Clinical trial NCT03479671: Low Dose Fat-Induced Insulin Resistance
Official title: A Dose Finding Study for Fat-Induced Insulin Resistance in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Diabetes Mellitus, Type 2
Insulin Resistance
Insulin Sensitivity
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2018-03-27
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 44
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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)

Primary outcomes:
measure: Insulin Sensitivity
timeFrame: 6 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Associate Professor of Medicine
name: Zoltan P Arany, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: