Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany.
Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.
Mol Metab. 2021 Sep;51:101235. doi: 10.1016/j.molmet.2021.101235. Epub 2021 Apr 16.
The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress, and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of patients with T2DM show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear whether hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we generated and characterized a mouse model of T2DM with IR, steatosis, and iron overload.
Lepr mice hallmarked by T2DM, IR and steatosis were crossed with Fpn mice with systemic iron overload to generate Lepr/Fpn mice. The resulting progeny was characterized for major diabetic and iron-related parameters.
We demonstrated that features associated with T2DM in Lepr mice, such as obesity, steatosis, or IR, reduce the degree of tissue iron overload in Fpn mice, suggesting an 'iron resistance' phenotype. Conversely, we observed increased serum iron levels that strongly exceeded those in the iron-overloaded Fpn mice. Increased hepatic iron levels induced oxidative stress and lipid peroxidation and aggravated IR, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver, we observed gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we showed that iron overload in Lepr/Fpn mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye.
Taken together, our data show that iron causes the worsening of symptoms associated with the MetS and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate IR and diabetic late complications.
2 型糖尿病（T2DM）相关晚期并发症的分子发病机制尚不完全清楚。虽然 HbA1c 升高所表明的高血糖水平仅能部分解释疾病进展和晚期并发症，但据推测，炎症状态、氧化应激和代谢过程中产生的反应性代谢物与此相关。患有代谢综合征（MetS）的个体常进展为 T2DM，其中 70%的 T2DM 患者存在非酒精性脂肪性肝病（NAFLD），这是 MetS 的肝脏表现，以及胰岛素抵抗（IR）。流行病学研究表明，T2DM 和脂肪变性与铁代谢改变和肝铁蓄积有关。过量的游离铁会引发氧化应激和向巨噬细胞炎症状态的转变。然而，到目前为止，尚不清楚肝铁蓄积是否在 IR 和 T2DM 的产生中起因果作用，或者它是否仅仅是肝代谢改变的表现。为了解决这个悬而未决的问题，我们生成并鉴定了一种具有 IR、脂肪变性和铁过载的 T2DM 小鼠模型。
以 T2DM、IR 和脂肪变性为特征的 Lepr 小鼠与全身性铁过载的 Fpn 小鼠交配，生成 Lepr/Fpn 小鼠。对所得后代进行主要糖尿病和铁相关参数的特征描述。
我们证明，Lepr 小鼠中与 T2DM 相关的特征，如肥胖、脂肪变性或 IR，会降低 Fpn 小鼠中铁组织过载的程度，表明存在“铁抵抗”表型。相反，我们观察到血清铁水平升高，远远超过铁过载的 Fpn 小鼠。升高的肝铁水平诱导氧化应激和脂质过氧化，并加重 IR，表现为 IRS1 磷酸化和 AKT 激活减少。此外，在肝脏中，我们观察到基因反应模式表明从头脂肪生成和糖异生增加，以及游离葡萄糖水平升高。最后，我们表明 Lepr/Fpn 小鼠中的铁过载会加剧视网膜病变中观察到的微血管并发症，表明铁蓄积会增强与肝脏和眼睛相关的糖尿病晚期并发症。
总的来说，我们的数据表明铁会导致与 MetS 和 T2DM 相关症状的恶化。这些发现意味着铁耗竭策略与抗糖尿病药物联合使用可能会改善 IR 和糖尿病晚期并发症。
