Insulin Infusion for Non-alcoholic Fatty Liver Disease

Overseen By Julia J. Wattacheril, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must not be taking: Antidiabetics, Corticosteroids, Opioids, others

Disqualifiers: Diabetes, Cardiovascular, Liver, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

42 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those who have used certain medications within 90 days before screening, like antidiabetic drugs other than metformin and some lipid-lowering drugs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug for Non-alcoholic Fatty Liver Disease?

Research suggests that insulin-sensitizing agents, which help the body use insulin more effectively, may improve liver health in people with Non-Alcoholic Fatty Liver Disease (NAFLD). These agents have been shown to reduce insulin resistance, which is a key factor in the development of NAFLD, and improve liver function in some studies. ^{1 2 3 4 5}

Is insulin infusion safe for humans?

Research shows that insulin, including lispro and recombinant human insulin, is generally safe for humans. Studies involving thousands of patients with diabetes found no significant differences in adverse events or disease progression when comparing different insulin types. ^{6 7 8 9 10}

How does insulin infusion differ from other treatments for non-alcoholic fatty liver disease?

Insulin infusion for non-alcoholic fatty liver disease is unique because it directly uses insulin, a hormone that helps regulate blood sugar, which may influence liver fat content. Unlike other treatments that focus on insulin sensitizers, this approach involves administering insulin itself, potentially offering a different mechanism to address the condition. ^{1 3 4 11 12}

What is the purpose of this trial?

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study. The investigators will recruit participants with a history of overweight/obesity and evidence of insulin resistance (i.e., fasting hyperinsulinemia plus prediabetes and/or impaired fasting glucose and/or Homeostasis Model Assessment of Insulin Resistance \[HOMA-IR\] score \>=2.73), and with evidence of, or clinically judged to be at high risk for, uncomplicated non-alcoholic fatty liver disease (NAFLD). Participants will undergo two pancreatic clamp procedures in which individualized basal IIR are identified, followed in one by maintenance of basal IIR (maintenance hyperinsulinemia, MH) and in the other by a stepped decline in IIR (reduction toward euinsulinemia, RE). In both clamps the investigators will closely monitor plasma glucose and various metabolic parameters. The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR.

Research Team

Joshua R. Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for adults aged 18-65 with a BMI of 25.0-39.9, who speak English or Spanish, have high fasting insulin levels and are at risk for non-alcoholic fatty liver disease (NAFLD). They must not be pregnant, breastfeeding, or have diabetes, severe infections recently, certain heart conditions or allergies to study materials.

Inclusion Criteria

Your blood insulin level is too high when you haven't eaten for a while.

I understand English or Spanish.

I have been diagnosed with or am at high risk for NAFLD/MAFLD by a specialist.

Exclusion Criteria

I can provide informed consent in English or Spanish.

Concerns arising at screening visit including unwillingness to comply with specified procedures, documented weight loss of ≥ 5% of baseline within the previous 6 months, abnormal blood pressure, abnormal resting heart rate, abnormal screening electrocardiogram, laboratory evidence of diabetes mellitus, positive qualitative β-hCG in women of childbearing potential, liver function abnormalities, abnormal fasting lipids at screening, abnormal screening serum electrolytes, abnormal complete blood count, not fully vaccinated against COVID-19, unwillingness to comply with masking requirements per hospital policy, active, documented COVID-19 at any time after screening, women of childbearing potential not using highly effective contraception, women currently pregnant or breastfeeding, history of diabetes mellitus, use of most antidiabetic medications within the 90 days prior to screening, concerns related to lipid metabolism, known, documented history of specified medical conditions, use of certain medications currently or within 90 days prior to screening, history of certain weight-loss (bariatric) surgery, clinical concern for alcohol overuse, positive urine drug screen, history of severe infection or ongoing febrile illness within 30 days of screening, any other disease, condition, or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data, known allergy/hypersensitivity to any component of the medicinal product formulations, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator, concurrent enrollment in another clinical study of any investigational drug therapy within 6 months prior to screening or within 5 half-lives of an investigational agent, whichever is longer

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pancreatic Clamp Procedure

Participants undergo two pancreatic clamp procedures to assess the impact of insulin infusion rate on blood glucose levels.

