Secreted proteins are important metabolic regulators and our objective was to identify proteins that are important regulators of β-cell function. Microarray data from multiple tissues including liver, adipose, gastrocnemius, islets from lean and obese mice were analyzed to identify candidate regulators. For this, we developed a data filtering approach to identify candidate secreted protein regulators. Next, cross-tissue correlation network and gene enrichment based analyses were performed to determine cellular pathways affected by each candidate secreted protein in the target tissue. By using this methodology, complement-1q-like-3 (C1ql3) was identified to affect ’secretory processes’ in islets. Preliminary data showed that the expression of C1ql3 was increased by 32-fold in islets of obese mice. Incubating islets with C1ql3 containing culture media inhibited high glucose, GLP-1 receptor agonist (exendin-4), cAMP, and potassium-induced insulin secretion in mouse islets. Interestingly, C1ql3 did not affect insulin secretion in response to low and submaximal concentrations of glucose, fatty acids, amino acids, and mitochondrial metabolites. We further observed that the expression of BAI3, a receptor for C1ql3, is elevated in islets of obese compared to lean mice. Knockdown of BAI3 in β-cells increased glucose-stimulated insulin secretion by 2-fold and soluble C1ql3-binding fragment of BAI3 completely blocked the inhibitory effects of C1ql3 on cAMP-stimulated insulin secretion. These findings report the identification of a novel pathway in C1ql3/BAI3 that antagonizes GLP-1/cAMP signaling to inhibit insulin secretion from β-cells. We propose that the activation of C1ql3/BAI3 signaling contributes to type 2 diabetes and may offer therapeutic alternatives to treat type 2 diabetes.


R. Gupta: None. M. Schaid: None. M.E. Kimple: None. J.E. Koltes: None. S. Bhatnagar: None.

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