The hypothesis of the ERC Consolidator project METAPTPs is that specific signalling pathways are dysregulated by obesity, inflammation and oxidative stress in the pancreas and liver. The oxidative stress caused by inflammation and/or obesity affects the activity of important metabolic molecules known as protein tyrosine phosphatases, which could trigger the processes that cause metabolic diseases such as diabetes and liver dysfunction. To test our hypothesis, we developed tools which will allow us to identify major inactivated metabolic proteins and their role in cellular responses. We specifically focussed on the role of protein tyrosine phosphatases in the pancreas in type 1 and type 2 diabetes and in the liver for obesity-associated hepatic dysfunction. We have shown that inactivation of phosphatases by inflammatory-mediated oxidative stress severely affects pancreatic β-cell function and survival in the context of type 1 diabetes (Figure 1). Testing our hypothesis that protein tyrosine phosphatase dysregulated activity is a common mechanism in autoimmunity will increase our understanding of the pathogenesis and postulate novel targets for future clinical interventions in type 1 diabetes. For instance, identification of the mechanisms by which protein tyrosine phosphatases modulate cytokine activity may provide relevant and realistic targets for the design of pharmacological agents and diets. The present project has the potential to explain many of the “unknowns” that still linger regarding the disease. In the METAPTPs project, we take advantage of human stem cells and CRISPR/Cas gene editing to directly elucidate mechanisms modulated by aberrant signalling in differentiated metabolic cells. The differentiation method has been successfully implemented in our lab with the generation of insulin-producing β-cells and albumin-producing hepatocytes. Our knowledge accumulated in recent years enable us to study the mechanisms by which different subcomponents of the JAK-STAT signalling influence obesity and type 2 diabetes, i.e. acting as regulators of β-cell function (Figure 2). In addition, based on our previous data and unpublished observations, we predict that research strategies based on a family of proteins tyrosine phosphatases will allow us to better understand the transition from fat accumulation in the hepatocytes to hepatic cancer development (Figure 3). This information will be critical for new pharmacology screening. We aim to restore protein tyrosine phosphatase activity and associated dysfunctional signalling in patients.
