Sirtuin 1–Mediated Cellular Metabolic Memory of High Glucose Via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin

Zheng, Zhi; Chen, Haibing; Li, Jun; Li, Tao; Zheng, Bo; Zheng, Ying; Jin, Huiyi; He, Yayi; Gu, Qing; Xu, Xun

doi:10.2337/db11-0416

Cited by 234 publications

(200 citation statements)

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“…3e, f). To further verify that the transient exposure to high glucose (2 days) induced cellular metabolic memory in HRECs, we prolonged the high-glucose exposure time to 1 week and the total treatment time to 3 weeks, as in our previous study [14]. The results were consistent with the original test using the shorter high-glucose exposure time (ESM Fig.…”

Section: Screening Of Sirt1-targeting Mirnas In Diabetic Metabolic Mesupporting

confidence: 78%

“…Mut, mutant increased 6 months later in STZ-induced diabetic rats [32], suggesting the persistent activation of inflammatory signalling pathways. Using the cell and rat models of metabolic memory induced by high glucose established in our previous study, we demonstrated that SIRT1 activation suppressed the cellular metabolic memory of high glucose in retinal endothelial cells by inhibiting the inflammatory gene NF-κB (also known as Rela) and the apoptosis gene Bax [14]. In the present study, Produced as small, non-protein-coding RNAs, miRNAs are endogenous regulators that play significant roles in many cellular processes [33,34].…”

Section: Discussionmentioning

confidence: 97%

“…In situ hybridisation was used to detect miR-23b-3p expression in retinal tissue sections. Retinal digest procedures were performed to measure the acellular capillaries in trypsin-digested retinal blood vessels as described previously [14]. Details are in the ESM Methods.…”

Section: Microarray and Quantitative Rt-pcr Analysis Of Mirnamentioning

confidence: 99%

“…Sirtuin 1 confers resistance to the high-glucoseinduced cellular metabolic memory through an inflammatory signalling pathway in diabetic retinopathy [14]. However, the mechanisms of SIRT1 regulation remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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Aims/hypothesis The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. Methods The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. Results High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. Conclusions/interpretation These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucoseinduced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

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Section: Screening Of Sirt1-targeting Mirnas In Diabetic Metabolic Mesupporting

confidence: 78%

Section: Discussionmentioning

confidence: 97%

Section: Microarray and Quantitative Rt-pcr Analysis Of Mirnamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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“…Metformin, a commonly used anti-diabetic drug, decrease insulin resistance and hyperglycemia via inhibiting gluconeogenesis, hepatic glucose output and activation of free fatty acid oxidation in skeletal muscle [67]. Some of these beneficial effects of metformin were attributed to SIRT1 activation via AMPK pathway [68].…”

Section: Novel Therapeutic Agents Of Sirt1 Activators In Treatment Ofmentioning

confidence: 99%

The Emerging Role of Sirtuin 1,-3 and -4 in Glucose and Lipid Metabolism and in Diabetes Mellitus

Akbas¹

2014

J Mol Genet Med

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Diabetes mellitus has been accepted as an epidemic worldwide during the last two decades. Despite the diagnostic tools and therapeutic approaches, the pathophysiology of this metabolic disorder and cellular defensive mechanisms remain mysterious. The maintenance of cellular homeostasis requires well-organized network between glucose, amino acid and lipid metabolism. Sirtuins are a group of nicotinamide adenine dinucleotide dependent proteins that are involved in cellular homeostasis by their deacetylating activity. Among them, sirtuin 1,-3 and -4 have been the most extensively explored. In the present review, we aimed to discuss the role of associated sirtuins in glucose and lipid metabolism and in the pathogenesis and treatment of diabetes mellitus.

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Association of Metformin Use With Age-Related Macular Degeneration

et al. 2021

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IMPORTANCE Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD.OBJECTIVE To determine whether metformin use is associated with reduced odds of developing AMD. DESIGN, SETTING, AND PARTICIPANTSThis case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020.EXPOSURES Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. MAIN OUTCOMES AND MEASURES Risk of developing AMD.RESULTS A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI,).CONCLUSION AND RELEVANCE In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

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Sirtuin 1–Mediated Cellular Metabolic Memory of High Glucose Via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin

Cited by 234 publications

References 49 publications

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

The Emerging Role of Sirtuin 1,-3 and -4 in Glucose and Lipid Metabolism and in Diabetes Mellitus

Association of Metformin Use With Age-Related Macular Degeneration

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