Low Dose Fat-Induced Insulin Resistance

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.

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.

Eligibility Criteria:
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)