Low Dose Fat-Induced Insulin Resistance

Overview

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.

Full Title of Study: “A Dose Finding Study for Fat-Induced Insulin Resistance in Healthy Volunteers”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Basic Science
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 2025

Detailed Description

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 study is critical for future studies on free-fatty acid induced insulin resistance. Healthy male and healthy female volunteers will undergo a 6 hour hyperinsulinemic-euglycemic clamp, in order to establish insulin sensitivity parameters in the presence of fatty acid co-infusion. The subjects will then return 1-3 weeks later, and undergo another 6 hour HIE clamp, this time in the presence of low-dose fatty acid co-infusion (30ml/hr). If this dose does not achieve ~25% reduction in the rate of glucose disposal, then the dose-confirmation study will be repeated 1-3 weeks later with a medium-dose fatty acid co-infusion (60ml/hr). A dose-response effect of fatty acids on insulin resistance has been demonstrated before, but not in the precise conditions of our study. This dose-finding study is critical because future studies require a reliable dose of fatty acid infusion, and the exact dose of fatty acid infusion that causes mild insulin resistance may be different in the conditions of our study.

Interventions

  • Drug: Intralipid, 20% Intravenous Emulsion
    • Fatty Acid Infusion, either in low-dose (30 ml/hr) or medium-dose (60 ml/hr)

Arms, Groups and Cohorts

  • No Intervention: Saline
    • Insulin sensitivity (rate of glucose disposal)
  • Experimental: Low Dose Fatty Acids
    • Insulin sensitivity (rate of glucose disposal) in response to 30 ml/hr fatty acid infusion
  • Experimental: Medium Dose Fatty Acids
    • Insulin sensitivity (rate of glucose disposal) in response to 60 ml/hr fatty acid infusion

Clinical Trial Outcome Measures

Primary Measures

  • Insulin Sensitivity
    • Time Frame: 6 hours
    • Rate of Glucose Disposal (mg/kg/min)

Participating in This Clinical Trial

Inclusion Criteria

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

  • History of diabetes – History of diabetes in more than one first-degree relative – Body mass index (BMI) <19 or >27 kg/m2 – HbA1c >5.7% – Blood Pressure: systolic >160 mmHg or diastolic > 100 mmHg – Baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men – Estimated glomerular filtration rate < 55 ml/min/1.73 m2 (calculated using the subject's measured serum creatinine and the Modification of Diet in Renal Disease [MDRD] study estimation formula). – Presence of soy or egg allergies (due to possible reactions with fat infusate) – For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable. – Known active alcohol or substance abuse – Use of tobacco within the previous year – Severe co-existing cardiac disease, characterized by any one of these conditions: 1. history of myocardial infarction within past 6 months; 2. history of ischemia on functional cardiac exam within the last year; 3. history of left ventricular ejection fraction < 30%. – Persistent elevation of liver function tests > 1.5 times normal upper limits – Hyperlipidemia (fasting LDL cholesterol > 130 mg/dl, treated or untreated; and/or fasting triglycerides > 200 mg/dl) – Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for the use of ≤ 5 mg prednisone daily, or an equivalent physiological dose of hydrocortisone – Presence of a seizure disorder – Use of any investigational agents within 4 weeks of enrollment – Any medical condition, which in the opinion of the investigator, will interfere with the safe completion of the study – History of pancreatitis – Presence of a metal allergy (aluminum)

Gender Eligibility: All

Male or Female at birth.

Minimum Age: 18 Years

Maximum Age: 44 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Pennsylvania
  • Provider of Information About this Clinical Study
    • Principal Investigator: Zoltan Arany, Associate Professor Of Medicine – University of Pennsylvania
  • Overall Official(s)
    • Zoltan P Arany, MD, PhD, Principal Investigator, Associate Professor of Medicine
  • Overall Contact(s)
    • Paola Alvarado, MS, 215-746-2081, Paola.Alvarado@Pennmedicine.upenn.edu

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