GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells
Kimberley El, Sarah M. Gray, Megan E. Capozzi, Emily R. Knuth, Enyou Jin, Berit Svendsen, Alexis L. Clifford, Jennifer Brown, Sara E. Encisco, Bryanna M. Chazotte, Kyle W. Sloop, Derek J. Nunez, Matthew J. Merrins, David A. D’Alessio, Jonathan E. Campbell
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid-stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to β cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.