Fatty Acid Interventions for Insulin Resistance
Recruiting in Palo Alto (17 mi)
Overseen byMichael D Jensen, MD
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Mayo Clinic
Must not be taking: Fish oil, Statins, Niacin, others
Disqualifiers: Ischemic heart disease, Smokers, others
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.
12345Is 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.
23678How 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.
145910Eligibility 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.
+1 more
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.
+3 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Placebo Group
Group I: Palm OilExperimental Treatment1 Intervention
Group II: IntralipidExperimental Treatment1 Intervention
Group III: SalinePlacebo Group1 Intervention
Intralipid is already approved in United States, European Union, Canada for the following indications:
πΊπΈ Approved in United States as Intralipid for:
- Parenteral nutrition
- Caloric supplementation
πͺπΊ Approved in European Union as Intralipid for:
- Parenteral nutrition
- Caloric supplementation
π¨π¦ Approved in Canada as Intralipid for:
- Parenteral nutrition
- Caloric supplementation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo ClinicRochester, MN
Loading ...
Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
References
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]The aim of this study is to test whether the choice of the lipid emulsion in total parenteral nutrition (TPN), that is, n-3 fatty acid-based Omegaven versus n-6 fatty acid-based Intralipid, determines inflammation in the liver, the incretin profile, and insulin resistance.
Parenteral lipids: safety aspects and toxicity. [2014]Lipid emulsions (LEs) used in modern parenteral nutrition formulations are indispensable sources of calories and (essential) fatty acids ((E)FAs). Several generations of LEs based on various FA sources have been developed, and issues related to their safe use deserve attention. The relevant issues concern LE composition, stability and sterility, while other problems are related to the lipid infusion rate, including hypertriglyceridemia and lipid overload syndrome. The FA structure of LEs translates into effects on inflammatory processes and immune cell function and affects the functions of organs, such as the liver and lungs. In addition, disturbed balances of (anti)oxidants and the presence of other bioactive agents in LEs, such as phytosterols, are mechanisms that may underlie the potential adverse effects. Lipid emulsions (LEs) are key components of parenteral nutrition (PN) that bypass the need for (essential) fatty acids ((E)FAs) and provide sufficient energy to decrease the need for the infusion of large amounts of dextrose, thus preventing its associated complications. The oldest available LEs are based on soybean oil (SO-LE) and meet these requirements. (Pre)clinical evidence suggests that various, next-generation LEs based on alternative oil sources are safe and effective; particularly, those based on fish oil (FO-LEs) have less pro-inflammatory characteristics that may convey beneficial effects on the immune system and organ functions. With the exception of decreased liver damage with the use of FO-LEs instead of SO-LEs, the clinical relevance of many of these data needs further validation.
Parenteral Lipid Tolerance and Adverse Effects: Fat Chance for Trouble? [2022]Lipid emulsions (LEs) are indispensable sources of fuel calories and (essential) fatty acids (FAs) in modern parenteral nutrition formulations. The use of LE, however, also remains associated with the development of adverse effects. Intolerance for LE mostly becomes apparent upon the development of patient complaints or disturbed blood function tests, mainly of the liver. These issues may be associated with the composition, stability, or the infusion rate of the emulsion. Also, altered balances of (anti)oxidants or the presence or absence of protective or toxic bioactive agents such as phytosterols and tocopherol in LE may lead to complications, especially in already vulnerable patients with an inflammatory condition. While the oldest available LEs are based on pure soybean oil (SO-LE), rich in the proinflammatory Ο-6 polyunsaturated fatty acid linoleic acid, more recent next-generation LEs where alternative FA sources such as olive and fish oil (partially) replace soybean oil to lower the content of linoleic acid seem safe and effective. Especially LEs containing fish oil (FO-LE) have less proinflammatory characteristics that promise to convey beneficial effects on immune system and organ functions, although much of the available evidence awaits more robust clinical validation.
Fat emulsion for intravenous administration: clinical experience with intralipid 10%. [2023]A 10% soybean oil emulsion (Intralipid 10%), used extensively in Europe for intravenous alimentation, has now been clinically evaluated in the United States. Controlled studies have shown that the soybean oil emulsion can be substituted for glucose to supply one-third to two-thirds of the total calories, and can be administered peripherally without significant vein irritation. Essential fatty acid deficiencies, frequently encountered in patients dependent on parenteral alimentation with fat-free solutions, are prevented and corrected by use of this preparation. Data on long-term tolerance to Intralipid 10% infusions are presented for 292 patients treated for more than 6,000 patient days. The soybean oil emulsion was usually well tolerated. Side effects were reported in two of 133 adults and 12 of 159 pediatric patients.
