The Role of PKM2 in Diabetic Microangiopathy

Tu, Chao; Wang, Liangzhi; Wei, Lan

doi:10.2147/dmso.s366403

Cited by 7 publications

(2 citation statements)

References 57 publications

(61 reference statements)

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“…Pyruvate kinase M2 (PKM2) was more expressed in ASCs in DS compared to NS after 6 days of culture. This high expression can be correlated with the activation of the protective mechanism of ASCs against the DS microenvironment, as suggested by previous findings [ 79 ], since chronic inflammation related to diabetes tends to increase PKM2 levels [ 28 , 80 ]. Prolonged exposure of MSCs to oxidative stress upregulated SIRT1 expression, which activates the antioxidant protective factors that inhibit oxidative stress through AMPK activation [ 81 – 85 ].…”

Section: Discussionsupporting

confidence: 65%

Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells

Ahmed,

Elkhenany,

Ahmed

et al. 2024

Diabetol Metab Syndr

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Background Type 2 diabetes is an endocrine disorder characterized by compromised insulin sensitivity that eventually leads to overt disease. Adipose stem cells (ASCs) showed promising potency in improving type 2 diabetes and its complications through their immunomodulatory and differentiation capabilities. However, the hyperglycaemia of the diabetic microenvironment may exert a detrimental effect on the functionality of ASCs. Herein, we investigate ASC homeostasis and regenerative potential in the diabetic milieu. Methods We conducted data collection and functional enrichment analysis to investigate the differential gene expression profile of MSCs in the diabetic microenvironment. Next, ASCs were cultured in a medium containing diabetic serum (DS) or normal non-diabetic serum (NS) for six days and one-month periods. Proteomic analysis was carried out, and ASCs were then evaluated for apoptosis, changes in the expression of surface markers and DNA repair genes, intracellular oxidative stress, and differentiation capacity. The crosstalk between the ASCs and the diabetic microenvironment was determined by the expression of pro and anti-inflammatory cytokines and cytokine receptors. Results The enrichment of MSCs differentially expressed genes in diabetes points to an alteration in oxidative stress regulating pathways in MSCs. Next, proteomic analysis of ASCs in DS revealed differentially expressed proteins that are related to enhanced cellular apoptosis, DNA damage and oxidative stress, altered immunomodulatory and differentiation potential. Our experiments confirmed these data and showed that ASCs cultured in DS suffered apoptosis, intracellular oxidative stress, and defective DNA repair. Under diabetic conditions, ASCs also showed compromised osteogenic, adipogenic, and angiogenic differentiation capacities. Both pro- and anti-inflammatory cytokine expression were significantly altered by culture of ASCs in DS denoting defective immunomodulatory potential. Interestingly, ASCs showed induction of antioxidative stress genes and proteins such as SIRT1, TERF1, Clusterin and PKM2. Conclusion We propose that this deterioration in the regenerative function of ASCs is partially mediated by the induced oxidative stress and the diabetic inflammatory milieu. The induction of antioxidative stress factors in ASCs may indicate an adaptation mechanism to the increased oxidative stress in the diabetic microenvironment.

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Section: Discussionsupporting

confidence: 65%

Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells

Ahmed,

Elkhenany,

Ahmed

et al. 2024

Diabetol Metab Syndr

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“…7 Glucose metabolic disorders can cause renal microangiopathy, leading to changes in glomerular filtration rate and renal blood flow. 8 Dyslipidemia promotes the subcutaneous deposition of lipids in blood vessels, leading to atherosclerosis and cardio-cerebrovascular diseases (ASCVD). 9 Long-term hyperglycemia and lipid disorders in T2DM could lead to ASCVD.…”

Section: Introductionmentioning

confidence: 99%

Serum Lipoprotein(a) and High-Density Lipoprotein Cholesterol Associate with Diabetic Nephropathy: Evidence from Machine Learning Perspectives

Gao¹,

Liu²,

Yang³

et al. 2023

DMSO

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Diabetic nephropathy (DN) is a common complication of type 2 diabetes mellitus (T2DM) that significantly impacts the quality of life for affected patients. Dyslipidemia is a known risk factor for developing cardiovascular complications in T2DM patients. However, the association between serum lipoprotein(a) (Lp(a)) and high-density lipoprotein cholesterol (HDL-C) with DN requires further investigation. Patients and Methods: For this cross-sectional study, we randomly selected T2DM patients with nephropathy (DN, n = 211) and T2DM patients without nephropathy (T2DM, n = 217) from a cohort of 142,611 patients based on predefined inclusion and exclusion criteria. We collected clinical data from the patients to identify potential risk factors for DN using binary logistic regression and machine learning. After obtaining the feature importance score of clinical indicators by building a random forest classifier, we examined the correlations between Lp(a), HDL-C and the top 10 indicators. Finally, we trained decision tree models with top 10 features using training data and evaluated their performance with independent testing data. Results: Compared to the T2DM group, the DN group had significantly higher serum levels of Lp(a) (p < 0.001) and lower levels of HDL-C (p = 0.028). Lp(a) was identified as a risk factor for DN, while HDL-C was found to be protective. We identified the top 10 indicators that were associated with Lp(a) and/or HDL-C, including urinary albumin (uALB), uALB to creatinine ratio (uACR), cystatin C, creatinine, urinary ɑ1-microglobulin, estimated glomerular filtration rate (eGFR), urinary β2-microglobulin, urea nitrogen, superoxide dismutase and fibrinogen. The decision tree models trained using the top 10 features and with uALB at a cut-off value of 31.1 mg/L showed an average area under the receiver operating characteristic curve (AUC) of 0.874, with an AUC range of 0.870 to 0.890. Conclusion:Our findings indicate that serum Lp(a) and HDL-C are associated with DN and we have provided a decision tree model with uALB as a predictor for DN.

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Inhibition of Pyruvate kinase M2 (PKM2) by shikonin attenuates isoproterenol-induced acute myocardial infarction via reduction in inflammation, hypoxia, apoptosis, and fibrosis

Rihan

Sharma

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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The Role of PKM2 in Diabetic Microangiopathy

Cited by 7 publications

References 57 publications

Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells

Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells

Serum Lipoprotein(a) and High-Density Lipoprotein Cholesterol Associate with Diabetic Nephropathy: Evidence from Machine Learning Perspectives

Inhibition of Pyruvate kinase M2 (PKM2) by shikonin attenuates isoproterenol-induced acute myocardial infarction via reduction in inflammation, hypoxia, apoptosis, and fibrosis

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