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

Trial Summary

What is the purpose of this trial?

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. The investigators do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. The investigators propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. an overnight intra-duodenal Intralipid infusion (both compared to saline control). The investigators will compare the muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates, providing the first measure of how different FFA profiles alter muscle FFA trafficking and insulin action at the whole body and cellular/molecular levels. By identifying which steps in the insulin signaling pathway are most affected, the investigators will determine the site-specific effect of ceramides and/or DG on different degrees of insulin resistance. Hypothesis 1: Palm oil infusion will result in abnormal FFA trafficking into intra-myocellular ceramides and abnormal insulin signaling. Hypothesis 2: Intralipid infusion will result in abnormal FFA trafficking into intra-myocellular saturated DG and abnormal insulin signaling.

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.

What data supports the effectiveness of the treatment Intralipid for insulin resistance?

Research suggests that lipid emulsions like Intralipid, which are used in parenteral nutrition, can provide essential fatty acids and calories, potentially preventing complications associated with glucose-based nutrition. However, the specific impact of Intralipid on insulin resistance needs further validation. ^{1 2 3 4 5}

Is the fatty acid treatment safe for humans?

Lipid emulsions, used in treatments like parenteral nutrition, are generally considered safe, but they can cause issues like liver problems and inflammation, especially if not properly balanced or if infused too quickly. Newer formulations using oils like fish oil may have fewer side effects compared to older soybean oil-based emulsions. ^{2 3 6 7 8}

How does the drug Intralipid differ from other treatments for insulin resistance?

Intralipid is a soybean oil-based emulsion that provides essential fatty acids and calories intravenously, which can help prevent deficiencies in patients who cannot eat normally. Unlike other treatments for insulin resistance, it is primarily used for nutritional support rather than directly targeting insulin signaling or glucose uptake. ^{1 4 5 9 10}

Research Team

Michael D Jensen, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Parenteral lipids: safety aspects and toxicity. [2014]

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

Parenteral Lipid Tolerance and Adverse Effects: Fat Chance for Trouble? [2022]

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

Fat emulsion for intravenous administration: clinical experience with intralipid 10%. [2023]

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

The dose-related hypoglycemic effects of insulin emulsions incorporating highly purified EPA and DHA. [2019]

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

A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. [2015]

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

State of the art review: Intravenous fat emulsions: Current applications, safety profile, and clinical implications. [2022]

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

Emergence of Mixed-Oil Fat Emulsions for Use in Parenteral Nutrition. [2019]

9. United States 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. [2020]

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

Lipid Use in Hospitalized Adults Requiring Parenteral Nutrition. [2021]