Application of High-dose Insulin Therapy to Improve Liver Function and Regeneration

Study Overview
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Brief Summary
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The primary objective of this interventional study is determine if the future liver remnant can be optimized by improving liver function pre-operatively in patients who are scheduled for major hepatectomy. The main questions it aims to answer are: Does high-dose insulin therapy improve liver function in the pre-operative setting? What is the effect of high-dose insulin therapy on liver function and liver regeneration after a liver venous deprivation (LVD) procedure? What is the relationship between volume hypertrophy and function in the regenerating liver? Participants will receive a 6-hour infusion of insulin and dextrose to maintain a hyperinsulinemic-normoglycemic state in the weeks prior to planned liver surgery to assess its effect on liver function measured by 99m-Tc-Mebrofenin hepatobiliary scintigraphy.

Official Title
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Application of High-Dose Insulin Therapy Using a Hyperinsulinemic Normoglycemic Clamp to Improve Liver Function and Regeneration

Conditions
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Liver Dysfunction, Liver Metastasis Colon Cancer, Liver Regeneration

Intervention / Treatment
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* Drug: High-Dose Insulin Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years old Candidate for major liver resection Resectable colorectal liver metastasis Exclusion Criteria: Inability to give consent Type 1 diabetes mellitus Uncontrolled blood glucose levels (fasting level > 10 mmol/L) Unresectable colorectal liver metastasis Extrahepatic metastatic disease that is unresectable

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Group 1 will consist of participants scheduled for liver resection and will undergo high-dose insulin therapy preoperatively to determine if baseline liver function can be optimized/improved, as measured by 99mTc-Mebrofenin HBS. Cytokine profiling will also be collected and analyzed pre- and post-insulin infusion. Group 2 will consist of participants scheduled for liver resection that require LVD. They will then be randomized to two different arms -- control vs high-dose insulin therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Effect of high-dose insulin therapy on pre-operative liver function<br>Group 1 will consist of participants scheduled for liver resection and will undergo high-dose insulin pre-operatively to determine if baseline liver function can be optimized/improved, as measured by 99mTc-Mebrofenin HBS. | Drug: High-Dose Insulin Therapy<br>* A baseline blood glucose value will be obtained. Two units of insulin will be administered IV if the blood glucose is > mmol/L. An insulin infusion of 0.12 units/kg/hr will be started. Ten minutes after starting the insulin, and when the blood glucose is < 6 mmol/L, dextrose 20% supplemented with phosphate (30 mmol/L) will be infused. Blood glucose levels will be measured every 15 minutes, and the dextrose infusion rate adjusted to maintain glycemic levels between 4 and 6 mmol/L for a duration of 6 hours. At the end of the 6 hour period, the insulin will be stopped and the dextrose will be weaned off.<br>|
| Experimental: Group 2: Effect of high-dose insulin therapy on pre-operative liver function after LVD<br>Group 2 will consist of participants scheduled for liver resection that require LVD. The participants in the experimental arm will receive high-dose insulin therapy after LVD. | Drug: High-Dose Insulin Therapy<br>* A baseline blood glucose value will be obtained. Two units of insulin will be administered IV if the blood glucose is > mmol/L. An insulin infusion of 0.12 units/kg/hr will be started. Ten minutes after starting the insulin, and when the blood glucose is < 6 mmol/L, dextrose 20% supplemented with phosphate (30 mmol/L) will be infused. Blood glucose levels will be measured every 15 minutes, and the dextrose infusion rate adjusted to maintain glycemic levels between 4 and 6 mmol/L for a duration of 6 hours. At the end of the 6 hour period, the insulin will be stopped and the dextrose will be weaned off.<br>|
| No Intervention: Group 3: Effect of high-dose insulin therapy on pre-operative liver function after LVD<br>Group 3 will consist of participants scheduled for liver resection that require LVD. The participants in the no intervention arm will not undergo intervention with high-dose insulin therapy after LVD. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver function improvement after high-dose insulin therapy measured with 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBS). | 99mTc-Mebrofenin HBS is a diagnostic nuclear medicine imaging procedure used to evaluate liver function by measuring radiotracer uptake and excretion. The outcome will be evaluating a measurable increase in 99mTc-Mebrofenin (measured %/min/meter^2) from baseline scan to post-treatment scan. | Baseline to 24-hours post treatment | 
| Liver function improvement after high-dose insulin therapy after LVD measured with 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBS). | 99mTc-Mebrofenin HBS is a diagnostic nuclear medicine imaging procedure used to evaluate liver function by measuring radiotracer uptake and excretion. The outcome will be evaluating a measurable increase in 99mTc-Mebrofenin (measured %/min/meter^2) from baseline scan to post-treatment scan. | Baseline to 7 days post treatment | 
| Liver regeneration improvement after high-dose insulin therapy after LVD measured CT volumetry | The volume of the liver can be measured from liver protocoled CT scans | Baseline to 7 days post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperinsulinemic-Normoglycemic Clamp, High Dose Insulin Therapy, 99mTc-Mebrofenin Hepatobiliary Scintigraphy, Colorectal Cancer Liver Metastasis, Liver Resection