Low-Dose Fatty Acids for Insulin Resistance

(BCAA Trial)

Overseen By Paola Alvarado, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids

Disqualifiers: Diabetes, Hypertension, Hyperlipidemia, 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: 2

Duration: 1 day

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the right dose of fatty acids that temporarily reduces insulin sensitivity in healthy individuals. Insulin is a hormone that helps control blood sugar. By testing different doses, researchers seek to identify which one causes mild insulin resistance, a condition where the body doesn't use insulin effectively. This information will aid in designing future studies. Healthy individuals who are not diabetic and have a body mass index between 19 and 27 may be suitable for this trial. The treatment used in this study is a 20% Intralipid Emulsion. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking scientific knowledge.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic steroids, you may need to adjust your dose to 5 mg of prednisone daily or an equivalent dose of hydrocortisone.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Intralipid is usually safe for people. Earlier tests found that different strengths of Intralipid, such as 10%, 20%, and 30%, are generally well-tolerated, meaning most people did not experience major issues when given Intralipid.

However, some serious side effects have been reported in certain cases. For instance, very young babies have sometimes experienced severe reactions, such as breathing problems and issues with fat metabolism. These reactions are rare and typically occur under specific conditions.

Intralipid has been used in medical settings for many years, providing some confidence in its safety. Still, individuals with certain health issues, like kidney problems or uncontrolled diabetes, should exercise caution.

Overall, Intralipid is expected to be safe for most healthy adults, especially at lower doses. However, as with any treatment, monitoring and guidance from healthcare professionals are important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using low-dose fatty acids for insulin resistance because this approach may provide a novel way to improve insulin sensitivity. Unlike traditional treatments such as metformin or insulin therapy, which focus on managing blood sugar levels, this treatment utilizes fatty acids to potentially enhance how the body processes glucose. By administering fatty acids through an infusion, it directly targets glucose disposal rates, offering a unique mechanism of action. This could open up new avenues for managing insulin resistance, especially for those who may not respond well to existing medications.

What evidence suggests that this trial's treatments could be effective for insulin resistance?

This trial will compare the effects of different doses of fatty acids on insulin sensitivity. Research has shown that high levels of certain fats in the blood, such as free fatty acids and triglycerides, can hinder the body's ability to use insulin effectively. Participants in this trial will receive either a low or medium dose of Intralipid, a fat mixture, or a saline solution. Studies have found that administering a fat mixture like Intralipid can temporarily raise insulin levels in the blood, which return to normal after stopping the mixture. Specifically, one study showed that using Intralipid reduced the body's response to insulin by 25% after a few hours. This finding suggests that Intralipid can help researchers understand how these fats might lead to insulin resistance. ^{6 7 8 9 10}

Who Is on the Research Team?

Zoltan P Arany, MD, PhD

Principal Investigator

Associate Professor of Medicine

Are You a Good Fit for This Trial?

Healthy volunteers who can consent and follow study procedures, without soy or egg allergies, severe heart disease, kidney issues, high cholesterol/triglycerides, diabetes history in family, BMI between 19-27 kg/m2. Must not have used investigational drugs recently or have certain chronic diseases.

Inclusion Criteria

Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol

Exclusion Criteria

Use of any investigational agents within 4 weeks of enrollment

I have a history of diabetes.

More than one of my immediate family members has diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a 6-hour hyperinsulinemic-euglycemic clamp with low-dose fatty acid infusion (30ml/hr) to test insulin sensitivity

1 day

1 visit (in-person)

Dose Confirmation

If initial low-dose does not achieve desired insulin resistance, participants return for another 6-hour clamp with medium-dose fatty acid infusion (60ml/hr)

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Intralipid

Trial Overview The trial is testing how a low dose of fatty acids (Intralipid/heparin infusion) affects insulin sensitivity in healthy people to find the right dose that causes mild insulin resistance for future research.

How Is the Trial Designed?

Group I: Medium Dose Fatty Acids Experimental Treatment 1 Intervention

Insulin sensitivity (rate of glucose disposal) in response to 60 ml/hr fatty acid infusion

Group II: Low Dose Fatty Acids Experimental Treatment 1 Intervention

Insulin sensitivity (rate of glucose disposal) in response to 30 ml/hr fatty acid infusion

Group III: Saline Active Control 1 Intervention

Insulin sensitivity (rate of glucose disposal)

Intralipid is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Intralipid for:

• Parenteral nutrition
• Caloric supplementation

Approved in European Union as Intralipid for:

• Parenteral nutrition
• Caloric supplementation

Approved in Canada as Intralipid for:

• Parenteral nutrition
• Caloric supplementation

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

In a study involving 90 critically ill patients (55 septic and 35 trauma), both 30% and 20% fat emulsions used in total parenteral nutrition were found to be clinically safe, showing no significant adverse effects on renal, hematologic, or hepatic functions.

