Improvements in circulating cytokine levels have occurred in patients with endometriosis and chronic heart disease when prescribed the type 2 diabetes (T2D) drug metformin. However it is unclear how metformin exerts these effects and whether or not they are related to antihyperglycaemic effects in T2D. The purpose of this study is to investigate the relationship between anti-inflammatory and anti-hyperglycaemic effects of metformin in the liver, the main target tissue of the drug.
Hepatic responses to metformin were studied using primary mouse hepatocytes.
Metformin exhibits anti-inflammatory effects in hepatocytes alongside antihyperglycaemic responses, co-ordinated by AMPK and NF-κB. Comparing metformin with the IKKβ inhibitor BI605906, we found that both drugs inhibited TNFα-dependent IκB degradation and expression of pro-inflammatory cytokines IL-6, IL-1β, VEGF & CXCLl/2, whilst metformin but not BI605906 suppressed lipogenic genes SREBP1, PPARγ, FASN and glucose production. These results suggest NF-κB mediates effects of metformin on hepatic pro-inflammatory cytokines but is insufficient by itself for effects on hepatic glucose production and lipogenesis, which are likely to be more closely related to the drugs ability to inhibit mitochondrial enzymes. Studies in obese pre-diabetic and db/db mice are currently underway and will provide signalling knowledge on how metformin behaves in pathophysiological contexts more relevant to diabetes. Initial results indicate differences in hepatocyte responses between obese and control when treated with differing doses of metformin. Hepatocytes extracted from obese animals require a higher concentration of metformin to elicit responses, including glucose output and ATP production. We believe that hepatocytes extracted from obese animals may be impaired in their ability to take up metformin.
This study indicates that metformin exhibits a dual anti-inflammatory and antihyperglycaemic effect which might contribute to its therapeutic advantage over other T2D treatments. Importantly, the separation of these properties that we have identified suggests that metformins immune modulatory properties merit investigation in patients without diabetes.