Seminars

Multiple endocrine cell types come together in pancreatic islets, supported by a constellation of ancillary cell types. Most of the attention field has understandably been directed at pancreatic beta cells, as the only source of insulin in our body and the only islet cells that cause endocrine disorders upon dysfunction. Too little insulin secretion relative to demand leads to nutrient excess and diabetes. Rarer cases of excess insulin release typically caused by monogenic defects can drive severe hyperinsulinemic hypoglycemia. While there are no disorders associated with primary failure of pancreatic alpha or delta cells, the glucagon and somatostatin they release locally modulates beta cell activity to match insulin need to the demands imposed by circulating nutrients. To aid in this task, each of the three main islet endocrine cells expresses a large and non-redundant repertoire of cell surface receptors. Disentangling the complex and indirect actions by which hormones, nutrients and neurotransmitters that act on the islet modulate insulin secretion can be complex. However, advances in functional imaging where distinct subsets of islet cells can be outfitted with genetically encoded biosensors to observe the kinetics of intracellular signaling directly now enable the direct observation of the site or sites of action integrated across multiple signaling cascades. Inevitably, our ability to observe functional responses across hundreds or thousands of individual cells across a population reveals considerable heterogeneity. Defining the relevance of this functional heterogeneity and how it changes in diabetes is one of the next challenges in our field.