In primary hepatocytes from healthy animals,
metformin and the IKKβ (inhibitor of kappa B
kinase) inhibitor
BI605906 both inhibited
tumor necrosis factor-α-dependent IκB degradation and expression of proinflammatory mediators
interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif
ligand 1/2).
Metformin suppressed IKKα/β activation, an effect that could be separated from some metabolic actions, in that
BI605906 did not mimic effects of
metformin on lipogenic gene expression,
glucose production, and
AMP-activated protein kinase activation. Equally
AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages,
metformin specifically blunted secretion of proinflammatory
cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive
diabetes mellitus population cohort, we observed differences in the systemic
inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either
metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure,
metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02-0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22-2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic
heart failure (trial registration: NCT00473876),
metformin suppressed plasma
cytokines including the aging-associated
cytokine CCL11 (C-C motif
chemokine ligand 11).
CONCLUSION: