Low-Dose Fatty Acids for Insulin Resistance
(BCAA Trial)
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: University of Pennsylvania
Must not be taking: Systemic steroids
Disqualifiers: Diabetes, Hypertension, Hyperlipidemia, others
No Placebo Group
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?
The primary goal of this study is to determine the dose of fatty acids that acutely induces mild insulin resistance in healthy volunteers. We hypothesize that a low-dose of fatty acid infusion (Intralipid/heparin) will cause a mild insulin resistance. The dose of fatty acid infusion that reliably causes mild insulin resistance will be selected for use in future studies.
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.
What data supports the effectiveness of the treatment Intralipid for insulin resistance?
Is the use of low-dose fatty acids, like Intralipid, generally safe for humans?
Intralipid, a type of fat emulsion, has been used safely in humans for over 40 years, primarily as a nutritional supplement. Studies show it is generally well-tolerated, but caution is advised in severely ill patients due to potential metabolic effects like increased fat levels in the blood. Newer formulations with alternative oils, such as fish oil, may offer additional safety benefits.36789
How does the drug Intralipid differ from other treatments for insulin resistance?
Intralipid is unique because it is a fat emulsion that can be used to deliver fatty acids intravenously, potentially affecting insulin resistance by altering free fatty acid levels and promoting glucose conservation. Unlike typical oral medications for insulin resistance, Intralipid is administered directly into the bloodstream, which may lead to different metabolic effects.1341011
Research Team
ZP
Zoltan P Arany, MD, PhD
Principal Investigator
Associate Professor of Medicine
Eligibility Criteria
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.
You are allergic to metal, specifically aluminum.
See 17 more
Trial Timeline
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
Treatment Details
Interventions
- Intralipid (Fatty Acid Infusion)
Trial OverviewThe 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.
Participant Groups
3Treatment groups
Experimental Treatment
Active Control
Group I: Medium Dose Fatty AcidsExperimental Treatment1 Intervention
Insulin sensitivity (rate of glucose disposal) in response to 60 ml/hr fatty acid infusion
Group II: Low Dose Fatty AcidsExperimental Treatment1 Intervention
Insulin sensitivity (rate of glucose disposal) in response to 30 ml/hr fatty acid infusion
Group III: SalineActive Control1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who Is Running the Clinical Trial?
University of Pennsylvania
Lead Sponsor
Trials
2118
Patients Recruited
45,270,000+
References
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.
Lipid emulsion use precluding renal replacement therapy. [2014]Intralipid emulsion (ILE) is a nutritional fatty acid supplementation that is emerging as a potential therapy for local anesthetic systemic toxicity and is also being considered as a therapy for other lipophilic medication intoxications. Isolated reports of pulmonary edema or severe lipemia exist as a complication of therapy.
Comparison of Intralipid 10% and Intralipid 20% as a source of energy and essential fatty acids--a multicenter study. [2013]A multicenter clinical study was done which directly compared efficacy and safety of Intralipid 10% and Intralipid 20%. Twenty-nine patients received the 10% concentration, 30 patients received the 20% concentration. Both groups of patients received equivalent amounts of calories, amino acids, dextrose and fat for seven day study periods. Analysis of nitrogen balance data showed that the two preparations were equally effective in maintaining nitrogen balance. Both concentrations of fat emulsion were effective in reversing or correcting the changes of essential fatty acid deficiency. Analysis of clinical laboratory data indicated that both preparations were equally well tolerated by the patients. No adverse effects attributed to the fat emulsions were observed.
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.
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.
Lipid injectable emulsions: Pharmacopeial and safety issues. [2022]Lipid injectable emulsions have been routinely used in patients worldwide for over 40 years as a nutritional supplement in patients requiring parenteral nutrition. They can be given as a separate infusion or added into total parenteral nutrition admixtures. Despite such broad use, no pharmacopeial standards exist with respect to the optimal pharmaceutical characteristics of the formulation. Several attempts to establish standard physical and chemical attributes have been attempted by various pharmacopeias around the world, but without success largely due to technical issues regarding the creation of globule size limits. Recently, the United States Pharmacopeia has revised its previous efforts and developed two methods and criteria (under Chapter ) to measure the mean droplet size (Method I), and the large-diameter tail > 5 mum (Method II) of the globule size distribution to verify the stability of lipid injectable emulsions. Importantly, it is the latter size limits of Method II that have the greatest implications for infusion safety. The major safety issues involving lipid injectable emulsions include impairments in plasma clearance in susceptible patients, and the infusion of an unstable emulsion containing large quantities of potentially embolic fat globules. Recent animal studies investigating the toxicity from the infusion of unstable lipid injectable emulsions have shown evidence of oxidative stress and tissue damage to the liver when recommended globule size limits determined by Method II of the USP are exceeded. Adoption of Chapter of the USP seems appropriate at this time.
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.
[The problem of dosage and importance of fats in parenteral feeding]. [2018]Using human volunteers the metabolic effects of continuous infusions of fat emulsions (Intralipid and Lipofundin S) without and with addition of carbohydrates and amino acids were investigated. A steady state for triglyceride concentration was attained even at an infusion rate of 0.25 gm/kg BW for Lipofundin S. This fat emulsion was utilized during parenteral administration of 0.1 gm/kg BW almost without an increase in triglyceride concentration. In the case of parenteral administration of Intralipid, however, we did not find indications for the existence of a steady state for serum triglyceride concentration. Without the addition of carbohydrates the parenteral application of fat emulsions causes hyperlipacidemia and ketosis even in metabolically healthy volunteers. These metabolic effects are suppressed by the simultaneous administration of fructose or glucose. The concentration of inorganic phosphate is elevated merely during the highly dosed infusions of Lipofundin S and not by Intralipid. Liver functions were not altered even by highly dosed intravenous fat. According to the results of these investigations in human volunteers Intralipid is eliminated considerably slower than Lipofundin S. There should be qualitative differences also. Lipofundin S is obviously to a greater extent metabolized by the physiological intravasal fat metabolizing system. The small elimination capacity for Intralipid, however, demands caution in the uncontrolled application of this fat emulsion to severely ill patients. Even the better metabolized Lipofundin S should be infused principally with the addition of carbohydrates. By taking these precautions the undesirable metabolic effects of intravenous fat (i.e. lipacidemia and ketosis) are prevented.
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 ω-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.
Effects of intravenous infusion of a ten percent soybean emulsion on hormones, amino acids and other substrates in blood. [2019]Acute responses in hormone and substrate concentrations to intravenous administration of a fat emulsion were studied in metabolically normal subjects. Eight subjects were infused with either a fat emulsion or an aqueous solution of glycerol for 3 h. Serum triglycerides (TG), free fatty acids (FFA), glucose, glycerol, 3-hydroxybutyrate (3-OH butyrate), insulin, thyroid hormones, plasma glucagon, norepinephrine, and amino acids were measured. The infusion of a fat emulsion induced a 30% increase in glucose and a 22% decrease in alanine together with significant elevations of TG (> 10 mM) and FFA (> 1 mM). A small increase in insulin (4 microU/ml) and a reduction in glucagon (40 pg/ml) were observed. Eight-fold increases in glycerol occurred with both the fat emulsion and glycerol infusions. The administration of a fat emulsion resulted in a 4-fold increase in 3-OH butyrate, whereas glycerol infusion reduced its level by 50%. Glycerol infusion produced no measurable effects on the substrates other than glycerol or 3-OH butyrate. No significant changes were observed in thyroid hormones or norepinephrine after either solution was given. The data suggest that acute elevation of FFA by means of intravenous fat emulsions leads to preferential oxidation of FFA and stimulates hepatic ketogenesis with resulting glucose conservation as well as inhibition of alanine production without many alterations in hormonal concentrations.
Safety and metabolic tolerance of a concentrated long-chain triglyceride lipid emulsion in critically ill septic and trauma patients. [2017]A concentrated fat emulsion (Intralipid 30%) with a phospholipid/triglyceride ratio of 0.04 was tested for clinical tolerance and metabolic effects in the short-term parenteral nutrition of septic and trauma critically ill patients and compared with Intralipid 20% (phospholipid/triglyceride ratio of 0.06).