The 30% long-chain triglyceride emulsion resulted in fewer lipid metabolic disturbances compared to the 20% emulsion, suggesting it may be a better option for managing fat intake in septic patients during parenteral nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and metabolic tolerance of a concentrated long-chain triglyceride lipid emulsion in critically ill septic and trauma patients. García-de-Lorenzo, A., López-Martínez, J., Planas, M., et al.[2017]

Lipid injectable emulsions have been safely used for over 40 years in parenteral nutrition, but there have been no established standards for their optimal formulation until recently.

The United States Pharmacopeia has introduced new methods to measure droplet size in these emulsions, which are crucial for ensuring safety during infusion, as larger fat globules can lead to serious complications like oxidative stress and liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid injectable emulsions: Pharmacopeial and safety issues. Driscoll, DF.[2022]

In this case report, a 26-year-old male with a medication overdose showed initial improvement after receiving intralipid emulsion (ILE) therapy, but subsequently developed severe complications including acute respiratory and renal failure, leading to his death.

The case highlights the potential risks associated with ILE therapy, such as pulmonary edema and severe lipemia, emphasizing the need for emergency physicians to be aware of these complications when considering ILE as a treatment for toxic ingestions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid emulsion use precluding renal replacement therapy. Rodríguez, B., Wilhelm, A., Kokko, KE.[2014]

In a study involving 59 patients, both Intralipid 10% and Intralipid 20% were found to be equally effective in maintaining nitrogen balance and correcting essential fatty acid deficiency over a seven-day period.

Both concentrations of Intralipid were well tolerated by patients, with no adverse effects reported, indicating their safety for use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Intralipid 10% and Intralipid 20% as a source of energy and essential fatty acids--a multicenter study. Meng, HC., Zayan, M., Kahn, S., et al.[2013]

Insulin emulsions containing highly purified DHA and EPA showed a dose-dependent effect on serum insulin and glucose levels, with a notable rapid increase in insulin levels and decrease in glucose when administered rectally, particularly with DHA.

The study found that emulsions with DHA were less irritating to the intestinal mucosa compared to those with oleic acid, suggesting that DHA-based formulations could be a safer option for enteral insulin delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dose-related hypoglycemic effects of insulin emulsions incorporating highly purified EPA and DHA. Morishita, M., Kajita, M., Suzuki, A., et al.[2019]

In a study using C57BL/6 mice over 7 days, Omegaven (n-3 fatty acid-based) total parenteral nutrition (TPN) was found to reduce liver inflammation and improve insulin sensitivity compared to Intralipid (n-6 fatty acid-based) TPN.

While both TPN types increased insulin levels, Omegaven TPN led to a liver-protective metabolic profile, whereas Intralipid TPN was associated with higher inflammatory markers and negative metabolic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of Lipid Emulsion Determines Inflammation of the Gut-Liver Axis, Incretin Profile, and Insulin Signaling in a Murine Model of Total Parenteral Nutrition. Lou, PH., Lucchinetti, E., Wawrzyniak, P., et al.[2021]

Intralipid 10%, a 10% soybean oil emulsion, can effectively replace glucose in intravenous nutrition, providing one-third to two-thirds of total caloric needs without causing significant vein irritation.

In a study involving 292 patients over more than 6,000 patient days, Intralipid 10% was generally well tolerated, with side effects reported in only 2 adults and 12 pediatric patients, indicating its safety for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fat emulsion for intravenous administration: clinical experience with intralipid 10%. Hansen, LM., Hardie, BS., Hidalgo, J.[2023]

Infusing a fat emulsion in eight metabolically normal subjects led to significant increases in serum triglycerides and free fatty acids, along with a 30% rise in glucose levels and a 22% decrease in alanine, indicating a shift in metabolism towards fat utilization.

