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 Bruton's 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-3b pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-κB 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 proinflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1b and TNFa 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. inhibition or genetic deletion of components of the NF-kB pathway i) prevent the development of high fat diet induced insulin resistance (20)(21) and ii) slows the progression of microvascular disease. It has a been demonstrated that myeloid specific deletion of IKK-b, but not deletion in hepatocytes or adipocytes that contributes to the development of insulin resistance (18). Currently there are no medicines available for diabetes that target inflammation and/or prevent the development of microvascular complications. Repurposing existing FDA approved medications that have potent anti-inflammatory effects for new indications could be a cost-effective approach to prevent and/or treat the development of microvascular complications of diabetes. Antiinflammatory agents have been shown to be powerful tools in pre-clinical models. However, to date little translational research as followed up on these successes.Bruton's tyrosine kinase (BTK) is a tyrosine kinase that plays an essential role in B lymphocyte development. Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia. As well as, being highly expressed in B-lymphocytes, BTK is also highly expressed in monocytes/macrophages (22), the latter is the key cell types that drives the development of insulin resistance. Importantly, BTK is not expressed in hepatocytes or adipocytes the main cell types effected by obesity induced insulin resistance (23). In monocyte/macrophages BTK has a proposed role in signal transduction downstream of numerous TLR's. XID mice, which have non-signaling kinase domain in BTK, have redu...