Cadmium and Diabetes – CADMIDIA

The project Cadmidia aims at understanding the relationship between low level exposure to the widespread contaminant, cadmium, and dysfunction of pancreatic beta cells, which is a strongly contributing factor in the development of type II diabetes. Food contamination by cadmium and occurrence of type II diabetes are on the rise worldwide, with strong social and economic impact on human health, food processing, and means to sustain feeding of animal and human populations. A vast body of observations supports the link between cadmium and diabetes, but the lack of insight into the involved mechanisms impedes knowledge-based intervention.
To progress in this area, a Systems Biology approach will be conducted by four research groups. They span several scientific disciplines from physiology and toxicology to applied mathematics and computer science. The partners will implement an unprecedented integrative approach in the considered question combining i) newly designed studies on laboratory animals, ii) extensive and parallel in vitro work with validated cell lines, giving access to molecular and cellular events underlying adaptation to low level exposure to metal compounds, and iii) modeling and model-checking means necessary to comprehend the complex inter-relationship among the affected biological networks.
Conditions providing a realistic exposure to cadmium from food contamination will be initially explored with Wistar rats, since a large majority of previous studies implements excessive amounts of the toxic metal to be reasonably extrapolated to human populations. The investigated end-points will be cadmium loading, impact on the concentration of important trace elements, insulin resistance and anti-oxidant capacity of relevant organs (pancreas, liver, kidney) and in blood. The selected condition will be further investigated with large groups of animals. Measurements will include insulin secretion and islet mitochondrial functions. The metabolic consequences for the liver will be evaluated as ß-oxidation of fatty acids, gluconeogenesis and glycolysis, in addition to the mitochondrial status. Concentrations or activities of specific transcripts, signaling cascades, and proteins will be useful to give a molecular and cellular basis to the physiological studies. Besides supplementation with cadmium, high carbohydrate diet will be introduced as another studied parameter with relevance for some human sub-populations. Also, comparison will be made between adults and neonates.
The above animal studies will be mirrored by cellular ones in which model cell lines will experience similar conditions. The focus of the experimental approach will be on the regulatory and metabolic pathways which define the cellular response to chronic exposure to cadmium in pancreatic beta cells in particular. The sustained presence of metals, whether biologically essential or toxic, leads to adaptive mechanisms which remain very ill-defined. Our preliminary data in another biological context, which will be fully exploited in the present work, give us clues about the best way to tackle this question. The implemented measurements will include full assessment of the mitochondrial function and of the details of the permeability transition pore opening, as well as targeted evaluation of the biological networks which are sensitive to variations of cadmium concentrations, even after long term, low level, exposure.
These cellular studies will constitute the basis of model-building and model–checking studies with tools developed by partners of the consortium. These tools will be further developed in this project to handle large and more complex systems than usually done, with new heuristics to explore very high-dimensional parameter spaces and combination with quasi-random simulation.
Beyond shedding light on the obscure link between cadmium contamination and beta cells dysfunction, this project will provide a general approach of use for most toxicological problems.