Insulin Management for Non-alcoholic Fatty Liver Disease

Overseen By Joshua R Cook, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must not be taking: Antidiabetics, Antipsychotics, Antidepressants, others

Disqualifiers: Diabetes, Cardiovascular diseases, Liver disease, 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

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking most antidiabetic medications, except for metformin, within 30 days before screening. Certain lipid-lowering drugs and other specific medications must also be stopped 30 days prior to screening.

What data supports the effectiveness of the drug Insulin human, Humulin, Novolin, Recombinant Human Insulin for treating Non-alcoholic Fatty Liver Disease?

Research suggests that insulin therapy, like insulin pump therapy, may help reduce liver fat in some patients with type 1 diabetes, which could be relevant for treating non-alcoholic fatty liver disease (NAFLD). Additionally, insulin-sensitizing agents have been explored for their potential benefits in NAFLD, indicating a possible role for insulin in managing this condition. ^{1 2 3 4 5}

Is insulin safe for humans?

Insulin, under various names like Humulin and Novolin, has been used safely in humans for managing diabetes for many years. While the specific safety data for insulin in treating non-alcoholic fatty liver disease is not detailed in the provided research, insulin is generally considered safe for human use in other conditions. ^{1 6 7 8 9}

How does insulin human differ from other drugs for non-alcoholic fatty liver disease?

Insulin human, commonly used for diabetes, is being explored for non-alcoholic fatty liver disease (NAFLD) due to its role in managing insulin resistance, a key factor in NAFLD. Unlike other treatments like lifestyle changes or antidiabetic drugs such as metformin, insulin human directly addresses insulin levels, which may help in managing liver disease in patients with diabetes. ^{1 2 10 11 12}

What is the purpose of this trial?

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the impact of lowering insulin levels on hepatic glucose production (HGP) vs de novo lipogenesis (DNL) in people with insulin resistance. 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 metabolic dysfunction-associated steatotic liver disease (MASLD). Participants will undergo two pancreatic clamp procedures -- one in which serum insulin levels are maintained near hyperinsulinemic baseline (Maintenance Hyperinsulinemia or "MH" Protocol) and the other in which serum insulin levels are lowered by 50% (Reduction toward Euinsulinemia or "RE" Protocol). In both clamps the investigators will use stable-isotope tracers to monitor hepatic glucose and triglyceride metabolism. The primary outcome will be the impact of steady-state clamp insulinemia on HGP vs DNL.

Research Team

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for people who are overweight or obese, have insulin resistance (evidenced by high fasting insulin levels, prediabetes/impaired fasting glucose, or a HOMA-IR score of at least 2.73), and either have non-alcoholic fatty liver disease (NAFLD) or are at high risk for it.

Inclusion Criteria

Body mass index of 25.0-45.0 kg/m2

Evidence of insulin resistance, as indicated by meeting specific criteria including Hemoglobin A1c levels and fasting glucose levels

Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73

Exclusion Criteria

I am unwilling to use only a bedpan or urinal during certain procedures.

Abnormal screening electrocardiogram

I am not pregnant or at risk of becoming pregnant.

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 levels on hepatic glucose production and de novo lipogenesis.

Up to 6.5 hours 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

• Insulin human

Trial Overview The study tests how lowering insulin affects liver glucose production versus fat creation in the liver. Participants will undergo two procedures with different insulin levels while their liver metabolism is monitored using special tracers.

Participant Groups

Group I: Reduction toward euinsulinemia (RE) protocol Experimental Treatment 11 Interventions

On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.

Group II: Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol Experimental Treatment 11 Interventions

On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.

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+

University of California, Berkeley

Collaborator

Trials

193

Recruited

716,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

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]

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]

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]

In a 52-week weight management trial, semaglutide significantly reduced alanine aminotransferase (ALT) levels by 6%-21% in subjects with elevated ALT, indicating its potential effectiveness in treating non-alcoholic fatty liver disease (NAFLD).

Semaglutide also led to significant reductions in high-sensitivity C-reactive protein (hsCRP) levels by 25%-43% compared to placebo, suggesting an anti-inflammatory effect that may benefit individuals at risk for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Newsome, P., Francque, S., Harrison, S., et al.[2021]

Empagliflozin significantly reduces body mass index (BMI), liver stiffness measurement (LSM), aspartate aminotransferase (AST), and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD), based on a review of four randomized controlled trials involving 244 patients.

The findings suggest that empagliflozin improves liver health and metabolic parameters in NAFLD patients, indicating its potential as a new treatment option, although further research is needed to confirm its long-term efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Empagliflozin on Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Zhang, Y., Liu, X., Zhang, H., et al.[2022]

Incretin-based therapies, such as DPP-4 inhibitors and GLP-1 agonists, provide effective glycemic control for type 2 diabetes patients without the weight gain often seen with traditional treatments, making them a favorable option for many.

Clinical trial data suggest that these therapies are safe, showing no negative effects on cardiovascular health, and their integration into treatment plans can enhance options for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic options: management strategies to optimize glycemic control. Freeman, JS.[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]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease. [2020]

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

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

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

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Empagliflozin on Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH. [2021]

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

New therapeutic options: management strategies to optimize glycemic control. [2022]

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

Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. [2019]

10. Poland pubmed.ncbi.nlm.nih.gov

[Non-alcoholic liver disease - diagnosis and treatment]. [2018]

11. Mexico pubmed.ncbi.nlm.nih.gov

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

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

Finding a sweet spot for leptin. [2022]