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

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 We demonstrated that features associated with T2DM in Lepr 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.

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