Human Diabetes Proteome Project (HDPP)

The Human Diabetes Proteome Project | From Network Biology to Targets for Therapies and Prevention

Diabetes occurs when insulin secretion or use is inadequate and can no longer maintain normoglycemia. Failure of the ß-cell secretory machinery has been suggested as a primary cause for the reduced insulin secretion but loss in ß-cell mass by a skewed ratio of apoptosis versus proliferation has also been suggested. It has been demonstrated that a tight control of glycemia in T2DM improves insulin sensitivity and secretion, suggesting a toxic effect of elevated glucose levels on ß-cells and insulin target cells. Indeed, prolonged exposure of ß-cells to high levels of glucose decreases insulin secretion. Not only glucose but also fatty acids cause harmful actions depending on their concentration and exposure time. Chronic high glucose and lipid exposures modify a number of biological pathways including the expression of glucose and lipid metabolic enzymes as well as transcription factors. Two concepts have thus emerged: glucotoxicity and lipotoxicity. The concept of glucolipotoxicity with the hypothesis that elevation of both glucose and fat synergize their toxicity on cells has also been proposed, where glucose-induced reduction in fat oxidation and promotion of lipid esterification in ß-cells could contribute. This concept is potentially complementary to the fact that reactive oxygen species (ROS) and glycation of proteins are implicated in both glucotoxicity and lipotoxicity inducing cell apoptosis.

The goal of the HDPP initiative is to perform large-scale network biology-based experiments on various specialized cells and tissues as well as re-analysis of existing data. This strategy will allow dissection of the regulatory mechanisms that underlie the detrimental effects of glucose and lipids, as well as to list and target proteins of interest, which could be potential biomarkers of diabetes-related conditions or provides early evidence of developing disease. In parallel, HDPP intend to produce extended proteomes of diabetes-related cells/tissues/fluids, which will be the starting point for the discovery of “missing proteins” not previously described at the protein level.

These efforts are crucial for the development of new diagnostic tools and new therapeutic drugs protecting cells and organs from the toxicity of excess of these molecules.

Current lines of work:

The main aims and some current lines of work are the following:

• To create extended proteome databases on diabetes-related cells/fluids/tissues. Efforts were firstly concentrated on the creation of the human islet proteome, which was published in 2015, and which was updated in 2016. This led to highlighting of missing proteins, consequently linking the HDPP initiative to C-HPP initiatives.
• To establish various short lists of proteins of interest for diabetes-related conditions (HDPP-1000, HDPP-100, HDPP-25 and HDPP-popular). These lists encompass proteins of high importance for the scientific diabetes community (described in the first paper, 2015).
• To make publicly available targeted MS and antibody-based assays to enable any research group to quantify them.
• To develop targeted standardized methods for the quantification of clinically relevant proteins.

Related documents:

Papers:

Uppsala Longitudinal Study of Childhood Obesity: Protocol description. Forslund, A., Staaf, J., Kullberg, J., Ciba, I., Dahlbom, M., Bergsten, P.  (2014) Pediatrics, 133 (2)

Links to other HPP groups:

Leadership:

• Ali Tiss, Chair
• Domitille Schvartz, Co-Chair 
• Loïc Dayon, Co-Chair