Journal
DIABETES
Volume 65, Issue 9, Pages 2711-2723Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db15-0629
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-098853, T32-DK-087703, DK-020595]
- Kovler Diabetes Center at the University of Chicago
- Center for Neuroanatomy with Neurotropic Viruses by National Center for Research Resources at Princeton University, Jefferson University [P40RR018604]
- University of Pittsburgh
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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.
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