title: How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines.
abstract: BACKGROUND
  Recent investigations have revealed that control of hyperglycaemia with insulin improves outcomes. The cornerstone of hyperglycaemia in critically ill patients is insulin resistance and it remains refractory to intensive insulin protocols. We designed this study to evaluate the efficacy and safety of a new intensive insulin therapy (IIT) protocol combined with metformin.
  
  
  METHODS
  Twenty-one patients with systemic inflammatory response syndrome and a blood glucose level of >120 mg/dl admitted to an intensive care unit (ICU) were randomised to receive either intravenous infusion of IIT alone (n=11) or combined with metformin (IIT+MET; n=10) to maintain a blood glucose level (BGL) of 80-120 mg/dl. Blood samples were obtained at baseline and at 48 hours, 96 hours and 7 days after initiation of the study. Samples were analysed for interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) as inflammatory mediators; plasminogen activation inhibitor-1 (PAI-1) as a coagulation mediator; and thiobarbituric reactive substances (TBARS), total antioxidant power (TAP) and total thiol molecules (TTM) as oxidative stress parameters.
  
  
  RESULTS
  The addition of metformin to the IIT protocol decreased insulin requirement and concentration of insulin and C-peptide. With both treatments at most time points, the mean plasma levels of IL-6, TNF-alpha, NO, PAI-1 and TBARS were found to be significantly lower compared with baseline. Antioxidant activity was increased in both arms with increasing TAP and TTM (P<0.05). There was no significant difference between the two groups regarding reported beneficial effects on these parameters. Therapeutic Intervention Scoring System-28 (TISS-28) score, an index of nursing workload and number of therapeutic interventions, decreased in the IIT+MET group (P<0.01). We did not observe any occurrence of hyperlactataemia or acidosis in the IIT+MET group.
  
  
  CONCLUSIONS
  Metformin plus insulin appears to lower the incidence of insulin resistance, lower insulin requirement while maintaining blood glucose level control, and consequently lower the incidence of adverse effects related to high-dose insulin therapy, particularly hypoglycaemia, and also declined nursing workload. Both treatment protocols showed improvements in inflammatory cytokine levels. Further studies with larger sample sizes are warranted to determine the undiscovered facts of insulin-sensitising agents in critically ill patients.
authors.affiliation: Faculty of Pharmacy, and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ghazal
authors.initials: G
authors.lastname: Ansari
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Mojtahedzadeh
authors.forename: Farshad
authors.initials: F
authors.lastname: Kajbaf
authors.forename: Atabak
authors.initials: A
authors.lastname: Najafi
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Khajavi
authors.forename: Hossein
authors.initials: H
authors.lastname: Khalili
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Rouini
authors.forename: Hadi
authors.initials: H
authors.lastname: Ahmadi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdollahi
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis*; D002096:C-Peptide / Q000378:metabolism; D002985:Clinical Protocols; D016207:Cytokines / Q000378:metabolism*; D004359:Drug Therapy, Combination; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D007362:Intensive Care Units; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D009569:Nitric Oxide; D008687:Metformin