Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats

Abstract

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 μg·kg⁻¹·h⁻¹, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do₂) and consumption (V̇o₂) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do₂ all significantly decreased with trauma, but renal V̇o₂ was unchanged. GLP-1 treatment normalized RBF, GFR, and Do₂ without affecting V̇o₂. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

INTRODUCTION

Orthopedic trauma is one of the leading causes of morbidity and mortality in the United States each year, particularly in those under the age of 45 yr (14a). As compared with lean trauma patients, obese patients who experience severe trauma have a longer hospital stay, increased complications, a greater incidence of remote organ failure, and increased mortality (2, 3). Acute kidney injury (AKI) is one of the most frequently occurring components of multiple organ failure in obese trauma patients (11, 19) and is a major cause of chronic kidney disease and mortality (12, 24). However, there is a lack of early, prehospital treatment options after severe trauma to prevent the development of AKI.

Correlation between hyperglycemia and mortality is more pronounced in trauma patients than in other critically ill patients (18, 26, 35, 36). In obese patients, impaired glucose homeostasis after trauma is a better predictor of poor outcomes than increased body mass index (22, 26). We have previously found that either hemorrhage or orthopedic trauma induces a prompt and prolonged hyperglycemic response in obese rats, with this early posttrauma hyperglycemia (EPTH) associated with exacerbated inflammation, oxidative stress, lung injury, and mortality within 24 h (39, 40). There is evidence that suppressing hepatic glycogenolysis with β₂-adrenergic blockade before trauma decreased the EPTH and improved systemic inflammation and lung function (40). Unfortunately, this prophylactic therapy lacks clinical relevance because it has no effect on glucose uptake and must be administered before EPTH occurs.

Finding an effective (fast-acting) and safe (no risk of hypoglycemia) treatment for EPTH in prehospital settings is challenging (4), especially in the context of baseline insulin resistance, which is frequently seen in obese patients. Under physiological conditions, glucagon-like peptide-1 (GLP-1) is released from the intestine in response to hyperglycemia to suppress glucagon and facilitate insulin secretion in a glucose-dependent manner (10, 31). These glucose-lowering effects are diminished when glucose levels are normal, making it an attractive therapy with minimal safety concerns. Additionally, several GLP-1 receptor agonists have been approved by the United States Food and Drug Administration as second-line antidiabetic drugs. Therefore, the current study was designed to evaluate effects of GLP-1 on the EPTH in an animal model of obesity and insulin resistance.

Trauma-induced AKI is strongly correlated with morbidity and mortality (14). We have established an animal model of trauma-induced AKI by using obese Zucker rats, as evidenced by impaired renal blood blow (RBF) and glomerular filtration rate (GFR) within 24 h after orthopedic trauma (20, 21). The AKI model also exhibits increases in kidney injury molecule-1, albumin excretion, and systemic and renal inflammation and oxidative stress (20, 21). However, the renal function was not significantly altered in the lean Zucker rats within 24 h after the orthopedic trauma (20, 21). Additionally, we found EPTH in obese Zucker rats, associated with exacerbated inflammation and oxidative stress, whereas in the lean rats there was only a mild and transient increase in glucose levels after trauma (40). Therefore, in the current study, we used obese Zucker rats and tested the hypothesis that early treatment of GLP-1 can effectively and safely control EPTH and decrease the incidence of AKI.

METHODS

Animals

Male obese Zucker rats (12–14 wk old) were acquired from Harlan Laboratories (Indianapolis, IN). The obese Zucker rat is a widely used model of obesity and insulin resistance induced by a leptin receptor mutation. The animals were housed 2–3 per cage at 22°C, exposed to a 12-h light-dark cycle, and fed standard rat chow (Teklad, Harlan Laboratories). All protocols were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center and followed the guidelines set forth in the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Animal Groups and Procedures

Rats were anesthetized by inhalation of isoflurane (4–6%) mixed with 100% oxygen. Polyethylene catheters (Intramedic PE-50 tubing, BD, Franklin Lakes, NJ) were surgically inserted into the right common carotid artery for the measurement of blood pressure, the left internal jugular vein for the infusions, and the right femoral artery for the measurement of GFR via the inulin clearance method (see Glomerular filtration rate). After these surgical procedures, a small dose (~0.1 ml) of 0.25% bupivacaine (APP Pharmaceuticals, Schaumburg, IL) was injected locally to provide analgesia and reduce stress from the procedure. The animals regained consciousness quickly and did not show signs of stress after these operations.

