Age-Dependent Decline in the Coordinated [Ca²⁺] and Insulin Secretory Dynamics in Human Pancreatic Islets

Aging is associated with increased risk for type 2 diabetes, resulting from reduced insulin sensitivity and secretion. Reduced insulin secretion can result from reduced proliferative capacity and reduced islet function. Mechanisms underlying altered β-cell function in aging are poorly understood in mouse and human islets, and the impact of aging on intraislet communication has not been characterized. Here, we examine how β-cell [Ca²⁺] and electrical communication are impacted during aging in mouse and human islets. Islets from human donors and from mice were studied using [Ca²⁺] imaging, static and perifusion insulin secretion assays, and gap junction permeability measurements. In human islets, [Ca²⁺] dynamics were coordinated within distinct subregions of the islet, invariant with islet size. There was a marked decline in the coordination of [Ca²⁺] dynamics, gap junction coupling, and insulin secretion dynamics with age. These age-dependent declines were reversed by pharmacological gap junction activation. These results show that human islet function declines with aging, which can reduce insulin action and may contribute to increased risk of type 2 diabetes.