Defining a novel neurocircuit for stress-induced hyperglycemia

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the Regents of the University of Michigan $129,306 on December 9, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to define a novel neurocircuit for stress-induced hyperglycemia.

The research investigates the neurobiological mechanisms underlying stress-induced hyperglycemia (SIH)—the rapid elevation of blood glucose in response to psychological or physical trauma. Excessive SIH occurs in approximately 50 percent of critically ill patients and increases mortality risk twofold compared to appropriate SIH responses. The project uses single-nucleus RNA sequencing and neural silencing models to characterize specialized neuron classes in the ventromedial nucleus of the hypothalamus (VMH) that control glucose mobilization during stress. Preliminary findings indicate that silencing ventromedial hypothalamus GLIPR1-expressing neurons attenuates the rise in glucose and corticosterone that accompanies restraint stress, suggesting these neurons mediate SIH specifically. The work aims to clarify optimal individual blood glucose levels and underlying SIH mechanisms to enable more effective, targeted treatments.

Performance occurs at the University of Michigan in Ann Arbor, Michigan, with an ultimate completion date of June 30, 2028. The award is classified as a Project Grant.

Abstract

In emergency situations, such as psychological or physical trauma, glucose is the body's preferred source of fuel. Thus, to adapt to the situation the brain orchestrates a rapid increase in blood glucose, termed "stress-induced hyperglycemia" (SIH). Although SIH is vital to meet the increased metabolic demand of the brain and peripheral tissues, however, excessive SIH (as occurs in 50% of critically ILL patients) increases mortality risk twofold compared to those with appropriate SIH. Since optimal individual blood glucose levels and the underlying mechanism of SH are unclear, treatments remain inadequate and limited. Therefore, to develop more effective and targeted treatment IT is critical to understand the mechanism that coordinates SIH. SIH is achieved through central nervous system mediated sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis activation which mediates release of epinephrine/norepinephrine and corticosterone to rapidly increase and sustain appropriately elevated blood glucose. The ventromedial nucleus of the hypothalamus (VMH) controls SIH in addition to several other glucose related functions. To determine whether specialized SIH-mediated neurocircuitry exists in the VMH, we performed single nucleus RNA sequencing and identified 6 novel classes of VMH neurons. Of these, class 1 is localized to the dorsomedial VMH, which controls glucose related functions. Class 1 can be further divided into neurons that express leptin receptor (vmhlepr) and neurons that express GLIPR1 (VMHGLIPR1) with little overlap. Vmhlepr neurons control energy expenditure, but not glucose mobilization. We thus predicted that VMHGLIPR1 neurons specifically mediated SIH. Indeed, our preliminary data indicate that silencing VMHGLIPR1 neurons attenuates the rise in glucose and corticosterone that normally accompanies restraint stress, a model for SIH, but not other glucose stimulating stressors such as hypoglycemia or fasting. Therefore, we hypothesize that VMHGLIPR1 neurons mobilize glucose in response to psychological stressors through HPA axis-mediated corticosterone secretion. To test this hypothesis, we will: (1) define the regulatory inputs and circuitry of VMHGLIPR1 neurons, (2) identify the neurocircuitry and hormones modulated by VMHGLIPR1 neuron activation, and (3) establish the mechanisms through which VMHGLIPR1 neurons mediate SIH. These studies will define the specialized neurocircuitry for SIH and set the stage for the development of targeted therapeutics for patients experiencing excessive SIH.