Identification of VmnCckbr Neurons as Crucial Mediators of the Counterregulatory Response to Hypoglycemia

While the goal of diabetes treatment is normoglycemia, most therapeutics (especially insulin and insulin secretagogues) carry with them a significant risk of potentially life-threatening hypoglycemia; this risk increases with the intensity of therapy. While neurons of the ventromedial hypothalamic nucleus (VMN) play an essential role in the CRR, the VMN contains several populations of neurons that have distinct or even opposing effects, and the neurons that mediate the CRR have not previously been molecularly defined. Since we previously showed that cholecystokinin (CCK) neurotransmission plays an important role in the VMN-mediated CRR, we generated CCK receptor b (Cckbr)-cre mice to study the potential role of VMNCckbr neurons in the CRR. In addition to other expected brain areas that contain Cckbr neurons, CckbrCre reporter mice identified a substantial population of VMNCckbr neurons in the dorsomedial VMN. Consistent with a potential role in the CRR, VMNCckbr neurons project to regions that control sympathetic outflow, including the BST, PAG, and preoptic area. Furthermore, expression of tetanus toxin in VMNCckbr neurons to prevent their downstream neurotransmission reduces blood glucose at baseline and impairs the CRR to insulin-induced hypoglycemia and glucoprivation in both male and female mice. This effect is unique to silencing this discrete population of VMN cells; silencing all VMN neurons (SF1cre) does not alter the CRR, but instead results in obesity and hyperglycemia. Thus, VMNCckbr neurons play a crucial role in the CRR, and their dysfunction may underlie hypoglycemia associated autonomic failure. Disclosure J.N. Flak: None. A. Ansari: None. P. Sabatini: None. P.B. Goforth: None. C. Li: Employee; Self; Novo Nordisk Inc. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC. D. Olson: Research Support; Self; MedImmune, Novo Nordisk A/S. M.G. Myers: Research Support; Self; MedImmune, Novo Nordisk Inc.. Advisory Panel; Self; Merck & Co., Inc..