1254-P: ß-Cell Cdk1 Deletion Reveals a- and ß-Cell Compensatory Mechanisms for Hypoplasia

Diabetes is characterized by a loss of functional β-cell mass. With current rodent models of chemically-induced diabetes such as streptozotocin, it is difficult to distinguish the consequence of β-cell loss from the decline in individual β-cell function. Here, we generated a mouse model of severe β-cell mass loss by deleting β-cell CDK1 within the first week of life (Cdk1Ucn3Cre, Cdk1-floxed:Ucn3-Cre). At 4 weeks of age, islet mass in Cdk1Ucn3Cre islets is comparable to controls, although islet architecture is disrupted with α-cells having formed more heterotypic contacts with β-cells. By 12 weeks of age, Cdk1Ucn3Cre mice exhibit significantly reduced β-cell mass as well as α-cell mass, but maintain glucose tolerance and ex vivo insulin secretion in response to glucose, amino acids, and the gut incretin GIP. We therefore hypothesized that functional compensations in Cdk1Ucn3Cre islets arise from both β- and α-cells, which are insulinotropic in the fed state. Interestingly, α-cell glucagon secretion from Cdk1Ucn3Cre islets exhibits hypersensitivity to suppression by glucose, including when glucagonotropic amino acids are present. In parallel, we observed a reduction in amino acid-stimulated cAMP in β‑cells from Cdk1Ucn3Cre islets. We also found a left-shift in the glucose dependence of β-cell calcium oscillations in Cdk1Ucn3Cre islets, identifying β-cell recruitment as one mechanism offsetting the loss of α-cell paracrine signaling. Importantly, GIP elicited a much larger glucagon response from glucose- and amino-acid stimulated Cdk1Ucn3Cre islets, implying that α-cell compensation contributes significantly to the maintained insulin secretory output in vivo. In sum, the Cdk1Ucn3Cre model reveals the interdependence of α- and β-cell mass, and function, and will be useful to define the temporal sequence of islet compensation for chronic loss of β-cell mass under stressed conditions. Disclosure S. Sdao: None. M. Adams: None. H. R. Foster: None. B. Blum: None. M. J. Merrins: None.