Mark O. Huising

Proper control of glucose metabolism is essential to thrive. Consequently our bodies have evolved sophisticated and subtle yet remarkably effective ways to maintain tight blood glucose control over the course of many decades. Key to glucose homeostasis are the opposing actions of insulin, which promotes peripheral uptake of glucose, and glucagon, which is a signal to the liver to break down glycogen and release glucose. These hormones are made by beta and alpha cells, respectively, which co-localize in the islets of Langerhans to facilitate the coordinated regulation of their release. The islets also contain somatostatin-producing delta cells, which provide essential negative feedback to both alpha and beta cells. My group studies how the alpha, beta and delta cells within the islet communicate with each other and integrate signals from the central and peripheral nervous system, gastro-intestinal tract, liver, skeletal muscle and adipose tissue. We are only just starting to appreciate the depth and complexity of this intricate network, which contains potential therapeutic targets to treat or even cure diabetes.

One of the family of signals that the Huising lab studies, is named for the stress peptide Corticotropin Releasing Factor, or CRF in short. CRF was originally discovered as the principal hypothalamic factor to initiate the stress response by acting on the pituitary gland. It turns out that the insulin-producing beta cells of the pancreas can respond directly to CRF with increased insulin secretion, increased beta cell proliferation and reduced beta cell death in the face of pro-inflammatory insults, which is a promising set of beneficial characteristics united in a single molecule. Urocortin3 (Ucn3), a peptide related to CRF, is abundantly expressed by mature beta cells. We discovered that Ucn3 is co-released with insulin to trigger somatostatin release from neighboring delta cells, which in turn inhibits insulin secretion. In essence, Ucn3 triggers a negative feedback loop that attenuates insulin secretion, provided that glucose levels are successfully reduced. Ucn3 expression also distinguishes mature, functional beta cells from their immature progenitors, which is a trait that is particularly useful to track the differentiation of mature, glucose-responsive beta cells from embryonic or induced pluripotent stem cells. CRF and Ucn3 are just two examples of signaling molecules whose direct actions on the pancreas add a novel layer of complexity to the intricate network of signaling molecules that in concert governs beta cell mass and insulin and glucagon output of the pancreas. My group is focused on unraveling the contributions of these local pancreatic CRF family signaling cascades on glucose metabolism in healthy and diabetic individuals.