Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

Activation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Brutons tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3{beta} pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-{kappa}B and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the pro-inflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1{beta} and TNF after LPS stimulation. In the present study we provide proof of concept evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D.