The fat emulsion infusion also resulted in a four-fold increase in 3-hydroxybutyrate, suggesting that it stimulates ketogenesis and helps conserve glucose, while having minimal impact on hormonal levels like insulin and glucagon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of intravenous infusion of a ten percent soybean emulsion on hormones, amino acids and other substrates in blood. Chikenji, T., Yokoyama, M., Mashima, Y., et al.[2019]

Lipid emulsions (LEs) are crucial in parenteral nutrition, providing essential fatty acids and calories while reducing the need for dextrose, which can lead to complications.

Next-generation lipid emulsions, particularly those based on fish oil, show promise for being safer and less inflammatory compared to traditional soybean oil emulsions, potentially benefiting immune function and organ health, although further clinical validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parenteral lipids: safety aspects and toxicity. Wanten, GJ.[2014]

Continuous infusions of fat emulsions like Lipofundin S can achieve a steady state for triglyceride levels, while Intralipid does not, indicating different metabolic behaviors between the two emulsions.

Administering carbohydrates alongside fat emulsions prevents adverse metabolic effects such as hyperlipacidemia and ketosis, highlighting the importance of careful management when using these emulsions in severely ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The problem of dosage and importance of fats in parenteral feeding]. Förster, H., Quadbeck, R., Anschütz, A.[2018]

Lipid emulsions (LEs) are crucial for providing calories and essential fatty acids in parenteral nutrition, but they can cause adverse effects, particularly related to liver function, especially in vulnerable patients.

Next-generation lipid emulsions that incorporate olive and fish oil instead of traditional soybean oil show promise for being safer and less inflammatory, with fish oil emulsions potentially offering benefits for immune and organ function, although further clinical validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parenteral Lipid Tolerance and Adverse Effects: Fat Chance for Trouble? Wanten, GJ.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11298177/

Impact of Lipids on Insulin Resistance: Insights from Human ... Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0022030222007573

Effect of intravenous lipid infusion on biomarkers of insulin ... Lipid infusion significantly increased blood insulin concentration at 3 and 6 h of infusion. However, it returned to its basal concentration 18 h after the end ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03479671

NCT03479671 | Low Dose Fat-Induced Insulin Resistance This study is designed to test the hypothesis that a low-dose of fatty acid infusion (Intralipid/heparin) will cause mild insulin resistance. This dose-finding ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/12870166/

and long-term low-grade free fatty acid infusion in men with ... Insulin action was reduced 25% after 2 and 24 hours Intralipid infusion in both groups. In IGT relatives, the beta-cell responsiveness to glucose (measured ...

5. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0105681

Intralipid Decreases Apolipoprotein M Levels and Insulin ... These results suggest that Intralipid could decrease hepatic ApoM levels. ApoM overexpression may have a potential role in improving insulin resistance in vivo ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/017643s083,018449s050s051,019942s021,020248s027s028lbl.pdf

Intralipid - accessdata.fda.gov In the postmarketing setting, serious adverse reactions including acute respiratory distress, metabolic acidosis, and death have been reported in neonates and ...

7. rsc.niaid.nih.gov rsc.niaid.nih.gov/sites/default/files/SUMMARY%20OF%20PRODUCT%20CHARACTERISTICS%20of%20Intralipid.pdf

SUMMARY OF PRODUCT CHARACTERISTICS of Intralipid Intralipid should be given with caution in conditions of impaired lipid metabolism such as renal insufficiency, uncompensated diabetes mellitus,.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03479671?term=AREA%5BConditionSearch%5D(%22Type%202%20Diabetes%20Mellitus%22)%20AND%20AREA%5BInterventionSearch%5D(%22Soybean%20oil,%20phospholipid%20emulsion%22)&rank=9

Study Details | Low Dose Fat-Induced Insulin Resistance Insulin sensitivity (rate of glucose disposal) in response to 30 ml/hr fatty acid infusion. Intervention/Treatment, Drug : Intralipid, 20% Intravenous Emulsion.

9. fresenius-kabi.com fresenius-kabi.com/content/dam/fresenius-kabi/ca/products/product-documents/medical-nutrition/pn-products-intralipid_/Product%20Monograph.pdf.coredownload.inline.pdf

PRODUCT MONOGRAPH INTRALIPID® Lipid Injectable ... emulsions. Preclinical Safety Data. Preclinical safety studies with INTRALIPID 10%, 20% and 30% demonstrated good tolerance. TOXICOLOGY. Acute ...

10. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/i/Intralipidinf.pdf

NEW ZEALAND DATA SHEET There is no information available on the elimination half-life. 5.3 Preclinical safety data Intralipid has been in clinical use for many years. Safety ...