FUNCTIONAL PANCREATIC ISLET NETWORKS IN NUTRIENT HOMEOSTASIS IN MEN AND MICE – FUN-NET

Pancreatic islets are central to nutrient homeostasis and diabetes. They contain 4 cell types (alpha/beta/gamma/delta), which alter their electric activity that tightly regulates hormone secretion in a distinct biphasic and pulsatile manner for up to 3 hours after a meal to restore homeostasis. The different cell types of the islet micro-organ form regulatory networks. Previous work addressed mainly glucose effects but not physiological mixed nutrients and lacked sufficient temporal resolution to provide unbiased insight into dynamic supracellular organisation. Moreover, multiple combinations of cell-type ablations have not been feasible. Models of islet function in-silico have been proposed but mostly for B-cells during steady-state (2nd phase) and never been transposed into human organism status. Consequently the precise physiological relevance of cell types is still only partially known in nutrient homeostasis and its pathological derangement in nutrient stress or diabetes.

FUN-NET is an interdisciplinary project of 3 groups with distinct expertise: (i) The HERRERA group (U Genève, co-coordinator) is specialized in endocrine pancreas plasticity and metabolic outcome in-vivo. Using CRISPR technology the group has generated new and highly versatile genetic mouse models for differential or combined specific cell ablation or hormone inactivation. They have also developed human pseudo-islets of defined cell-type composition. (ii) The LANG group (U Bordeaux CNRS, co-coordinator) has developed a microfluidic islet-on-chip for extracellular electrophysiology using micro-electrode arrays (MEAs, µMEAs) coupled to secretion analysis. This allows read-outs over hours/days with high temporal resolution on single cells or whole islets and unbiased direct network analysis; high-density MEAs provide considerable spatial information. (iii) The RENAUD group (Bordeaux INP), specialized in conceiving electronic systems for real time interaction with biology, has designed real time analysis and automated net-work analysis. Using an FDA approved human in-silico simulator of metabolism (T1DMS), they developed an electrical islet signature based model for glycaemia regulation during several meals over days.

We will address the following QUESTIONS:
(i) What is the specific contribution of B-cells alone on islet activity, phases, networks and homeostasis of different nutrients?
(ii) How does each of the non-beta cells impact B-cell function and gene expression?
(iii) How do they impact on islet activity under disease-mimicking challenges?
(iv) How do these cell-type specific contributions translate into human whole body homeostasis?

THE DETAILED OBJECTIVES are:
OBJECTIVE 1: In-vivo exploration of cell-type influence on mixed nutrient handling including metabolic challenges/high fat diet (Leader HERRERA)
OBJECTIVE 2: In-vitro exploration of cell-type influence on dynamic nutrient handling, functional intra-islet organization and gene expression (Leader LANG)
OBJECTIVE 3: Human in-silico exploration (T1DMS) of cell-type influence on B-cells in the human organism (Leader RENAUD)

FUN-NET will impact understanding of nutrient homeostasis and lead to a new concept of the islet micro-organ network closer to physiology, its pathological derangements and will provide substantial information for surrogate islet generation for diabetes therapy. It will also constitute the first translation of islet function into a human whole-body simulator. Moreover, harnessing functional islet principles, optimized in 0.5 billion years of evolution, may contribute to optimize the artificial pancreas via bio-inspired algorithms as current control algorithms are underperforming. FUN-NET will impact in terms of technology as the combination of genetic models, µMEA and human in-silico simulator, may provide a powerful, modular and cost-effective platform to address a number of fundamental and applied research questions as well as clinical issues not feasible in man.