After 4 h of recovery and fasting with free access to water, rats were randomly divided into three groups: control, orthopedic trauma (OT), and orthopedic trauma treated with GLP-1 (OT-GLP). Control rats underwent all other procedures (e.g., anesthesia, catheterization surgery, metabolic cage, etc.) but no orthopedic trauma. Orthopedic trauma was induced as previously described by our laboratory (39, 40). Briefly, animals were anesthetized with isoflurane (4–6% via inhalation), and the retrofemoral soft tissue was clamped bilaterally for 30 s with an angled Kelly clamp (19 cm) to induce soft tissue injury. With the use of a 15-gauge needle, both the right and left fibulas were fractured, and 1.5 ml of homogenized bone components (2 g bone/5 ml PBS) were then injected bilaterally into the area of the injured tissue. The bones used for the bone component injection were collected from previously euthanized obese rats. To provide analgesia, buprenorphine was injected subcutaneously (0.01 mg/kg) directly before the trauma and every 8–12 h after the trauma at a dose of 0.05 mg/kg. After the brief period of anesthesia (< 5 min), rats regained consciousness and were able to ambulate.

Acute Hyperglycemic Response and Effect of GLP-1 After Trauma

After the trauma, rats were housed individually and quietly with access to water but no food. GLP-1 (OT-GLP, n = 7 rats) or vehicle 0.9% saline (OT, n = 6 rats) was continuously infused through the jugular catheter at a rate of 3 μg·kg·⁻¹·h⁻¹ from 30 to 300 min after trauma. Blood glucose was measured immediately before trauma and at 15, 30, 60, 120, 180, 240, and 300 min after trauma in conscious animals. Blood was sampled from the tail tips pretreated with 0.25% bupivacaine and glucose levels were measured using a glucometer (On Call Plus, ACON Laboratories, San Diego, CA). Throughout the 4.5 h of infusion, the total volume the rats received was ~1.5 ml/kg.

Measurements One Day After Trauma

Total urine sodium excretion.

After the glucose measurements and the GLP-1 or saline infusion was stopped, the OT and OT-GLP rats were placed in metabolic cages (Laboratory Products, Seaford, DE) with free access to food and water. An additional group of rats without trauma or GLP-1 treatment (n = 8) were placed in the metabolic cages as control. One day after trauma, urine volume and sodium concentration were recorded. Urine flow was calculated as urine volume divided by collection time. Total urine sodium excretion was calculated by multiplying urine flow rate by urine sodium concentration.

Renal oxygenation.

One day (20–22 h) after trauma, the rats from control, OT, and OT-GLP groups were removed from the metabolic cages and anesthetized with pentobarbital sodium (50 mg/kg ip). Body temperature was maintained with a heating pad. The carotid catheter was used to monitor mean arterial pressure (MAP) and heart rate (model ML118, PowerLab software, ADInstruments, Colorado Springs, CO). After a midline incision (~2 cm) on the abdomen, the left renal artery was isolated and RBF was measured using a transonic flow probe (Transonic Systems, Ithaca, NY). After 30–45 min of equilibration, RBF was recorded and renal vascular resistance (RVR) was calculated by MAP/RBF. Blood samples (~0.2 ml) were then collected through the renal vein and the carotid catheter using a 1-ml syringe with a 23-gauge needle to measure blood gases (ABL80 FLEX, Radiometer, Brea, CA). At the end of the experiment, the left kidney was removed and weighed, and then rats were euthanized with an overdose of isoflurane followed by exsanguination. The arterial and venous oxygen content ($\text{C}{\text{a}}_{\text{O}}{}_{{}_2}$ and $\text{C}{\text{v}}_{\text{O}}{}_{{}_2}$, ml O₂/100 ml), renal oxygen delivery (Do₂, ml·min⁻¹·g⁻¹), and renal oxygen consumption (V̇o₂, ml·min⁻¹·g⁻¹) were derived using the following formulas:

$$\begin{array}{l}\text{C}{x}_{\text{O}}{}_{{}_{\text{2}}}=\text{hemoglobin}\times 1.36\times \text{oxygen}\text{\hspace{0.17em}saturation}\\ \hspace{1em}\hspace{1em}\hspace{1em}\hspace{0.17em}+0.0031\times \text{partial}\text{\hspace{0.17em}pressure\hspace{0.17em}of\hspace{0.17em}oxygen,}\end{array}$$

where x denotes either arterial or venous content.

