Iron aggravates hepatic insulin resistance in the absence of inflammation in a novel db/db mouse model with iron overload

Altamura, Sandro; Müdder, Katja; Schlotterer, Andrea; Fleming, Thomas; Heidenreich, Elena; Qiu, Ruiyue; Hammes, Hans‐Peter; Nawroth, Peter P.; Muckenthaler, Martina U.

doi:10.1016/j.molmet.2021.101235

Cited by 66 publications

(69 citation statements)

References 59 publications

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“…A previous study has reported that iron levels play a role as a ‘second hit’ observed in T2DM patients [ 51 ] and db/db mice [ 27 ]. The iron contributes to the ROS pool through the Fenton reaction [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

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Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

Song

Chen

et al. 2022

Bioengineered

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Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that is widely used in the clinic and is approved to treat obesity and diabetes. However, the specific protection mechanism needs to be clarified. In the present study, db/db mice were used to simulate Type 2 diabetes mellitus (T2DM), and they were intraperitoneally injected daily with liraglutide (200 μg/kg/d) for 5 weeks. Hepatic function, pathologic changes, oxidative stress, iron levels, and ferroptosis were evaluated. First, liraglutide decreased serum AST and ALT levels, and suppressed liver fibrosis in db/db mice. Second, liraglutide inhibited the ROS production by upregulating SOD, GSH-PX, and GSH activity as well as by downregulating MDA, 4-HNE, and NOX4 expression in db/db mice. Furthermore, liraglutide attenuated iron deposition by decreasing TfR1 expression and increasing FPN1 expression. At the same time, liraglutide decreased ferroptosis by elevating the expression of SLC7A11 and the Nrf2/HO-1/GPX4 signaling pathway in the livers of db/db mice. In addition, liraglutide decreased the high level of labile iron pools (LIPs) and intracellular lipid ROS induced by high glucose in vitro. Therefore, we speculated that liraglutide played a crucial role in reducing iron accumulation, oxidative damage and ferroptosis in db/db mice.

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Section: Discussionmentioning

confidence: 99%

“…Based on our previous method, the Perls’ staining was applied to detect the Fe content and distribution in the liver tissue [ 27 ]. After dewaxing and rehydration, the hepatic sections were incubated with 3% H 2 O 2 at room temperature for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

Song

Chen

et al. 2022

Bioengineered

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“…The effect of metabolic disease on serum ferritin is still controversial ( 20 ), the relationship between insulin resistance, an important component and initiator of many metabolic diseases, and ferritin remains unknown ( 21 ), and low serum ferritin levels and iron overload are undoubtedly detrimental to the body. Our study found a positive and linear correlation between METS-IR and serum ferritin in United States females.…”

Section: Discussionmentioning

confidence: 99%

The Association Between METS-IR and Serum Ferritin Level in United States Female: A Cross-Sectional Study Based on NHANES

Han

Chen

et al. 2022

Front. Med.

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AimThe aim of this study was to investigate the association between the metabolic score for insulin resistance (METS-IR) and serum ferritin in females from the United States.MethodsWe conducted a cross-sectional study with 4,182 participants from the National Health and Nutrition Examination Survey (NHANES). We used METS-IR and serum ferritin as the independent and dependent variables in this study and investigated the relationship by using multiple linear regression and verified the non-linear relationship with a smooth curve fit and threshold effect model.ResultsThere was a positive relationship between METS-IR and serum ferritin, with an effect value of (β = 0.29, 95% CI: 0.14–0.44) in a fully adjusted model adjusted for potential confounders. This positive correlation became more significant as METS-IR increased (p for trend < 0.001). Subsequent subgroup analyses showed that sensitive cohorts were those aged ≥40 years, black, and with a body mass index (BMI) < 24.9 kg/m2. In a smoothed curve fit analysis, the correlation between METS-IR and serum ferritin was a straight linear relationship in all participants included in this study, but when stratified by age, race, and BMI, this positive correlation in the participants who were aged ≥40 years old, other race, and had a BMI < 24.9 kg/m2 was non-linear.ConclusionsThere was a positive association between METS-IR and serum ferritin in United States females, and this positive association was more pronounced in participants aged ≥40 years, black race and BMI < 24.9 kg/m2. This positive association was non-linear in the subgroups aged ≥40 years, white race and BMI < 24.9 kg/m2, with inflection points for METS-IR of 69.97, 67.84 and 35.84 in these respective subgroups.

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“…Many studies have shown that ferroptosis and ferritinophagy are involved in the development and progression of diabetes complications (some upstream core substances are involved in diabetes complications by regulating ferroptosis and ferritinophagy, as shown in Table 2 ). Studies have shown that iron overload, the key initiating factor of ferroptosis, will aggravate insulin resistance in the absence of inflammation in diabetic mice [ 79 ]. But there are limited reports of relevant mechanisms.…”

Section: Ferroptosis and Ferritinophagy Participate In The Pathogenes...mentioning

confidence: 99%

Ferroptosis and ferritinophagy in diabetes complications

Xia

et al. 2022

Molecular Metabolism

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Iron aggravates hepatic insulin resistance in the absence of inflammation in a novel db/db mouse model with iron overload

Cited by 66 publications

References 59 publications

Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

The Association Between METS-IR and Serum Ferritin Level in United States Female: A Cross-Sectional Study Based on NHANES

Ferroptosis and ferritinophagy in diabetes complications

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