Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice

Song, Yushuai; Liu, Ziyue; Zhu, Xiaoying; Hao, Chenyu; Hao, Wudi; Wu, Shengwen; Yang, Jinghua; Lu, Xinzheng; Jin, Cuihong

doi:10.1016/j.bcp.2022.115140

Cited by 12 publications

(4 citation statements)

References 48 publications

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“…Virtually all of these effects are attributed to metformin's beneficial impact on metabolism. Therefore, metformin is perceived to enhance metabolism through multiple pathways [52,[80][81][82][83].…”

Section: Discussionmentioning

confidence: 99%

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry

Shu,

Yang,

et al. 2024

Discovery Medicine

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Background: An imbalance in energy metabolism serves as a causal factor for type 2 diabetes (T2D). Although metformin has been known to ameliorate the overall energy metabolism imbalance, but the direct correlation between metformin and central carbon metabolism (CCM) has not been thoroughly investigated. In this study, we employed a high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) technique to examine the alterations and significance of CCM both before and after metformin treatment for T2D. Methods: We recruited 29 participants, comprising 10 individuals recently diagnosed with T2D (T2D group). Among these, 10 patients underwent a 4-6-week treatment with metformin (MET group). Additionally, we included 9 healthy subjects (CON group). Employing HPIC-MS/MS, we quantitatively analyzed 56 metabolites across 18 biologically relevant metabolic pathways associated with CCM. Univariate and multivariate statistical analyses were utilized to identify differential metabolites. Subsequently, correlation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted on the identified differential metabolites. Results: We identified seven distinct metabolites in individuals with T2D (p < 0.05). Notably, cyclic 3 ′ ,5 ′ -Adenosine MonoPhosphate (AMP), Glucose 6-phosphate, L-lactic acid, Maleic acid, and Malic acid exhibited a reversal to normal levels following metformin treatment. Furthermore, Malic acid demonstrated a positive correlation with L-lactic acid (r = 0.94, p < 0.05), as did succinic acid with malic acid (r = 0.81, p < 0.05), L-lactic acid with succinic acid (r = 0.78, p < 0.05), and L-lactic acid with glucose-6-phosphate (r = 0.72, p < 0.05). These metabolites were notably enriched in pyruvate metabolism (p = 0.005), tricarboxylic acid cycle (TCA) (p = 0.007), propanoate metabolism (p = 0.007), and glycolysis or gluconeogenesis (p = 0.009), respectively. Conclusions: We employed HPIC-MS/MS to uncover alterations in CCM among individuals recently diagnosed with T2D before and after metformin treatment. The findings suggest that metformin may ameliorate the energy metabolism imbalance in T2D by reducing intermediates within the CCM pathway.

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Section: Discussionmentioning

confidence: 99%

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry

Shu,

Yang,

et al. 2024

Discovery Medicine

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“…Previous studies have reported that increased AMPK activation promotes degradation of HIF-1α and suppresses glucose metabolic reprogramming (49,50). Song et al (51) found that AMPK activation reduced gene expression of HIF-1α and defects in glycolysis and oxidative phosphorylation. AMPK activators can facilitate the expression of p-AMPK and inhibit the expression of HIF-1α associated with downstream inflammatory mediators (40).…”

Section: Discussionmentioning

confidence: 99%

METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α–INDUCED AEROBIC GLYCOLYSIS

Zhong,

Tang,

Feng

et al. 2023

Shock

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Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis. However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α) induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide (LPS) increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. Additionally, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates pulmonary fibrosis associated with sepsis, which is caused by aerobic glycolysis, in mice. HIF-1α knockdown demonstrated similar protective effects in vivo. Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated pulmonary fibrosis.

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“…Due to its positive effects on insulin resistance and glucose metabolism, which play an important role in AD, it was investigated as a treatment option for dementia. In animal models, metformin increased glucose uptake and attenuated amyloid ß production [ 157 , 158 , 159 ]. Although the exact mechanism underlying metformin treatment is not fully understood, it improves cellular energy homeostasis via AMPK/insulin receptor/Akt signaling ( Figure 3 ).…”

Section: Protective Treatmentsmentioning

confidence: 99%

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

Fehsel

2023

Biomedicines

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Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer’s disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron–sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.

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Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice

Cited by 12 publications

References 48 publications

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry

METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α–INDUCED AEROBIC GLYCOLYSIS

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

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