$${\text{D}\text{O}}_{\text{2}}\text{=}\text{RBF}\text{×}\text{arterial\hspace{0.17em}oxygen\hspace{0.17em}content/100\hspace{0.17em}g}$$

$$\begin{array}{l}\dot{\mathrm{V}}{\text{o}}_{\text{2}}\text{=}\text{RBF}\text{×}\left(\text{arterial\hspace{0.17em}oxygen\hspace{0.17em}content\hspace{0.17em}–\hspace{0.17em}venous\hspace{0.17em}oxygen\hspace{0.17em}content}\right)/\\ \hspace{1em}\hspace{1em}\hspace{0.17em}\hspace{0.17em}\hspace{0.17em}\text{100\hspace{0.17em}g}\end{array}$$

Plasma interleukin-6 and sodium concentration.

Because of the possible effect of anesthesia on interleukin-6 (IL-6) levels or sodium concentrations, blood samples were taken from conscious rats by decapitation one day after trauma in separate experiments. Plasma and urine sodium concentrations were determined with ion selective electrodes (Nova Biomedical, Waltham, MA). IL-6 levels were measured by ELISA (R&D Systems, Minneapolis, MN).

Glomerular filtration rate.

Because of the infusion of radioactive substances required for the renal function measurement and the different techniques required for data collection, the same animals could not be used for GFR (in ml·min⁻¹·g kidney wt⁻¹) measurements. Therefore, GFR was measured in separate groups of animals (n = 6 for control, n = 5 for OT, and n = 6 for OT-GLP) using a scintillation counter (LS 6500, Beckman Coulter, Brea, CA) to determine levels of infused tritiated inulin (3H; Perkin-Elmer Health Sciences, Shelton, CT) as previously described (20, 21). At the end of the experiments, rats were euthanized by an overdose of isoflurane followed by exsanguination. The kidneys were then immediately removed and weighed.

Statistical Analysis

Data were analyzed using SPSS statistical software (version 12, Systat Software, San Jose, CA), with groups being compared using one-way ANOVA. The glucose levels were compared with two-way repeated measures ANOVA. Where significant effects were found, Holm-Sidak post hoc tests were performed. All data are presented as means ± SE, and the critical value of P < 0.05 (two-sided) was considered statistically significant.

RESULTS

Baseline blood glucose levels were similar between groups (Fig. 1). Trauma resulted in a prompt (within 15 min) increase in glucose levels in both groups. Blood glucose remained elevated in OT animals throughout the 5-h observation period but was significantly decreased toward normal in the OT-GLP group (Fig. 1). Significant differences in glucose levels between the saline- and GLP-1-treated animals were observed starting at 120 min after trauma.

Fig. 1.

Change in blood glucose levels over 5 h in orthopedic trauma (OT) animals treated with a 4.5-h infusion of glucagon-like peptide-1 (GLP) (OT-GLP) or vehicle (0.9% saline). *P < 0.05 vs. baseline (B) with each group, +P < 0.01 OT vs. OT-GLP; two-way repeated measures ANOVA, n = 6 rats for OT, n = 7 for OT-GLP.

One day after trauma, plasma IL-6 was markedly elevated in the OT group, as compared with the control group, and was significantly decreased with GLP treatment (Fig. 2A). Plasma sodium concentration was decreased in trauma rats but was normalized with GLP-1 treatment (Fig. 2B). The urine sodium concentration and urine sodium excretion (Fig. 3, A and B) were decreased, as compared with control rats. GLP-1 treatment did not alter the urine in the trauma rats but significantly increased urine sodium concentration and sodium excretion compared with OT animals.

Fig. 2.

