locomotive activity. In summary, these results suggested that methylglyoxal influenced the development of Caenorhabditis elegans, which is in part via the lin-41-dependent pathway.
Long-term intake of the reactive metabolite methylglyoxal is not toxic in mice
2020, Food and Chemical Toxicology
Citation Excerpt :
MG-induced diabetes is accompanied by an increase (Cheng et al., 2015; Dhar et al., 2010) or a decrease in the pancreatic production of insulin (Dhar et al., 2011; Lee et al., 2012). In addition to diabetes, MG can cause vascular and renal disorders (Berlanga et al., 2005; Choi et al., 2016; Golej et al., 1998; Tikellis et al., 2014). The main beneficial effect of MG reported is its anti-cancerogenic action in various mouse tumour models working with injected cancer cells (Apple and Greenberg, 1968; Bhattacharyya et al., 2008; Egyud and Szent-Gyorgyi, 1968; Ghosh et al., 2006; He et al., 2016).
Reactive carbonyls, including methylglyoxal (MG), are considered toxic compounds in foodstuffs because they irreversibly modify proteins and produce advanced glycation end products (AGEs). Therefore, we studied the long-term effect of increased MG intake in mature adult mice. Six-month-old C57BL/6N mice received MG by drinking water (2.5 mg/ml; i.e., 200–300 mg/kg BW/d) until death. This treatment caused an immediate strong increase in urine MG and a delayed moderate increase in plasma MG. At 24 months of age, mice administered MG showed no changes in the blood and tissue activity of glyoxalase-1 (Glo1), an intracellular MG-detoxifying enzyme; no signs of renal insufficiency and diabetes, including unchanged AGE modifications of plasma and vessel proteins; reduced tumour incidence; and slightly increased survival. Mice simultaneously deficient in the receptor for AGEs (RAGE) and overexpressing Glo1 exhibited higher basal plasma MG levels and did generally not respond to long-term MG intake. In vitro experiments supported the minor relevance of Glo1 in the detoxification of circulating MG but the important role of plasma albumin as an MG scavenger. In conclusion, the detoxification of dietary MG through renal excretion and further mechanisms largely prevents the toxicity of MG and possibly other food-derived reactive carbonyls in mature adults.
Elevated Levels of the Reactive Metabolite Methylglyoxal Recapitulate Progression of Type 2 Diabetes
2018, Cell Metabolism
Citation Excerpt :
MG reacts directly with lysine and arginine residues on proteins to form advanced glycation end products that affect protein function (Thornalley, 2008). Exogenous administration of MG, either orally to mice and rats or to cells in culture, results in physiological changes observed in diabetic patients such as collagen accumulation in kidneys, hypercholesterolemia, microvasculature degeneration, and insulin resistance (Berlanga et al., 2005; Golej et al., 1998; Riboulet-Chavey et al., 2006). The physiological relevance of these models, however, is unclear, since they rely on high exogenous MG applied from the outside of cells, rather than elevated levels of intracellular, endogenous MG.
The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA_1c < 6.5%) still develop diabetic complications. This suggests additional insulin- and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study.

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Oral administration of methylglyoxal leads to kidney collagen accumulation in the mouse

Abstract

Biochim Biophys Acta

Toxicol Lett

Biochem Biophys Acta

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Biochem Pharmacol

Biochem Pharmacol

Exp Eye Res

Arch Biochem Biophys

J Pediatr

J Biol Chem

Anal Biochem

J Biol Chem

J Biol Chem

J Biochem

J Biochem