Optimal glucose control remains elusive for many patients with diabetes despite current therapies, necessitating the development of novel therapeutic modalities. While the central nervous system (CNS) plays a crucial role in glucose homeostasis, specific CNS targets for therapeutic intervention in diabetes have remained elusive. We recently demonstrated that the cholecystokinin b receptor (CCKbR)-expressing subpopulation of ventromedial hypothalamic nucleus (VMN; VMNCCKBR) neurons not only mediate the counter-regulatory response, but also elevate blood glucose by insulin-independently modulating hepatic glucose production under normal physiologic conditions. To test the potential therapeutic utility of these neurons for the treatment of diabetes, we cre-dependently expressed tetanus toxin in the VMN of Cckbrcre mice to silence VMNCCKBR neurons in streptozotocin (STZ)-induced (insulinopenic; Type 1 model) and leptin-deficient (ob/ob; obese Type 2 model) mice. While STZ-treated control mice became hyperglycemic and lost approximately 20% of their body weight over two weeks, VMNCCKBR-silenced mice were protected from these effects of STZ, despite similar hormone levels in STZ-treated control and CCKBRTTmice. Similarly, silencing of VMNCCKBR neurons in ob/ob mice normalized fasting and ad libitum-fed blood glucose despite identical food intake, body weight and body composition in control and VMNCCKBR-silenced mice. While VMNCCKBR-silenced ob/ob mice exhibited no alterations in glucose or insulin tolerance compared to controls, glucose clamps demonstrated decreased hepatic glucose output in the VMNCCKBR-silenced animals. These data suggest that VMNCCKBR neurons represent potential targets to reduce hepatic glucose production and ameliorate hyperglycemia in diabetes.
A. Affinati: Research Support; Self; Novo Nordisk Inc. J. Flak: None. N. Bozadjieva: None. N. Kodur: None. C.M. Cras-Méneur: None. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.
National Institutes of Health (5T32DK7245-42, 1F32DK122660-01)