A: plasma interleukin-6 (IL-6) levels in control and orthopedic trauma (OT) rats with or without glucagon-like peptide-1 treatment (GLP). *P = 0.001 OT vs. control; +P = 0.001 OT vs. orthopedic trauma group treated with GLP-1 (OT-GLP); one-way ANOVA, n = 6 for each group. B: plasma sodium concentration. *P < 0.01 OT vs. control, +P < 0.01 OT vs. OT-GLP; n = 7 for control and OT; one-way ANOVA, n = 9 rats for OT-GLP.

Fig. 3.

A: urine sodium concentration. B: sodium excretion rate. *P < 0.01 orthopedic trauma group (OT) or OT group treated with glucagon-like peptide-1 (GLP) vs. control, +P = 0.04 OT vs. OT-GLP; one-way ANOVA, n = 8 rats for control, n = 6 rats for OT, n = 7 rats for OT-GLP.

One day after trauma, the OT group exhibited a fall in MAP without a significant change in heart rate, as compared to before trauma. In OT-GLP animals, MAP was unchanged, but there was significantly increased heart rate compared with the control animals (Fig. 4, A and B). RBF and GFR were significantly decreased in OT animals but remained unchanged in the OT-GLP group compared with the control animals (Fig. 5, A and B). RVR was not different among groups (Fig. 5C). Compared with the control group, renal Do₂ was decreased in OT but was normalized in OT-GLP animals (Fig. 6A). Neither trauma nor GLP-1 treatment significantly affected renal V̇o₂ (Fig. 6B). Additional information on body weight, food intake, and urine flow rate can be found in Supplemental Table S1, available online at https://doi.org/10.5281/zenodo.2575609.

Fig. 4.

Mean blood pressure (A) and heart rate (B) in control and orthopedic trauma (OT) rats with or without glucagon-like peptide-1 (GLP) treatment. *P < 0.05 OT or OT group treated with GLP-1 (OT-GLP) vs. control; one-way ANOVA, n = 8 rats for control, n = 6 rats for OT, n = 5 rats for OT-GLP.

Fig. 5.

Renal hemodynamics in control and orthopedic trauma (OT) rats with or without glucagon-like peptide-1 (GLP-1) treatment. Effect of GLP on renal blood flow (RBF, A), glomerular filtration rate (GFR, B), and renal vascular resistance (RVR, C) is shown. *P = 0.013 OT vs. control, +P = 0.045 OT vs. OT group treated with GLP-1 (OT-GLP); one-way ANOVA, n = 8 rats for control, n = 6 rats for OT, n = 5 rats for OT-GLP.

Fig. 6.

Renal oxygen delivery (A) and renal oxygen consumption (B) in control and orthopedic trauma (OT) rats with or without glucagon-like peptide-1 (GLP) treatment. *P < 0.01 OT vs. control, +P < 0.05 OT vs. OT group treated with GLP-1 (OT-GLP); n = 8 rats for OC, n = 6 rats for OT; one-way ANOVA, n = 5 rats for OT-GLP.

DISCUSSION

There are three major findings of the current study. First, obese rats exhibited EPTH and increased AKI after trauma, as evidenced by impaired renal hemodynamics and oxygenation. Second, GLP-1 infusion after trauma in obese rats normalized the EPTH without causing hypoglycemia. Third, one day after trauma, GLP-1-treated obese trauma rats exhibited normal renal hemodynamics and oxygenation.

