High-Dose Insulin Therapy for Liver Regeneration

Overseen By Jennifer Kalil, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Disqualifiers: Type 1 diabetes, Uncontrolled blood glucose, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

70 Participants Needed

Trial Summary

What is the purpose of this trial?

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: 1. Does high-dose insulin therapy improve liver function in the pre-operative setting? 2. What is the effect of high-dose insulin therapy on liver function and liver regeneration after a liver venous deprivation (LVD) procedure? 3. 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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment High-Dose Insulin Therapy for liver regeneration?

Research shows that insulin can help liver regeneration in animal models, such as rats, by increasing DNA and RNA levels, which are important for cell growth. However, in human studies, insulin therapy did not significantly enhance liver regeneration in patients with severe liver failure. ^{1 2 3 4 5}

Is high-dose insulin therapy generally safe for humans?

High-dose insulin therapy has been used safely in humans for treating overdoses of certain medications, with the main side effects being low blood sugar (hypoglycemia) and low potassium levels (hypokalemia). Regular monitoring and glucose supplementation are necessary to manage these effects. ^{6 7 8 9 10}

How does High-Dose Insulin Therapy for liver regeneration differ from other treatments?

High-Dose Insulin Therapy is unique because it uses the Hyperinsulinemic-Normoglycemic Clamp Technique, which involves maintaining high insulin levels while keeping blood sugar normal, potentially promoting liver regeneration. This approach is different from standard insulin treatments that primarily focus on managing blood sugar levels in diabetes. ^{6 8 11 12 13}

Eligibility Criteria

This trial is for adults over 18 who are set to undergo major liver surgery due to resectable colorectal liver metastasis. It's exploring whether high-dose insulin therapy can help improve the liver's function and its ability to regenerate before the operation.

Inclusion Criteria

My liver cancer from colorectal origin can be surgically removed.

I am a candidate for major surgery to remove part of my liver.

I am older than 18 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-operative Treatment

Participants receive a 6-hour infusion of insulin and dextrose to maintain a hyperinsulinemic-normoglycemic state in the weeks prior to planned liver surgery

2-4 weeks

1 visit (in-person)

Post-operative Monitoring

Participants are monitored for liver function improvement and liver regeneration using 99mTc-Mebrofenin Hepatobiliary Scintigraphy and CT volumetry

7 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• High-Dose Insulin Therapy

Trial Overview The study tests if a pre-surgery treatment involving a 6-hour infusion of insulin and dextrose, which keeps blood sugar normal but raises insulin levels, can enhance how well the liver works and regrows after part of it is removed (hepatectomy).

Participant Groups

Group I: Group 2: Effect of high-dose insulin therapy on pre-operative liver function after LVD Experimental Treatment 1 Intervention

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.

Group II: Group 1: Effect of high-dose insulin therapy on pre-operative liver function Experimental Treatment 1 Intervention

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.

Group III: Group 3: Effect of high-dose insulin therapy on pre-operative liver function after LVD Active Control 1 Intervention

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.

High-Dose Insulin Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Insulin for:

• Diabetes Mellitus Type 1
• Diabetes Mellitus Type 2
• Hyperkalemia
• Hyperglycemia

Approved in European Union as Insulin for:

• Diabetes Mellitus Type 1
• Diabetes Mellitus Type 2
• Hyperkalemia
• Hyperglycemia

Approved in Canada as Insulin for:

• Diabetes Mellitus Type 1
• Diabetes Mellitus Type 2
• Hyperkalemia
• Hyperglycemia

Who Is Running the Clinical Trial?

McGill University Health Centre/Research Institute of the McGill University Health Centre

Lead Sponsor

Trials

476

Recruited

170,000+

Findings from Research

Intraportal administration of insulin in 15 adult patients undergoing right lobe living donor liver transplantation significantly enhanced liver graft regeneration during the first week post-surgery, as indicated by a greater increase in graft volume compared to a control group.

Insulin treatment also improved liver function markers, such as total bilirubin and liver enzymes, suggesting that it not only aids in regeneration but also supports overall hepatic function in the early postoperative period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial clinical effect of intraportal insulin administration on liver graft regeneration in adult patients underwent living donor right lobe liver transplantation. Xu, MQ., Yan, LN., Li, B., et al.[2011]

In a study involving 30 adult patients who underwent living donor right lobe liver transplantation, those receiving postoperative intraportal insulin showed significantly greater liver graft volume regeneration at 7 days compared to those who did not receive insulin.

Additionally, the group receiving intraportal insulin had lower levels of liver enzymes and bilirubin at 7 days post-surgery, indicating improved liver function during the early recovery period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Augmented hepatic regeneration of living donor liver graft by intraportal insulin administration]. Xu, MQ., Yan, LN., Li, B., et al.[2019]

Long-term intraportal infusion of insulin significantly enhances liver regeneration in rats after partial hepatectomy, particularly within the first 24 hours post-surgery.

Insulin treatment leads to increased levels of DNA, RNA, and TTK activity in the liver, indicating its positive role in promoting liver cell growth and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of long term insulin infusion into rat portal vein on regenerating liver. Rokicki, M., Rokicki, W., Czyzewski, K.[2011]

Insulin therapy does not enhance liver regeneration after partial hepatectomy in normal fed rats, as indicated by unchanged liver dry weight and thymidine uptake, which peaked at 24 hours post-surgery.

The study found that partial hepatectomy led to significant metabolic changes, including decreased ATP levels and increased triglycerides, but insulin treatment had only minor effects on these metabolic alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic regeneration and metabolism after partial hepatectomy in normal rats: effects of insulin therapy. Johnston, DG., Johnson, GA., Alberti, KG., et al.[2019]

In a randomized controlled trial involving 18 patients in severe coma due to liver failure, insulin and glucagon infusion did not significantly improve survival rates or enhance liver function compared to controls.

Only one patient in each group showed signs of liver regeneration post-mortem, indicating that the treatment did not effectively stimulate hepatic regeneration despite raising insulin and glucagon levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Failure of insulin and glucagon infusion to stimulate liver regeneration in fulminant hepatic failure. Harrison, PM., Hughes, RD., Forbes, A., et al.[2019]

The new short-term intensive insulin therapy (N-SIIT) for type 2 diabetes, applied to 74 subjects, showed a remission rate of 67.3% with a low hypoglycemia rate of only 5.6%, compared to 47.3% remission and 38.1% hypoglycemia in conventional therapy.

N-SIIT allows for flexible insulin dosing based on individual target blood glucose levels, making it a simple and cost-effective approach that adapts to each patient's unique needs and lifestyle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical application of short-term intensive insulin therapy based on the concept of "treat to target" to reduce hypoglycaemia in routine clinical site. Nakashima, K., Okamura, N., Sanefuji, H., et al.[2021]

In two cases of patients treated with high-dose insulin therapy for calcium channel blocker and beta-adrenergic antagonist overdoses, insulin levels remained significantly elevated for longer than expected, with half-lives of 13.0 hours and 6.0 hours, indicating a prolonged pharmacokinetic response.

The prolonged elevation of insulin concentrations suggests that patients may be at an increased risk of hypoglycemia even after stopping high-dose insulin infusions, highlighting the need for careful monitoring post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin concentrations following termination of high-dose insulin euglycemic therapy. Wiener, BG., Smith, CT., Patel, S., et al.[2023]

Chronic hyperinsulinemia for 28 days led to a significant 23% decrease in maximal insulin-stimulated glucose utilization in dogs, indicating that prolonged high insulin levels can impair insulin responsiveness.

Despite the decrease in glucose utilization, insulin sensitivity (ED50) remained unchanged, suggesting that the observed insulin resistance may be primarily due to reduced insulin responsiveness rather than a change in sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity. McGuinness, OP., Myers, SR., Neal, D., et al.[2019]

A case study of a 79-year-old man in cardiogenic shock due to medication overdose demonstrated that high-dose insulin therapy (up to 20 units/kg/hour) can be safely administered with minimal adverse effects, such as only a few episodes of hypoglycemia and hypokalemia.