The dose-related hypoglycemic effects of insulin emulsions incorporating highly purified EPA and DHA. [2019]The dose-related pharmacological effects of insulin emulsion incorporating highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were investigated. Water-in-oil-in-water multiple emulsions (insulin dose, 0, 10, 25 and 50 IU/kg) incorporating 2% DHA or EPA were administered directly into the colonic and rectal loops in situ. Serum insulin levels rose and serum glucose levels decreased in an insulin dose-related fashion. The relationship of insulin dose and C(max) or AUC(insulin) was linear at the rectum, but a non-linear relationship was observed at the colon. The trend was more predominant in DHA. In the in vivo rectal absorption experiment using emulsions incorporating 2% DHA, 5 IU/kg of insulin emulsion produced a rapid, transitory increase in serum insulin levels and strong reduction of serum glucose levels. The pharmacological availability determined from the dose-response curve by s.c. administration of insulin reached 43.2+/-26.3% (mean+/-S.D.). Mucosal irritation caused by administration of emulsions incorporating 2% EPA or DHA was evaluated by a lactate dehydrogenase (LDH) release study, and compared with those of the emulsion incorporating 2% oleic or linolenic acid. Only when emulsion incorporating 2% oleic acid was applied in the intestine did significant LDH release into the mesenteric veins occur. Our results indicate that emulsion incorporating highly purified long-chain polyunsaturated fatty acid, especially DHA, has the potential of becoming the formulation for enteral delivery of insulin.
A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. [2015]The currently available, standard soybean oil (SO)-based intravenous fat emulsions (IVFEs) meet the needs of most parenteral nutrition (PN) patients. There are alternative oil-based fat emulsions, such as medium-chain triglycerides (MCTs), olive oils (OOs), and fish oils (FOs), that, based on extensive usage in Europe, have an equivalent safety profile to SO. These alternative IVFEs are metabolized via different pathways, which may lead to less proinflammatory effects and less immune suppression. These alternative oil-based IVFEs are not currently available in the United States. Many patients who require IVFEs are already in a compromised state. Such patients could potentially have better clinical outcomes when receiving one of the alternative IVFEs to diminish the intake of the potentially proinflammatory Ο-6 fatty acid-linoleic acid-which comprises more than 50% of the fatty acid profile in SO. Further research is needed on these alternative oil-based IVFEs to identify which IVFE oils or which combination of oils may be most clinically useful for specific patient populations.
State of the art review: Intravenous fat emulsions: Current applications, safety profile, and clinical implications. [2022]To review the current state of the science regarding intravenous fat emulsions (IVFEs), with an emphasis on their safety profile.
Emergence of Mixed-Oil Fat Emulsions for Use in Parenteral Nutrition. [2019]Since early work by Wretlind and Schuberth led to the development of a stable and safe intravenous fat emulsion (IFE) using soybean oil (SO) and egg phospholipid emulsifier, IFEs have become a crucial source of essential fatty acids and nonprotein energy in parenteral nutrition. However, largely due to their high Ο-6 polyunsaturated fatty acid (PUFA) and phytosterol content, SO IFEs have been associated with complications, including a proinflammatory profile and hypertriglyceridemia, as well as intestinal failure-associated liver disease. Subsequent generations of IFEs have used other sources of triglycerides, including medium-chain triglycerides (MCTs), olive oil (OO), and fish oil (FO), to reduce the SO component. Although these IFEs showed some improvement in complications compared with SO IFE, the quest to develop an IFE with a better side effect profile and beneficial physiologic effects led to the development of a mixed-oil (MO) IFE (Smoflipid; 30% SO, 30% MCTs, 25% OO, and 15% FO) that was recently approved by the Food and Drug Administration. The use of a MO approach is theoretically and intuitively more physiologically similar to normal dietary human consumption. Although the data are from small, short-term trials, MO IFE results thus far have been promising, with some studies showing improved liver function tests, improvement in triglycerides, higher Ο-3/Ο-6 PUFA ratio, and higher Ξ±-tocopherol. Larger long-term studies are needed to ensure these theoretical benefits lead to significant improvement in clinical outcomes.
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]It is currently unknown whether acute exposure to n3 fatty acid-containing fish oil-based lipid emulsion Omegaven as opposed to the n6 fatty acid-containing soybean oil-based lipid emulsion Intralipid is more favorable in terms of insulin signaling and glucose uptake in the intact beating heart.
Lipid Use in Hospitalized Adults Requiring Parenteral Nutrition. [2021]In hospitalized patients, lipid emulsions are an integral part of balanced parenteral nutrition. Traditionally, a single lipid source, soybean oil, has been given to patients and was usually regarded as just a source of energy and to prevent essential fatty-acid deficiency. However, mixtures of different lipid emulsions have now become widely available, including mixtures of soybean oil, medium-chain triglycerides, olive oil, and fish oil. Fish oil is high in the Ο-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). There is a growing body of evidence that these Ο-3 fatty acids can exert beneficial immunomodulatory, anti-inflammatory, and inflammation-resolution effects across a wide range of patient groups including surgical, cancer, and critically ill patients. At least in part, these effects are realized via potent specialized pro-resolution mediators (SPMs). Moreover, parenteral nutrition including Ο-3 fatty acids can result in additional clinical benefits over the use of standard lipid emulsions, such as reductions in infection rates and length of hospital and intensive care unit stay. Clinical and experimental evidence is reviewed regarding lipid emulsion use in a variety of hospitalized patient groups, including surgical, critically ill, sepsis, trauma, and acute pancreatitis patients. Practical aspects of lipid emulsion use in critically ill patients are also considered, such as how to determine and fulfill energy expenditure, how and when to consider parenteral nutrition, duration of infusion, and safety monitoring.