Fatty Acid Interventions for Insulin Resistance

Overseen By Pamela Reich

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Mayo Clinic

Must not be taking: Fish oil, Statins, Niacin, others

Disqualifiers: Ischemic heart disease, Smokers, others

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different types of fats might affect insulin resistance in muscles, a condition linked to obesity and Type 2 diabetes. Researchers are testing two treatments: one with palm oil and another with a fat mixture called Intralipid (a 20% fat emulsion), both compared to a saline solution. The goal is to determine how these fats alter the way muscles process fatty acids and insulin. Individuals who are not obese, maintain a stable weight, and do not smoke heavily may be suitable candidates for this trial. As an unphased trial, this study provides a unique opportunity to contribute to foundational research that could lead to new insights into managing insulin resistance.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that can alter your serum lipid profile, such as high dose fish oil, statins, niacin, fibrates, thiazolinediones, beta-blockers, and atypical antipsychotics.

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

Previous studies have examined the safety of both Intralipid and palm oil emulsion, revealing some clear findings. Intralipid, a fat mixture administered through an IV, is generally well-tolerated but can raise blood pressure. It should be used cautiously in individuals with certain health issues, such as liver damage or poorly controlled diabetes.

Conversely, palm oil emulsion has been shown to affect insulin usage in the body, potentially leading to insulin resistance. This may make it harder for the body to use insulin effectively, possibly resulting in higher blood sugar levels.

Both treatments have known effects and specific risks. Prospective trial participants should consider these factors and discuss any concerns with health professionals. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments for insulin resistance because they explore new ways of using fatty acids to manage the condition. Unlike traditional medications that often rely on improving insulin sensitivity through oral drugs or injections, Intralipid and Palm Oil Emulsion offer a novel approach by directly influencing the lipid metabolism. This could potentially provide a more targeted way to combat insulin resistance. By utilizing these fatty acid interventions, there's hope for a different pathway that could lead to better management of insulin levels in the body.

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

This trial will compare the effects of Intralipid and palm oil on insulin resistance. Studies have shown that increasing free fatty acids (FFAs) with Intralipid reduces muscle responsiveness to insulin, meaning the body doesn't use insulin as effectively. Research suggests that an Intralipid infusion alters fat processing in the body, potentially leading to insulin resistance. Meanwhile, palm oil interferes with insulin's ability to function in certain tissues, which could also cause insulin resistance. Current evidence indicates that both Intralipid and palm oil, tested in separate arms of this trial, can affect how the body handles fatty acids, potentially impacting insulin function and muscle sugar absorption. ^{3 5 6 7 8}

Who Is on the Research Team?

Michael D Jensen, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for healthy, non-obese adults with a BMI of 18-27 who are not pregnant or nursing and have maintained their weight. Women must be premenopausal. It excludes those on certain lipid-altering meds, smokers, individuals with specific heart diseases or lidocaine allergy.

Inclusion Criteria

Not pregnant/nursing

This applies to both women and men, including women who have not gone through menopause.

Your body mass index (BMI) is between 18 and 27.

Exclusion Criteria

You are taking certain medications that can change the levels of fat in your blood.

You smoke more than 20 cigarettes per week.

Both ovaries have been removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-clamp

Volunteers receive an intravenous infusion of C13-labelled palmitate as a tracer for enrichment calculations pre-clamp. One muscle biopsy is obtained.

9 hours

Insulin Clamp

Volunteers receive an intravenous infusion of a second tracer, D-9 palmitate, to calculate enrichments during the insulin clamp stage. A second muscle biopsy is performed.

9 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Intralipid
• Palm Oil Emulsion
• Saline

Trial Overview

The study tests how palm oil emulsion and Intralipid infusions affect muscle insulin resistance by altering fatty acid profiles in the body compared to saline control. It aims to understand how these fats impact insulin signaling and glucose uptake in muscles.

How Is the Trial Designed?

Group I: Palm Oil Experimental Treatment 1 Intervention

Group II: Intralipid Experimental Treatment 1 Intervention

Group III: Saline Placebo Group 1 Intervention

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

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]

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]

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]

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]

Omegaven, an n3 fatty acid-containing lipid emulsion, preserves insulin-mediated glucose uptake in rat hearts, unlike Intralipid, which decreases glucose uptake due to reduced glycolysis and glycogen synthesis.

