The Effect of the Preoperative Oral Carbohydrate Attenuating Immediate Postoperative Insulin Resistance on PI3K Dependent Signaling Pathway
Condition: Colorectal Disease
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to delineate the effects of preoperative oral carbohydrate on
      immediate postoperative insulin resistance (PIR) in patients undergoing elective open
      colorectal cancer resection, and to further clarify the hypotheses that preoperative oral
      carbohydrate treatment attenuates PIR in patients by enhancing insulin signaling to
      PI3K-dependent pathway.
    

Detailed description: 
      Postoperative insulin resistance (PIR) is a central feature of postoperative metabolism
      response to surgical injury, resulting in decreased insulin-stimulated glucose uptake in
      skeletal muscle and adipose tissue, increased glucose release and hyperglycaemia. The PIR is
      most pronounced on the day after surgery and lasts for about 3 weeks after uncomplicated
      elective open abdominal operations, and has been considered as a factor of clinical
      importance for the postoperative patient. Recent evidences have elucidated the toxicity of
      hyperglycemia and suggest a causal relation between PIR and complications in the
      postoperative state and the degree of PIR has been considered as an independent factor
      determining the length of postoperative hospital stay.

      The degree of PIR is proportional to the degree of surgical trauma. Although overcoming PIR
      by insulin infusion is one way of combating hyperglycemia, prevention of its development can
      also be achieved by preoperative oral carbohydrate instead of overnight fasting which proven
      in different kinds of surgery, such as in total hip replacement surgery, colorectal surgery
      and in elderly patients undergoing coronary artery bypass grafting. As a single intervention
      in patients given 2-3 hours before anaesthesia, the efficacy of preoperative oral
      carbohydrate has been shown to be equally as good as the intravenous infusion of glucose with
      regard to PIR, and attenuated the development of PIR by 50% measured on the first
      postoperative day after major abdominal surgery. In a placebo-controlled randomized
      controlled trial of 65 patients undergoing major abdominal surgery, patients who received
      preoperative oral carbohydrate lost 0.5 cm of the mid-arm circumference by discharge, while
      the placebo group had more than twice the reduction (1.1 cm). Furthermore, patients receiving
      the oral carbohydrate-rich beverage before colorectal surgery had a smaller reduction in
      their quadriceps muscle strength after the operation up to 1 month than those without
      carbohydrate-rich beverage. These studies suggest that whole-body protein balance, muscle
      function as well as the suppressive effect of insulin on endogenous glucose release are
      better maintained and enhanced when patients receive a carbohydrate-rich beverage before
      surgery. Moreover, in patients who undergo surgery of moderate to severe degree of PIR, the
      PIR can be overcome if a sufficient amount of insulin is infused to maintain euglycemia, and
      both glucose uptake and whole body substrate utilization could be normalized in the presence
      of elevated insulin concentrations. The intensive insulin treatment to maintain
      normoglycaemia in post-surgical patients in intensive care unit substantially reduces
      morbidity and mortality. These findings show that excessive insulin can compensate for the
      defects in insulin action as well, suggesting that PIR might be due to a block in
      intracellular mechanisms that lead to the decrease in glucose uptake.

      The human insulin receptor is a transmembrane glycoprotein, whose cytoplasmic domain contains
      an insulin-activated protein tyrosine kinase (PTK). Insulin signaling is initiated by binding
      of insulin to the extracellular α-subunit of insulin receptor, resulting in the stimulation
      of β-subunit, which contains intrinsic receptor tyrosine kinase activity, autophosphorylation
      of the receptor at multiple tyrosine residues. Autophosphorylation of the receptor enhances
      the intrinsic tyrosine kinase activity and evokes a series of phosphorylation events. These
      include tyrosyl phosphorylation of intracellular substrates named insulin receptor substrates
      (IRS 1 to 4), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB). The
      phosphorylated proteins mediate the cellular actions of insulin. On the other hand, the
      glucose uptake stimulated by insulin in muscle and adipocytes is through the translocation of
      glucose transporters 4 (GLUT4) from intracellular pools to the plasma membrane. The
      translocation of GLUT4 to plasma membrane was established to be mediated by PI3K, based on
      the use of pharmacological inhibitors and expression of a dominant negative mutant or
      constitutively active form of PI3K.

      As molecular switch to regulate the activity of serine/threonine-specifc kinase, PTK and PI3K
      signaling pathways act cascades important in mediating insulin's effects on endpoint
      responses. Defects in the receptor kinase activity and signal transduction in the skeletal
      muscle have been shown previously as a major contributor to the pathogenesis of
      insulin-resistant states, such as obesity and type II diabetes. Despite these findings, the
      mechanism by which preoperative oral carbohydrate beverage consumption exerts the effect that
      attenuating immediate PIR in patients is still unknown. Defects of insulin signal
      transduction via PI3K-dependent pathway may be possible involved in the development of PIR,
      and are highly speculated as the main molecular signaling mechanism.
    

Intervention name(s): Preoperative Oral Carbohydrate; Preoperative Oral Carbohydrate
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Patients in OCH group consumed 400 ml Nutricia preOp® (12.5% carbohydrates, 0.5 kcal/ml, 240 mOsm, pH 4.9, Nutricia Zoetermeer, The Netherlands) 3 hours prior to induction of anaesthesia and finished the ingestion within 1 hour; Patients in FSD group were fasted from midnight the night before surgery, and no preoperative oral carbohydrate loading
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Basic Science
Keywords: Preoperative oral carbohydrate; Insulin resistance; phosphatidylinositol-3-kinase