Up to 425 minutes per procedure

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the pancreatic clamp procedures.

4 weeks

Treatment Details

Interventions

• 20% D-glucose (aq)
• [6,6-2H2] D-glucose
• Glucagon
• Growth Hormone, Human
• Insulin human
• Octreotide Acetate

Trial Overview The study tests how different rates of insulin infusion affect blood glucose during a pancreatic clamp procedure in overweight individuals with NAFLD and insulin resistance. Participants will undergo two procedures comparing maintenance versus reduction of insulin infusion.

Participant Groups

Group I: Reduction toward euinsulinemia (RE) protocol Experimental Treatment 10 Interventions

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the basal IIR will be reduced by up to 50%. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.

Group II: Maintenance hyperinsulinemia (MH) protocol Active Control 10 Interventions

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of underlying insulin resistance.

Insulin human is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Humulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in United States as Humulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in Canada as Novolin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in Japan as Recombinant Human Insulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in China as Recombinant Human Insulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Albert Einstein College of Medicine

Collaborator

Trials

302

Recruited

11,690,000+

Findings from Research

In a study of 659 type 1 diabetes patients, those using continuous subcutaneous insulin infusion (CSII) had significantly lower Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) compared to those using multiple daily injections (MDI), indicating a potential benefit of CSII in reducing non-alcoholic fatty liver disease (NAFLD) risk.

The lower NAFLD indices were particularly notable in women using CSII, who also had lower daily insulin doses and plasma triglyceride levels, suggesting that CSII may provide metabolic advantages in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin pump therapy in type 1 diabetes is associated with lower indices of Non-Alcoholic Fatty Liver in non-obese women but not men. Pepa, GD., Lupoli, R., Masulli, M., et al.[2023]

Insulin sensitizers, particularly metformin and thiazolidinediones, have been shown to improve insulin resistance and liver function tests in patients with nonalcoholic fatty liver disease (NAFLD), based on a systematic review of nine studies.

However, the evidence is limited, with only two placebo-controlled trials conducted, and while some beneficial histological changes were reported, these need further validation through randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review. Chavez-Tapia, NC., Barrientos-Gutierrez, T., Tellez-Avila, FI., et al.[2019]

In a study of 64 NAFLD patients over 12 months, treatment with rosiglitazone (4 mg/day) led to significant improvements in liver enzyme levels and NAFLD activity scores, indicating better metabolic control and histological improvement compared to metformin alone.

The combination of metformin and rosiglitazone also showed benefits, particularly in reducing liver enzyme levels, but metformin alone did not result in significant changes, highlighting the superior efficacy of rosiglitazone in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Omer, Z., Cetinkalp, S., Akyildiz, M., et al.[2022]

In a study of 219 morbidly obese patients, type 2 diabetes mellitus was found to be an independent risk factor for severe liver conditions, including severe steatosis and severe fibrosis, indicating its significant role in worsening non-alcoholic fatty liver disease.

Insulin therapy was associated with non-alcoholic steatohepatitis and fibrosis in the overall patient group, but did not show this association when only patients with diabetes were analyzed, suggesting that insulin's impact may vary based on the patient's overall health status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Diabetes Mellitus and Insulin on Nonalcoholic Fatty Liver Disease in the Morbidly Obese. Strey, CBM., de Carli, LA., Fantinelli, M., et al.[2021]

Weight loss and lifestyle modifications are the primary interventions for non-alcoholic fatty liver disease (NAFLD), especially in overweight or obese individuals, but require a multidisciplinary approach that is often lacking.

Insulin-sensitizing agents show promise as a treatment for NAFLD by reducing insulin resistance, which contributes to fat accumulation in the liver, with studies indicating improvements in liver function, although long-term outcomes are still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review article: the treatment of fatty liver disease associated with the metabolic syndrome. Marchesini, G., Natale, S., Manini, R., et al.[2017]

In a study of 108 individuals with type 2 diabetes and compensated liver disease, lispro insulin resulted in lower glycemic excursions compared to recombinant regular human insulin (RHI), particularly during the night and late post-absorption phases.