Early glucose control during hospital and intensive care unit care has been emphasized in trauma patients, as early hyperglycemia was found to have a strong relationship with organ (e.g., kidney and lung) failure and mortality (36). Interestingly, a better predictor of adverse outcomes in obese patients after trauma is EPTH and not body mass index or dyslipidemia (22, 26). We have shown that inhibition of EPTH in obese rats decreased systemic inflammation and acute lung injury that occurred one day after trauma (40). In the current study, obese rats exhibited a dramatic increase in plasma IL-6 one day after trauma, similar to our previous reports (20, 21, 39, 40), and was decreased after early GLP-1 treatment. Circulating IL-6 levels had been shown to strongly correlate with systemic inflammatory response syndrome and organ injury after trauma (12, 26). We also found that early control of EPTH led to improved renal function and oxygenation one day after trauma. However, our preliminary data show that GFR was not altered within the first 6 h (see Supplemental Figure S3, available online at https://doi.org/10.5281/zenodo.2575609) after trauma in the obese rats when the EPTH was present. The underlying mechanisms by which EPTH causes later AKI and inflammation are unclear. We have previously shown that EPTH-stimulated reactive oxygen species (40) may facilitate innate immune responses that play prominent roles in systemic inflammation and organ failure after trauma (15, 17, 23, 41). In fact, we have also shown that antioxidant treatment ameliorates the trauma-induced inflammation and AKI in the obese rats (21). Additionally, GLP-1 has been shown to have direct anti-inflammatory or immunomodulatory effects, which may interfere with the early innate immune response after trauma (13, 16). Although the mechanisms are unclear, these results emphasize the importance of early glucose control during the prehospital care of trauma patients.

Acute glucose control with exogenous insulin after trauma could be challenging in the presence of insulin resistance. We have previously demonstrated that increased sympathetic outflow after trauma and the resultant hepatic β₂-adrenoreceptor-mediated glycogenolysis play an important role in EPTH, and blockade of this pathway ameliorates the inflammatory response and organ damage in obese rats (40). However, this treatment lacks clinical relevance because it has no effect on glucose uptake and it must be administered before EPTH occurs. As an incretin, GLP-1 inhibits glucagon secretion at glucose levels above fasting levels and facilitates insulin release in a glucose-dependent manner (10, 31), which means these glucose-lowering effects are profound when hyperglycemia is present but diminished when glucose is normalized. We have previously shown that trauma only induced a mild (up to 160 mg/dl) and transient increase in glucose levels (40), and continuous infusion of GLP-1 resulted in a normalization of glucose levels without causing hypoglycemia (Fig. 1). Thus, GLP-1 may be suitable for the control of EPTH in trauma patients during prehospital care, when accurate glucose readings and appropriate insulin doses may be difficult, especially in insulin-resistant patients. Notably, GLP-1 secretion may be reduced in overweight individuals, prediabetics, or type 2 diabetics. However, it is unlikely the case with presence of orthopedic trauma because obese rats exhibited much higher levels of EPTH than the posttrauma glucose response in lean rats (1). In addition to the insulinotropic effect of GLP-1, insulin secretion is regulated by multiple mechanisms, such as the autonomic nerve system. The increased sympathetic activity in response to trauma may suppress insulin release and override the insulinotropic effect of endogenous GLP-1 despite an increase in the stress glucose (1, 2). Therefore, after trauma, exogenous GLP-1 may be specifically important because it safely improves insulin sensitivity and restores the glucose-dependent insulin release.

Our previous studies have already shown that trauma induces AKI in obese Zucker rats but not in lean rats (20, 21). The AKI is mainly supported by decreases in GFR and RBF, with additional evidence such as increases in urine albumin excretion, tubular injury markers, plasma creatinine, and systemic/renal inflammation and oxidative stress (20, 21). In clinical practice, the diagnosis of AKI is traditionally based on GFR evidenced by a rise in serum creatinine. Therefore, the current study determines the beneficial effect of GLP-1 mainly based on the changes in GFR, the hallmark of renal function. According to the Kidney Disease Improving Global Outcomes (KDIGO), the most recent AKI definition and classification, AKI is diagnosed if serum creatinine rises to at least 1.5-fold from baseline within 7 days (17a). In the current study, we found that GFR decreased by 50% one day after trauma along with decreased urine sodium concentration. GLP-1 treatment normalized the renal hemodynamics and improved urine concentration in obese rats. Preliminary data show that early GLP-1 treatment after trauma did not affect the GFR in the lean rat (see Supplemental Figure S2, available online at https://doi.org/10.5281/zenodo.2575609). These results provide significant evidence in support of our hypothesis. Similar to previous studies, we also found that obese rats exhibited decreased MAP one day after trauma, which may be due to a loss of peripheral arteriolar tone (37, 38). Although the mechanism is unclear, the decreased blood pressure was still within autoregulation range and unlikely responsible for the altered renal hemodynamics. We found that RBF and GFR were decreased with no change in RVR in the obese trauma rats, raising a possibility of a blunted tubuloglomerular feedback (32). In the OT-GLP group, RVR and MAP were not statistically altered one day after trauma compared with control animals.

