SAT596 Evidence That Corticotropin-releasing Hormone Receptor 2 Activation Mediates Stress-induced Hyperglycemia

Abstract

Abstract Disclosure: R.B. McCosh: None. M.J. Kreisman: None. J. Jang: None. J. Jung: None. K.M. Breen Church: None. Stress-induced hyperglycemia refers to the transient increase in blood glucose (BG) levels during stress, which occurs in healthy and diabetic patients. In critically ill patients, stress-induced hyperglycemia is associated with a 2-fold increase in risk of incident diabetes. Thus, stress-induced hyperglycemia is a predictor of or may contribute to glucose dysregulation. In mice, activation of catecholamine neurons in the rostral ventral lateral medulla (rVLM) is necessary for stress-induced hyperglycemia; however, the mechanism by which these cells become activated during stress is not clear. Here, we tested the possibility that corticotropin-releasing hormone receptor 2 (CRHR2) signaling mediates stress-induced hyperglycemia in adult, ovariectomized mice. First, BG levels and rVLM cell activation were examined in two stress models. For psychosocial stress, BG levels were not altered by control treatment. In contrast, placement in a restraint device increased BG levels ∼2-fold, within 30 min, from pretreatment values and BG remained elevated for an additional 90 min. For immune stress, BG was significantly elevated (21% increase) at 30 min post IP injection of lipopolysaccharide (LPS, 10ng/g bw), then returned to baseline levels whereas BG levels were not altered from pretreatment levels in saline injected mice. In tissue collected 2 hr after initiation of restraint stress, the percentage of tyrosine hydroxylase (TH, marker of catecholamine cells) neurons in the rVLM that contained c-Fos (a marker of neural activation) was significantly greater than control mice. Next, we assessed the sufficiency of CRHR2 activation to induce hyperglycemia using the CRHR2 agonist urocortin 2 (UCN2), injected intracerebroventricular (ICV). BG was significantly increased 30 min after injection of both saline and UCN2 (60-80%); however, BG subsequently returned to baseline in saline-treated mice, but remained elevated in mice that received UCN2, similar to restraint stress. To test necessity of CRHR2 activation to induce hyperglycemia, we delivered ICV either the specific CRHR2 antagonist Astressin 2B (A2B) or saline 1 hr before psychosocial or immune stress. In no stress controls, A2B did not alter BG levels compared to saline, yet, BG levels in both groups decreased over time. BG levels were elevated in saline-treated controls 30 min after restraint stress; and, this increase was delayed, although not prevented, by 30 min by A2B pre-treatment. Following LPS injection, BG was increased at 30 min then decreased relative to baseline in saline-treated controls; yet, A2B pre-treatment blocked these changes. Together these data support the hypothesis that CRHR2 signaling is an important mediator of stress-induced hyperglycemia. Assessment of rVLM TH cells is ongoing. Presentation: Saturday, June 17, 2023