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

NCT ID: NCT00755729

Last Updated: 2008-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-11-30
• Study Completion Date: 2007-03-31

Brief 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.

Conditions

Colorectal Disease

Keywords

Preoperative oral carbohydrate; Insulin resistance; phosphatidylinositol-3-kinase

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

OCH

fast from midnight the night before surgery, and consume 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

Group Type: EXPERIMENTAL

Preoperative Oral Carbohydrate

Intervention Type: DIETARY_SUPPLEMENT

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

FSD

fast from midnight the night before surgery, and no preoperative oral carbohydrate loading

Group Type: NO_INTERVENTION

Preoperative Oral Carbohydrate

Intervention Type: DIETARY_SUPPLEMENT

Patients in FSD group were fasted from midnight the night before surgery, and no preoperative oral carbohydrate loading

Interventions

Preoperative Oral Carbohydrate

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

Intervention Type: DIETARY_SUPPLEMENT

Preoperative Oral Carbohydrate

Patients in FSD group were fasted from midnight the night before surgery, and no preoperative oral carbohydrate loading

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• The present study employed 32 patients, who underwent elective open colorectal resection for colorectal carcinoma

Exclusion Criteria

• Diabetes mellitus or impaired glucose tolerance
• Medication affecting insulin sensitivity
• Weight loss greater than 10 per cent during the previous 6 months
• Signs of distant metastasis by CT scanning
• Renal insufficiency (creatinine, > 3 mg/dl; hemodialysis)
• Hepatic insufficiency (Child-Pugh class, ≥ B)
• Gastro-oesophageal reflux disease
• Gastrointestinal obstruction
• Conditions (including pharmacological treatment) known to affect gastric emptying rate

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Changzheng Hospital

OTHER

Sponsor Role: lead

Responsible Party

Shanghai Chang Zheng Hospital

Principal Investigators

Qiang Wang, MD

Role: STUDY_CHAIR

Shanghai Chang Zheng Hospital

Zhi Guo Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Department of General Surgery, Shanghai Chang Zheng Hospital

Locations

Department of General Surgery, Shanghai Chang Zheng Hospital,

Shanghai, Shanghai Municipality, China

Countries

China

References

Wang ZG, Wang Q, Wang WJ, Qin HL. Randomized clinical trial to compare the effects of preoperative oral carbohydrate versus placebo on insulin resistance after colorectal surgery. Br J Surg. 2010 Mar;97(3):317-27. doi: 10.1002/bjs.6963.

Reference Type: DERIVED

PMID: 20101593 (View on PubMed)

Other Identifiers

SCZH-0809-110

Identifier Type: -

Identifier Source: org_study_id