Low Dose Fat-Induced Insulin Resistance

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.

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)