The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic Arcuate (ARC), Ventromedial (VMN), and Lateral (LHA) areas significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase (GK). Then, experimentally lowering glucose-sensing specifically in the ARC resulted in glucose intolerance due to deficient insulin secretion, no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance, and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.
- Received May 13, 2015.
- Accepted April 6, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.