The Brain–to–Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions

Abstract

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 that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and 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 that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.

Cystic Fibrosis and the Nervous System

“…65 Decreased neuronal glucosesensing in specific subregions of the hypothalamus induces glucose intolerance and deficient insulin secretion. 118 Thus, it is possible that defects in the neural mechanisms governing endocrine pancreatic function and glucose regulation contribute to CFRD.…”

Orphaned No More? Glucose-Sensing Hypothalamic Neurons Control Insulin Secretion

“…Nevertheless, the mechanisms by which brain glucosesensing neurons regulate glucose homeostasis have remained unclear. This question is robustly addressed by the study by Rosario et al (13) in this issue of Diabetes. Using elegant improved retrograde pseudorabies viral (PRV) techniques, these investigators traced the connectivity from the brain to the pancreas to b-cells, using an inducible mouse insulin promoter Cre-recombinase construct.…”

“…As with all good studies, the study by Rosario et al (13) should stimulate many further studies. For example, it will be of great interest to assess which subset of hypothalamic neurons mediates the effects of HK1 on insulin secretion.…”

“…To address the functional significance of this pathway, Rosario et al (13) assessed the effect of overexpressing hexokinase I (HK1) in hypothalamic neurons on pancreatic function. A similar manipulation in b-cells basically mimics the effects of glucose, enhancing basal insulin secretion but not glucose-stimulated insulin secretion, although overexpression of HK1 enhanced insulin secretion relative to controls even in the stimulated state (14).…”

Neuro-Insular Complexes in the Human Pancreas

“…Since the classical study by Claude Bernard, which showed that an injury to the floor of the fourth cerebral ventricle caused hyperglycemia, the involvement of the nervous system in the regulation of pancreatic endocrine function and metabolic control has been shown in many studies [17][18][19]. At the same time, the precise innervation patterns of islets were unknown, particularly in humans [9].…”