Mechanisms of islet compensation for β-cell mass deficiency in diabetes

ABSTRACT Type 2 diabetes (T2D) is associated with insulin insufficiency. Increased glucagon secretion from pancreatic α-cells exacerbates hyperglycemia by increasing endogenous glucose production. However, a model in which hyperglucagonemia is completely maladaptive does not align well with recent observations indicating that α-cells boost the function of neighboring β-cells. These studies, which identify an insulinotropic role of glucagon under physiological conditions, raise the possibility that increased glucagon secretion mediates an adaptive response to the loss of functional β-cell mass in T2D. Consistent with this model, recent human studies suggest that α-cell signaling via β-cell G-protein coupled receptors (GPCRs) is accentuated in T2D—however these correlative studies do not test causality. To investigate how the loss of functional β-cell mass impacts islet cell crosstalk and glycemic control, we generated a novel strain of β-cell replication-deficient mice (hereafter, abbreviated ‘βRD’). Studies performed in vivo, and in isolated islets, suggest that increased glucagon release from α-cells is essential for the preservation of insulin secretion and organismal glycemia in βRD mice. Single-cell RNA sequencing (scRNAseq) of βRD islet cells indicates α-cell intrinsic reprogramming of metabolism and hormone secretion. Based on these findings, our central hypothesis is that α-cell hypersecretion is essential to preserve insulin secretion in response to β-cell mass deficiency. Testable predictions of this model include: increased glucagon secretion in βRD mice is insulinotropic; signaling through β-cell GLP1R and/or GCGR is essential for the observed β-cell adaptations in βRD mice; and that similar mechanisms occur in human islets with reduced β-cell mass. We will: (1) Determine the signaling mechanisms underlying β-cell compensation in a novel mouse model of β-cell replication deficiency, (2) Determine mechanisms of α-cell compensation in β-cell mass-deficient mouse islets, and finally, by transplanting human pseudoislets with controlled α:β ratios, we will test whether increased α-cell signaling can compensate for β-cell mass deficiency in vivo. Completion of these aims will test the concept of adaptive hyperglucagonemia in T2D. Whether or not this hypothesis proves correct, these studies will identify islet mechanisms of functional compensation for β-cell mass deficiency, elucidate α-cell signals that functionally rescue insulin secretion, and identify GPCR pathways for therapeutic targeting in diabetes.