Role of Preoperative Carbohydrates Drinks, Dichloroacetate and Exercise on Postoperative Muscle Insulin Resistance

Forty patients undergoing open elective gastrointestinal surgery, will be randomized to four groups of 10 each. The patients will be randomised to receive either preoperative (1) oral carbohydrate drinks (CHO) or (2) infusion of Dichloroacetate with oral carbohydrate drinks (3) exercise or (4) standard care.

Since the interventions are qualitatively different and only the physiological mechanisms are being studied rather than the clinical outcomes, the study is not blinded and no placebo is used.

Analysis for cytokines, insulin, glucagon levels will be performed at screening, during surgery and on the 2nd postoperative day. Muscle biopsies will be taken at the beginning and end of surgery, from rectus abdominus and vastus lateralis muscles for analysis of mRNA (IL-6, TNF-α, Akt1, IRS-1, FOXO1, MAFbx, MURF1 and PDK4) and protein (MafBx, FOXO1, PDK4) expression and muscle metabolites (glycogen, lactate, triglycerides and FFA). Oral Glucose Tolerance Test (GTT) to be performed at the screening visit and on the 2nd postoperative day using a standard protocol. The techniques to be employed to study the above will include RT-PCR, radioimmunoassay, spectophotometry, bioluminometry, Western blotting and ELISA.

Primary outcome: The changes in indices of muscle insulin resistance and muscle protein breakdown at the beginning and at the end of surgery, in response to surgical stress.

Secondary outcomes: (a) The expression of muscle metabolites, reflecting muscle protein turnover (b) Clinical Outcomes: Length of stay and incidence of postoperative complications.

• Dichloroacetate (Drug), also known as sodium dichloroacetate: Dichloroacetate, an analog of acetic acid has been shown to increase the activation of PDC by inhibiting PDK4 in humans. This drug is expected to shift the metabolism of pyruvate from glycolysis and towards oxidative pathway in the mitochondria
• Carbohydrate drinks (Dietary supplement): preoperative carbohydrate drinks
• Moderate intensity exercise (Behavioral): 30 min exercise using a semi-recumbent exercise bike, at about 70% of their age estimated heart rate

Primary outcomes

• insulin resistance [48 hours after surgery]: Relative changes in indices of muscle insulin resistance namely PDC activity, PDK4 mRNA and protein expression.

Secondary outcomes

• muscle carbohydrate oxidation [48 hours after surgery]: Changes in muscle metabolites such as glycogen, glucose, lactate, reflecting the changes in skeletal muscle carbohydrate oxidation.
• Mitochondrial ATP production [48 hours after surgery]: Mitochondrial ATP production rates in patients undergoing major abdominal surgery.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* All patients over 18 years of age, who are undergoing major elective open abdominal surgery will be included in the study. Patients should be able to provide a written informed consent to participate in the study.

Exclusion Criteria:

* Patients who are

  1. Undergoing emergency surgery
  2. Suffering from chronic illness, (e.g. diabetes) or other debilitating diseases
  3. On long term anti-inflammatory drugs, (e.g. NSAIDS, Steroids, immunosuppressant)
  4. On long term antibiotics
  5. On Statins
  6. On full therapeutic dose of anticoagulants, or aspirin >325 mg/day, Clopidrogel >75mg/day
  7. Suffering from bleeding diathesis
  8. Unable to give consent
  9. Pregnant or breastfeeding.

• Dileep N Lobo, Professor, Principal investigator, University of Nottingham