Impaired renal oxygenation is a pivotal factor in the pathogenesis of other AKI models (e.g., sepsis and ischemia-reperfusion) and chronic kidney diseases (9, 25, 33, 42). Thus, the current study determined renal oxygenation to further characterize the trauma-related AKI model and understand the potential benefit of GLP-1. To our knowledge, this is the first study measuring renal oxygenation after trauma (Fig. 6, A and B). The decreased renal Do₂ with unchanged renal V̇o₂ in the OT group (Fig. 5) suggests an increase in renal oxygen extraction, a clinical marker of intrarenal injury (27). Under physiological conditions, total renal sodium reabsorption is correlated with filtered sodium, which is determined by GFR and plasma sodium concentration. Similarly, renal V̇o₂ is closely correlated with GFR and sodium reabsorption and is RBF-dependent (27). In the current study, GFR and plasma sodium concentration were both significantly decreased after trauma, suggesting a decrease in sodium reabsorption. However, the suppressed GFR failed to reduce renal V̇o₂, raising the possibility of a leftward shift of the GFR-to-V̇o₂ relationship after trauma, similar to clinical reports of AKI (27, 28).

Based on the levels of GFR, plasma sodium concentration, and renal V̇o₂, the decrease in sodium excretion after trauma was likely secondary to a decrease in sodium filtration rather than an increase in the total renal sodium reabsorption. However, despite the low plasma sodium concentration and unchanged renal V̇o₂, we found a fivefold increase in aldosterone levels in the obese rats one day after trauma (see Supplemental Figure S4, available online at https://doi.org/10.5281/zenodo.2575609). Although the mechanism is unclear, the hyponatremia along with “aldosterone resistance” in obese trauma rats might further indicate an impaired renal function. Relative to saline treatment (OT), GLP-1 treatment was associated with normalized GFR and plasma sodium concentration, suggesting that the total sodium reabsorption was restored without signs of AKI. Notably, GLP-1 has been shown to directly increase renal blood flow and diuresis (1, 5, 29, 30, 34, 43). Therefore, GLP-1 may acutely improve renal hemodynamics and oxygenation and warrant consideration in future studies if using GLP-1 analogs with a longer half-life. Meanwhile, it should also be recognized that high levels of GLP-1 may impair water/electrolyte balance, and clinical evidence indicates that a long-term treatment with GLP-1 actually increases the risk of AKI (8).

Perspectives and Significance

EPTH (in obese rats) was correlated with increased inflammation and AKI. One day after orthopedic trauma, this AKI was characterized by decreased GFR and RBF, as well as impaired renal oxygenation and increased inflammation. GLP-1 treatment after the trauma normalized EPTH to steady levels within 30 min after starting treatment, and continuous infusion in the hours following did not decrease glucose levels further. Inflammation was reduced and renal function was completely restored with GLP-1 treatment. This study advances the understanding of trauma-induced AKI and demonstrates a novel treatment option for insulin-resistant trauma patients. Aside from renal protection, it is likely that this treatment may have other beneficial effects, such as preventing systemic inflammation and acute lung injury (40), which can be validated in future animal studies and potentially applied in the clinical setting. Future studies will be needed to determine the effect of longer-acting GLP-1 analogs and evaluate other posttrauma outcomes with these treatments.

GRANTS

This work was supported by the American Heart Association (AHA) Grants 12SDG12050525, 14PRE17810005, and 17POST33661071 and National Institutes of Health Grants P20GM104357, HL51971, HL89581, and T32-HL105324.

DISCLAIMERS

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.X. conceived and designed research; L.X., M.S.T., P.N.M., and T.K. performed experiments; L.X., M.S.T., and J.S.C. analyzed data; L.X. interpreted results of experiments; L.X. prepared figures; L.X. and J.S.C. drafted manuscript; L.X., M.S.T., J.S.C., P.N.M., T.K., and R.L.H. approved final version of manuscript; J.S.C., P.N.M., and R.L.H. edited and revised manuscript.