Previously, we identified complement-1q like-3 (C1ql3) secreted protein as a hub gene affecting pancreatic islet function in obese mice using network biology. We demonstrated that the recombinant C1ql3 protein inhibits insulin secretion stimulated by exendin-4 (an agonist for GLP-1 receptor) from human and mouse islets. Our goal is to investigate the role of β-cell C1ql3 in pancreatic β-cell function in physiological and pathophysiological states. We generated mice with β-cell-specific deletion of C1ql3 (βKO) by crossing C1ql3fl/fl and RIP-Cre+mice. C1ql3 βKO mice showed significantly improved glucose clearance after oral glucose challenge than control mice, whereas no difference in insulin action was observed. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. C1ql3 βKO islets significantly increased insulin secretion stimulated by cAMP and Exendin-4 than control islets. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. Obesity increases the expression-coupled secretion of C1ql3 from mouse islets. Adenovirus mediated overexpression of C1ql3 in islets showed increased ER stress - a key trigger for β-cell dysfunction in obesity- as well as decreased expression of genes involving β-cell function and maintenance. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased glucose stimulated insulin secretion from islets of C1ql3 βKO Leptinob/ob compared to Leptinob/ob control mice. These findings identify that the loss of β-cell C1ql3 maintains ER stress to compensate β-cell workload during obesity and increases insulin secretion to maintain glucose homeostasis. Our work shows that an autocrine regulation of the C1ql3-signaling pathway contributes to β-cell dysfunction in obesity and type 2 diabetes.


M.Rahman: None. H.Alsharif: n/a. S.Bhatnagar: None.


American Diabetes Association (1-18-PDF-103) ; 1R01DK120684-01

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