Low Dose Fat-Induced Insulin Resistance

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Dose Finding Study for Fat-Induced Insulin Resistance in Healthy Volunteers

Conditions
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Diabetes Mellitus, Type 2, Insulin Resistance, Insulin Sensitivity

Intervention / Treatment
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* Drug: Intralipid, 20% Intravenous Emulsion


Participation Criteria
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Eligibility Criteria
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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: history of myocardial infarction within past 6 months; history of ischemia on functional cardiac exam within the last year; 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Baseline insulin sensitivity will be measured in healthy volunteers, and then 1-3 weeks later insulin sensitivity will be measured in response to a low-dose fatty acid infusion. If there is no response to this low-dose infusion, then 1-3 weeks later insulin sensitivity will be measured in response to a medium-dose fatty acid infusion.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Saline<br>Insulin sensitivity (rate of glucose disposal) | |
| Experimental: Low Dose Fatty Acids<br>Insulin sensitivity (rate of glucose disposal) in response to 30 ml/hr fatty acid infusion | Drug: Intralipid, 20% Intravenous Emulsion<br>* Fatty Acid Infusion, either in low-dose (30 ml/hr) or medium-dose (60 ml/hr)<br>|
| Experimental: Medium Dose Fatty Acids<br>Insulin sensitivity (rate of glucose disposal) in response to 60 ml/hr fatty acid infusion | Drug: Intralipid, 20% Intravenous Emulsion<br>* Fatty Acid Infusion, either in low-dose (30 ml/hr) or medium-dose (60 ml/hr)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Rate of Glucose Disposal (mg/kg/min) | 6 hours |