Loss of glucose homeostasis during sepsis is associated with increased organ dysfunction and higher mortality. Novel therapeutic strategies to promote euglycemia in sepsis are needed. We have previously shown that early low-level intravenous (IV) dextrose suppresses pancreatic insulin secretion and induces insulin resistance in septic mice, resulting in profound hyperglycemia and worsened systemic inflammation. In this study, we hypothesized that administration of low-level dextrose via the enteral route would stimulate intestinal incretin hormone production, potentiate insulin secretion in a glucose-dependent manner, and thereby improve glycemic control in the acute phase of sepsis. We administered IV or enteral dextrose to 10-week-old male C57BL/6J mice exposed to bacterial endotoxin and measured incretin hormone release, glucose disposal, and proinflammatory cytokine production. Compared with IV administration, enteral dextrose increased circulating levels of the incretin hormone glucose-dependent insulinotropic peptide (GIP) associated with increased insulin release and insulin sensitivity, improved mean arterial pressure, and decreased proinflammatory cytokines in endotoxemic mice. Exogenous GIP rescued glucose metabolism, improved blood pressure, and increased insulin release in endotoxemic mice receiving IV dextrose, whereas pharmacologic inhibition of GIP signaling abrogated the beneficial effects of enteral dextrose. Thus, stimulation of endogenous GIP secretion by early enteral dextrose maintains glucose homeostasis and attenuates the systemic inflammatory response in endotoxemic mice and may provide a therapeutic target for improving glycemic control and clinical outcomes in patients with sepsis.

Rationale: Synthetic opioids like fentanyl are contributing to the rise in rates of opioid use disorder and drug overdose deaths. Sleep dysfunction and circadian rhythm disruption may worsen during opioid withdrawal and persist during abstinence. Severe and persistent sleep and circadian alterations are putative factors in opioid craving and relapse. However, very little is known about the impact of fentanyl on sleep architecture and sleep-wake cycles, particularly opioid withdrawal.Further, circadian rhythms regulate sleep-wake cycles, and the circadian transcription factor, neuronal PAS domain 2 (NPAS2) is involved in the modulation of sleep architecture and drug reward. Here, we investigate the role of NPAS2 in fentanyl-induced sleep alterations. Objectives:To determine the effect of fentanyl administration and withdrawal on sleep architecture, and the role of NPAS2 as a factor in fentanyl-induced sleep changes.Methods: Electroencephalography (EEG) and electromyography (EMG) was used to measure non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) at baseline and following acute and chronic fentanyl administration in wild-type and NPAS2-deficient male mice.Results: Acute and chronic administration of fentanyl led to increased wake and arousal in both wild-type and NPAS2-deficient mice, an effect that was more pronounced in NPAS2-deficient mice. Chronic fentanyl administration led to decreased NREMS, which persisted during withdrawal, progressively decreasing from day 1 to 4 of withdrawal. The impact of fentanyl on NREMS and arousal was more pronounced in NPAS2-deficient mice.Conclusions: Chronic fentanyl disrupts NREMS, leading to a progressive loss of NREMS during subsequent days of withdrawal. Loss of NPAS2 exacerbates the impact of fentanyl on sleep and wake, revealing a potential role for the circadian transcription factor in opioid-induced sleep changes.

Sepsis is characterized by a dysregulated immune response to infection. Nutrition is important in the care of septic patients, but the effects of specific nutrients on inflammation in sepsis are not well defined. Our prior work has shown benefits from early enteral dextrose infusion in a preclinical endotoxemia model of sepsis. In the current study, we extend our initial work to examine the effects of dextrose infusions, varying by route of administration, on inflammation and glycemic control in a more clinically relevant and translational model of Klebsiella pneumoniae (KP) bacteremia. Ten-week old C57BL6/J male mice (n = 31) underwent the implantation of indwelling vascular catheters, followed by inoculation with oropharyngeal KP. The mice were randomized 24 h after inoculation to (1) intravenous (IV) dextrose, (2) enteral dextrose, or (3) enteral saline (control) to study the effects on systemic inflammation, hemodynamics, and glycemic control. At 72 h, 77% of the control mice died, whereas IV dextrose induced 100% mortality, associated with increased inflammation, hyperglycemia, and hypotension. Enteral dextrose reduced mortality to 27%, promoted euglycemia, and reduced inflammation compared to IV dextrose. We conclude, in a bacteremic model of sepsis, that enteral (but not IV) dextrose administration is protective, suggesting that the route of nutrient support influences inflammation in sepsis.

Glucocorticoid signaling controls many key biological functions ranging from stress responses to affective states. The putative transcriptional coregulator CREB3 regulatory factor (CREBRF) reduces glucocorticoid receptor levels in vitro suggesting that CREBRF may impact behavioral and physiological outputs. In the present study, we examined adult male and female mice with global loss of CREBRF (CrebrfKO) for anxiety-like behaviors and circulating glucocorticoids in response to various acute stress conditions. Results demonstrate that both male and female CrebrfKO mice have preserved locomotor activity but reduced anxiety-like behaviors during the light-dark box and elevated plus maze. These behavioral phenotypes were associated with lower plasma corticosterone after restraint stress. Further studies using unhandled female mice also demonstrated a loss of the diurnal circulating corticosterone rhythm in CrebrfKO mice. These results suggest that CREBRF impacts anxiety-like behavior and circulating glucocorticoids in response to acute stressors and serves as a basis for future mechanistic studies to define the impact of CREBRF in glucocorticoid-associated behavioral and physiological responses.

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