title: Resveratrol ameliorates mitochondrial dysfunction but increases the risk of hypoglycemia following hemorrhagic shock.
abstract: BACKGROUND
  Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.
  
  
  METHODS
  With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.
  
  
  RESULTS
  RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.
  
  
  CONCLUSIONS
  Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.
authors.affiliation: From the Department of Critical Care Medicine (H.W.), Qilu Hospital of Shandong University, Jinan, China; The Trauma Center at Penn (H.W., Y.G., P.M.R., C.A.S.), University of Pennsylvania, Philadelphia, Pennsylvania; The Center for Resuscitation Science (Y.G., L.B.B., C.A.S.), University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism and Department of Physiology (A.L.W., J.A.B., C.A.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Science, Systems and Models (A.L.W.), Roskilde University, Roskilde, Denmark; Department of Emergency Medicine (L.B.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Biochemistry and Molecular Biophysics Graduate Group (C.A.S.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Guan
authors.forename: Anne Lykkegaard
authors.initials: AL
authors.lastname: Widlund
authors.forename: Lance B
authors.initials: LB
authors.lastname: Becker
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Reilly
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Sims
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007003:Hypoglycemia / Q000139:chemically induced* / Q000209:etiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D012151:Resuscitation / Q000379:methods*; D000077185:Resveratrol; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D013267:Stilbenes; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077185:Resveratrol; D003345:Corticosterone