Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signalling pathways in vitro and in vivo

Jiao, Zhenyu; Chen, Yingqun; Xie, Yang; Li, Yanbing; Zhi, Li

doi:10.1111/jcmm.16677

Cited by 15 publications

(11 citation statements)

References 43 publications

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“…Accumulating evidence from clinical observational studies suggests the involvement of asymptomatic hyperuricemia, independent of crystal formation, in hypertension, atherosclerosis, acute and chronic kidney disease, obesity, metabolic syndrome, fatty liver, insulin resistance (IR), and diabetes ( 3 – 5 ). Our previous studies also confirmed that hyperuricemia induced an IR state in several peripheral tissues ( 6 – 8 ), including the liver, myocardium, skeletal muscles, and adipose tissue as well as pancreatic β cells ( 9 ), and was a strong risk factor for type 2 diabetes mellitus (T2DM).…”

Section: Introductionsupporting

confidence: 77%

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Zhao

et al. 2022

Front. Immunol.

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AimNumerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear.MethodsTo assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions.ResultsCompared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 μM versus KO, 421.9 ± 45.47 μM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions.ConclusionThe data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation

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Section: Introductionsupporting

confidence: 77%

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Zhao

et al. 2022

Front. Immunol.

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“…It has been observed that the AMPK activation induced by metformin enhanced translocation of membrane GLUT4 and glucose uptake in insulin-resistant cardiomyocytes [ 86 , 87 ]. Moreover, in hypertrophied rat heart metformin intensified the glycolysis by activating the rate-limiting phosphofructokinase 1 (PFK1) [ 88 ].…”

Section: Mechanisms Of Beneficial Impact Of Metformin On Heart Failurementioning

confidence: 99%

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

et al. 2021

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Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.

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“…Diabetes regularly requires the administration of hypoglycemic drugs to maintain appropriate blood glucose levels and to reduce complications. Data from in vitro and in vivo research showed that hypoglycemic drugs can decrease the concentration of serum uric acid ( 41 ). Further study is needed to determine the exact mechanisms of these observations.…”

Section: Discussionmentioning

confidence: 99%

The visceral and liver fat are significantly associated with the prevalence of hyperuricemia among middle age and elderly people: A cross-sectional study in Chongqing, China

et al. 2022

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BackgroundThe prevalence of hyperuricemia (HUA) has been increasing in recent years. HUA is a crucial risk factor for gout and an independent risk factor for cardiovascular diseases (CVDs). Identifying potentially modifiable factors of HUA is vital for preventing gout and even CVDs. This study aimed to explore the associations of fat distribution with HUA among middle-aged and elderly people in Chongqing, China.Materials and methodsA cross-sectional study was conducted between July 2020 and September 2021. People who underwent quantitative computed tomography (QCT) scans were invited to participate in the study. A total of 3,683 individuals whose clinical characteristics and QCT-based fat distribution measurements included visceral fat area (VFA), subcutaneous fat area (SFA), and liver fat content (LFC) were well-recorded were included. HUA was defined as having a serum uric acid level greater than 420.0 μmol/L. Multivariate logistic regression models were used to evaluate the association between these adipose variables and HUA prevalence.ResultsThe HUA prevalence was 25.6% (943/3,683), which was 39.6% (817/2,063) in men and 7.8% (126/1,620) in women. In the fully adjusted model (model 4), the comparison of the highest one with the lowest quartiles of adipose variables showed that the multivariable OR (95% confidence intervals) of HUA were 2.08 (1.36–3.16; P for trend = 0.001) for VFA, 0.89 (0.63–1.25; P for trend = 0.651) for SFA, and 1.83 (1.42–2.34; P for trend < 0.0001) for LFC. For VFA, the association was more evident in men than in women.ConclusionHigher VFA and LFC were significantly associated with the increased prevalence of HUA in middle-aged and elderly Chinese individuals. VFA and LFC may have a predictive effect on HUA. Controlling visceral and liver fat accumulation may be beneficial for middle-aged and older people. HUA can be prevented with specific effective healthy physical activity and balanced diet guidelines.

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Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signalling pathways in vitro and in vivo

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 43 publications

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

The visceral and liver fat are significantly associated with the prevalence of hyperuricemia among middle age and elderly people: A cross-sectional study in Chongqing, China

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