Islet ultrastructure: past achievements and future directions

Islets of Langerhans constitute the endocrine component of the pancreas and comprise the main cell types responsible for the regulation of glucose homeostasis. Beta cells produce and secrete insulin, the principal hormone capable of lowering blood glucose. However, the interplay of beta cells with other endocrine cell types, such as alpha cells and delta cells, is critical for proper blood glucose regulation. The failure of beta cells to produce sufficient amounts of insulin leads to diabetes, a major metabolic disease. Since their discovery by Paul Langerhans using a simple light microscope in 1869, islets have been imaged using many different modalities. From the middle of the 20th century, electron microscopy has been a key tool in resolving the ultrastructure of islet cells, thereby making important contributions to the understanding of protein trafficking in general, and islet cell function as well as dysfunction in diabetes. Recent advances in microscopy techniques as well as the broader availability of analysis tools have elevated islet imaging from two dimensions into three dimensions and enable nanoscale imaging within the tissue context. Here, we review work on islet ultrastructure, from landmark studies published in the 1960s and 1970s to recent advances in imaging. Finally, we discuss open questions and propose ideas for integrating different modalities into structural imaging with the goal of better understanding islet function and dysfunction.