Investigating the Effects of ADGRB3 Signaling on Incretin-Mediated Insulin Secretion from Pancreatic Beta-Cells

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The prevalence of diabetes has reached epidemic proportions worldwide. According to the Centers for Disease Control and Prevention, more than 37 million individuals in the US have diabetes (~10% of the adult population), and another 84.1 million are prediabetic. Elevated blood sugar is the hallmark of diabetes, and insulin secreted from the β-cells of the pancreatic islets is critical for maintaining proper blood sugar levels. It is currently accepted that β-cell dysfunction is an early and essential event in the development of diabetes, including obesity-linked type 2 diabetes (T2D). Cyclic AMP (cAMP) and ionic calcium (Ca2+) are key cellular signaling molecules that stimulate β-cell insulin secretion. Ca2+ is the trigger for insulin secretion, while cAMP is required for the maximal insulin secretion response. Preliminary data from our group suggests brain angiogenesis inhibitor-3 (BAI3: aka ADGRB3), a G protein-coupled receptor for complement 1q like-3 secreted protein (C1ql3), may be a key player in the β-cell dysfunction of T2D. BAI3 expression, and C1ql3 expression and secretion are both higher in pancreatic islets from T2D mice and humans. BAI3 and C1ql3 are specifically expressed in islet β-cells and not in other islet cell types. Finally, C1ql3 treatment reduces insulin secretion from islets stimulated by glucose and drugs that raise β-cell Ca2+ or cAMP levels. Yet, the precise molecular mechanisms underlying β-cell C1ql3/BAI3 signaling, particularly in the pathophysiological states of obesity and T2D, remain uncharacterized. A full understanding of these processes is required to achieve our long-term goal of discovering ways to modulate BAI3 activity to improve or reverse the β-cell dysfunction of T2D. The overarching goal of this project, which is the next logical step towards this goal, is to define BAI3 and C1ql3 levels, signaling mechanisms, and effects on glucose-stimulated and cAMP-potentiated insulin secretion and how these change during β-cell compensation for obesity and T2D β-cell failure. With our unique combination of scientific expertise and technically innovative approaches, we are uniquely suited to complete this highly significant project. Tangible outcomes of the proposed work are: i) revealing how BAI3 expression and C1ql3 expression and secretion change in response to obesity and, ultimately, T2D; ii) quantifying the effects of BAI3 activation on β-cell Ca2+ influx and cAMP levels; and iii) establishing how C1ql3-mediated BAI3 signaling inhibits glucose-stimulated and cAMP-potentiated insulin secretion and the magnitude of its effects in the lean, obese, and T2D states. If successful, our work will both define the signaling mechanisms downstream of BAI3, a poorly-characterized G protein-coupled receptor, and provide strong preliminary data for future T2D drug development studies, leaving a high and long-lasting impact on the field.