This case supports the efficacy of high-dose insulin therapy in managing cardiogenic shock, suggesting that early and aggressive treatment can maintain cardiovascular function, even at the highest recorded infusion rates in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Insulin for Toxin Induced Cardiogenic Shock: Experience at a New High and Overview of the Evidence. Chad, T., Ulla, M., Garnelo Rey, V., et al.[2021]

High-dose insulin therapy has been shown to be superior to conventional treatments for severe beta-blocker and calcium channel-blocker poisoning, with mechanisms including increased heart contractility and improved glucose transport.

Animal studies and case reports suggest that high-dose insulin (1-10 U/kg/hour) is effective and safe, making it a recommended initial treatment for these types of poisoning, despite the need for careful monitoring of blood glucose and potassium levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Engebretsen, KM., Kaczmarek, KM., Morgan, J., et al.[2022]

Insulin therapy is recommended for non-insulin-dependent diabetes mellitus (NIDDM) patients with significant hyperglycaemic symptoms and high fasting blood glucose levels (above 15 mmol/l), as it addresses insulin deficiency rather than just insulin resistance.

Effective management of NIDDM may involve a combination of insulin and oral hypoglycaemic agents, and achieving better metabolic control can reduce the risk of weight gain and macrovascular complications, highlighting the importance of individualized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin treatment of non-insulin-dependent diabetes mellitus. Heine, RJ.[2019]

In a study involving 10 lean young adult rhesus monkeys, insulin during a euglycemic hyperinsulinemic clamp was found to activate liver glycogen synthase (GS) and inhibit glycogen phosphorylase (GP), which are key enzymes in glycogen metabolism.

The activation of GS by insulin was positively correlated with the overall rate of glucose disposal in the body, suggesting that insulin plays a crucial role in regulating liver glycogen metabolism and glucose homeostasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin regulates liver glycogen synthase and glycogen phosphorylase activity reciprocally in rhesus monkeys. Ortmeyer, HK., Bodkin, NL., Hansen, BC.[2017]

Infusing insulin at doses of 0.20 and 0.15 mU.kg(-1).min(-1) in healthy individuals significantly suppressed glucose production and lowered plasma glucose levels to subphysiological levels, indicating these doses may be excessive for insulin replacement.

The study suggests that the commonly used doses of insulin in the pancreatic clamp technique may need to be reassessed, as lower doses (0.10 mU.kg(-1).min(-1)) did not produce the same effects, highlighting the importance of selecting appropriate hormone doses for accurate biological assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Basal insulin, glucagon, and growth hormone replacement. Breckenridge, SM., Raju, B., Arbelaez, AM., et al.[2016]

References

1. United States pubmed.ncbi.nlm.nih.gov

Initial clinical effect of intraportal insulin administration on liver graft regeneration in adult patients underwent living donor right lobe liver transplantation. [2011]

2. China pubmed.ncbi.nlm.nih.gov

[Augmented hepatic regeneration of living donor liver graft by intraportal insulin administration]. [2019]

3. Poland pubmed.ncbi.nlm.nih.gov

Effect of long term insulin infusion into rat portal vein on regenerating liver. [2011]

4. England pubmed.ncbi.nlm.nih.gov

Hepatic regeneration and metabolism after partial hepatectomy in normal rats: effects of insulin therapy. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Failure of insulin and glucagon infusion to stimulate liver regeneration in fulminant hepatic failure. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Practical application of short-term intensive insulin therapy based on the concept of "treat to target" to reduce hypoglycaemia in routine clinical site. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Insulin concentrations following termination of high-dose insulin euglycemic therapy. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

High-Dose Insulin for Toxin Induced Cardiogenic Shock: Experience at a New High and Overview of the Evidence. [2021]

10. England pubmed.ncbi.nlm.nih.gov

High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Insulin treatment of non-insulin-dependent diabetes mellitus. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Insulin regulates liver glycogen synthase and glycogen phosphorylase activity reciprocally in rhesus monkeys. [2017]

13. United States pubmed.ncbi.nlm.nih.gov

Basal insulin, glucagon, and growth hormone replacement. [2016]