The diabetes epidemic affects ~10% of the US adult population. An elevated blood sugar level is the hallmark of
diabetes, and the coordinated secretion of endocrine hormones from critically important pancreatic islets of
Langerhans is required for the proper control of whole-body glucose metabolism. Increased metabolic stress
due to obesity causes each islet cell type (a, b, d) to adapt by altering their hormone secretion. However, in
certain obese individuals, failure of this adaptation, disrupts the islet microenvironment, leading to elevated blood
glucose levels and the onset of type 2 diabetes (T2D). The underlying mechanisms of how distinct islet cells
affect each other’s functions are not known. Secreted proteins are critical intra- and inter- cell type metabolic
regulators that have improved our understanding of mechanisms underlying obesity-induced T2D. Thus, the
premise of this project is that secreted proteins-mediated crosstalk in islets is essential for proper functioning
and adaptation of a, b, d-cells in lean, obese, and T2D states. Secreted proteins comprise ~11% of the total
human transcriptome, and our preliminary data have identified ~850 differentially expressed transcripts that
encode for secreted proteins in mouse islets with obesity. Yet, the function for only a handful of them has been
well-characterized. Our long-term goal is to identify secreted proteins that improve islet function for the treatment
of human T2D. A major roadblock towards achieving this goal is the technical limitations in identifying and costly
yet time-consuming functional characterization of secreted proteins in islets using conventional biochemical
approaches. In a test analysis of one data set at high stringency, 44 islet-derived secreted protein regulators
were identified to affect mouse islet function in obesity. Interestingly, the functional characterization of the top
candidate secreted protein led to the discovery of a novel pathway inhibiting insulin secretion from b-cells.
Excitingly, validation of the use of our quantitative bioinformatics framework is a leap towards effective data
mining in expediting the identification of novel secreted protein regulators of islet function associated with the
disease state (s). The objective here is to identify secreted protein regulators that affect islet function in human
T2D using network analysis on combined publicly available whole islet transcriptomics datasets. We propose
the following aims to achieve the objective: 1) Identify candidate secreted protein regulators; 2) superclusters for
functional prediction of candidate secreted proteins in islets associated with human obesity and T2D; and 3)
biological validation of the candidate secreted proteins to affect islet function. The successful completion will
identify novel regulators of islet function in human obesity and T2D, improving knowledge of mechanisms
underlying human T2D risks, and possibly identifying therapeutic targets to improve islet function in T2D.
Additionally, insights obtained by integrating multiple data sets accounting for variations in sample preparation
and sequencing (platform bias), sequencing depths, and networks/correlation architecture (due to sample
handling) will form the basis for elucidating the secreted protein network across distinct islet cell-types.