The mechanism by which Omegaven maintains glucose uptake involves enhanced phosphorylation of key proteins in the insulin signaling pathway, specifically the PP2A-Akt-PFK pathway, while also causing a prooxidant response that may inhibit redox-sensitive PP2A.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid Emulsion Containing High Amounts of n3 Fatty Acids (Omegaven) as Opposed to n6 Fatty Acids (Intralipid) Preserves Insulin Signaling and Glucose Uptake in Perfused Rat Hearts. Lou, PH., Lucchinetti, E., Hersberger, M., et al.[2020]

Alternative intravenous fat emulsions (IVFEs) like medium-chain triglycerides, olive oils, and fish oils may offer similar safety profiles to standard soybean oil-based IVFEs, but they are not yet available in the U.S.

These alternative IVFEs could potentially improve clinical outcomes for patients in compromised states by reducing the intake of proinflammatory ω-6 fatty acids found in soybean oil, suggesting a need for further research on their efficacy and optimal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. Vanek, VW., Seidner, DL., Allen, P., et al.[2015]

Intravenous fat emulsions (IVFEs) are generally safe and well tolerated when administered according to guidelines, with adverse effects (AEs) being more likely if the administration rate exceeds the enzyme lipoprotein lipase's clearance capacity.

The review highlights that using a 20% IVFE formulation, like that for clevidipine, is associated with a lower rate of lipid-related AEs compared to a 10% formulation, which can interfere with enzyme activity and increase risks like pancreatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State of the art review: Intravenous fat emulsions: Current applications, safety profile, and clinical implications. Mirtallo, JM., Dasta, JF., Kleinschmidt, KC., et al.[2022]

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]

Lipid emulsions, particularly those containing omega-3 fatty acids from fish oil, provide significant clinical benefits in hospitalized patients, including reduced infection rates and shorter hospital stays, compared to traditional soybean oil emulsions.

The beneficial effects of omega-3 fatty acids are linked to their immunomodulatory and anti-inflammatory properties, which are mediated by specialized pro-resolution mediators, making them valuable in the treatment of various patient groups such as surgical and critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid Use in Hospitalized Adults Requiring Parenteral Nutrition. Mayer, K., Klek, S., García-de-Lorenzo, A., et al.[2021]

Intravenous fat emulsions (IFEs) have evolved from soybean oil-based formulations, which can cause complications like inflammation and liver disease, to a mixed-oil (MO) IFE that combines soybean oil, medium-chain triglycerides, olive oil, and fish oil, aiming for a better safety profile.

Early results from small, short-term trials of the MO IFE (Smoflipid) show promising improvements in liver function, triglyceride levels, and a healthier omega-3 to omega-6 fatty acid ratio, but larger long-term studies are necessary to confirm these benefits in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of Mixed-Oil Fat Emulsions for Use in Parenteral Nutrition. Mundi, MS., Martindale, RG., Hurt, RT.[2019]

Citations

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pmc.ncbi.nlm.nih.gov

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

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Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity.

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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 ...

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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 ...

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Intravenous Intralipid-Induced Blood Pressure Elevation ...

FMD decreased by 11% at 24 h and by 18% at 48 h of Intralipid infusion. Clinical and experimental data indicate that changes in lipid metabolism may contribute ...

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ahajournals.org/doi/10.1161/01.HYP.32.4.693

Intralipid Enhances α1-Adrenergic Receptor–Mediated ...

These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances α1-adrenoceptor–mediated pressor sensitivity. The findings suggest that ...

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accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2022/018449s049lbl.pdf

Intralipid® 20% (A 20% IV Fat Emulsion)

Caution should be exercised in administering of Intralipid 20% (A 20% Intravenous Fat. Emulsion) to patients with severe liver damage, pulmonary disease, anemia ...

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.

accessdata.fda.gov

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Intralipid® 20% (A 20% IV Fat Emulsion) - accessdata.fda.gov

Intralipid use. Aluminum Toxicity. This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration ...