Trial Information

The Effect of the Preoperative Oral Carbohydrate Attenuating Immediate Postoperative Insulin Resistance on PI3K Dependent Signaling Pathway

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.