Lispro also led to lower early postprandial glucose levels and reduced rates of late postprandial hypoglycemia, suggesting it may be the preferred treatment option for patients with type 2 diabetes and compensated liver disease due to its faster action and reduced liver glucose output.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus. Gentile, S., Guarino, G., Strollo, F., et al.[2018]

In a clinical trial involving 211 diabetic patients over 12 weeks, both Yousilin R and Novolin R significantly reduced glycosylated hemoglobin A1c (HbA1c) levels, indicating effective blood sugar control, with no significant difference between the two treatments.

The safety profiles of Yousilin R and Novolin R were comparable, with similar rates of hypoglycemic events and other adverse effects, suggesting that Yousilin R is a safe alternative to Novolin R for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of recombinant human insulin injection in the treatment of diabetic patients:a multicenter, randomized, controlled and open-labeled clinical trial]. Che, TT., Wang, X., Liu, YY., et al.[2014]

In a study involving 1008 patients, short-acting insulin lispro and regular insulin Humulin R showed similar effectiveness in controlling blood sugar levels and had comparable safety profiles, with no significant differences in hypoglycemia incidents.

After a year of continued lispro therapy, glycosylated hemoglobin (HbA1C) levels returned to baseline, indicating that while lispro was well tolerated in the short term, long-term efficacy may need further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. Daniels, AR., Bruce, R., McGregor, L.[2022]

A comparison of insulin lispro and regular human insulin (Humulin R) in 3634 patients with type 1 and type 2 diabetes showed no significant differences in treatment-emergent adverse events, indicating similar safety profiles for both insulins.

Both insulin therapies did not differ in their effects on the progression of chronic diabetes complications, such as retinopathy, neuropathy, cardiovascular disease, or kidney disease, suggesting that insulin lispro is as safe as Humulin R.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. Glazer, NB., Zalani, S., Anderson, JH., et al.[2019]

In a study involving 37 individuals with type 2 diabetes, both Gansulin and Humulin N® effectively reduced HbA1c levels, indicating similar efficacy in glycemic control.

There were no significant differences in fasting plasma glucose, bedtime plasma glucose, or hypoglycemic events between the two insulin formulations, suggesting that Gansulin is as safe as Humulin N® for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study between two recombinant human NPH insulin formulations for the treatment of type 2 diabetes mellitus. Rassi, N., Moraes, SM., Alves, AG., et al.[2023]

Pioglitazone was found to improve liver histology in patients with non-alcoholic fatty liver disease (NAFLD), while metformin showed mixed results and did not improve non-alcoholic steatohepatitis (NASH) stages, indicating that pioglitazone may be more effective for liver health.

Metformin led to weight loss and significant reductions in insulin resistance, but it was less effective than pioglitazone in improving liver parameters, highlighting the need for further research on insulin sensitisers in advanced NAFLD stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Shyangdan, D., Clar, C., Ghouri, N., et al.[2021]

Recombinant leptin treatment shows promising preliminary results in improving non-alcoholic fatty liver disease (NAFLD), a condition with no FDA-approved therapies.

This research highlights the potential of leptin as a therapeutic option for NAFLD, addressing a significant public health issue related to liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Finding a sweet spot for leptin. Brown, RJ., Reitman, ML.[2022]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Insulin pump therapy in type 1 diabetes is associated with lower indices of Non-Alcoholic Fatty Liver in non-obese women but not men. [2023]

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

Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. [2022]

4. Mexico pubmed.ncbi.nlm.nih.gov

Impact of Diabetes Mellitus and Insulin on Nonalcoholic Fatty Liver Disease in the Morbidly Obese. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Review article: the treatment of fatty liver disease associated with the metabolic syndrome. [2017]

6. Ireland pubmed.ncbi.nlm.nih.gov

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus. [2018]

7. China pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of recombinant human insulin injection in the treatment of diabetic patients:a multicenter, randomized, controlled and open-labeled clinical trial]. [2014]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. [2019]

10. Brazil pubmed.ncbi.nlm.nih.gov

Comparative study between two recombinant human NPH insulin formulations for the treatment of type 2 diabetes mellitus. [2023]

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

Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. [2021]

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

Finding a sweet spot for leptin. [2022]