Emptying the Pool: Modular Insulin Secretion From the Pancreas

The fundamental model of glucose-stimulated insulin secretion has remained essentially unchanged for decades. Rising blood glucose is transported into pancreatic β-cells, where it is metabolized to generate ATP. The change in the ATP/ADP ratio closes membrane potassium channels and eventually triggers the action potential that drives calcium influx and exocytosis. Secreted insulin typically comes from a very small portion of the available secretory granules (<1%) (1,2). This has led to much speculation concerning the vast majority of dormant secretory granules known as the “reserve pool.” Does it participate in phasic insulin secretion (3,4)? Is the number of reserve pool granules regulated (5)? And perhaps most importantly, what is the relationship between the reserve capacity and diabetes (6)? That this large unsecreted pool of granules is truly held in reserve has not been a commonly challenged idea and is in fact a part of a core assumption about islets isolated for ex vivo experimentation: Islets are all more or less functionally identical and respond similarly to the environmental changes that regulate secretion. The insulin that is secreted in response to rising blood glucose levels, it is therefore thought, arrives from all islets with each islet secreting a tiny bit of insulin from just a handful of secretory granules at a time.It is curious then that the β-cells are organized …