Clinical trial NCT01740817: A Study to Evaluate the Effect of Lipid Infusion on Toll Like Receptor 4 (TLR4) Signaling
Official title: A Randomized, Crossover Study to Evaluate the Effect of Lipid Infusion on TLR4 Signaling and Insulin Resistance in Human Muscle
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes
Obesity
Keywords: diabetes
obesity
inflammation
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2012-12-04
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to determine whether a lipid infusion can up-regulate toll-like receptor 4 (TLR4) signaling in human subjects

Detailed description: The investigators plan to examine the effect of a lipid infusion on TLR4 expression and insulin sensitivity. A group of 30 subjects aged 18-60 years old, lean (BMI \< 26 kg/m2) normal glucose tolerant subjects without a family history of type 2 diabetes will receive a lipid or saline infusion. The subjects will be randomly assigned to first receive either a 48 hour long lipid or saline infusion. Approximately 4-6 weeks later subjects will return to undergo another study (if, in the first study they received lipid, on the second study they will receive saline, and vice versa). A near-equal number of women and men will be included in each group.

Eligibility criteria: Inclusion Criteria:

1. Subjects must have the following laboratory values: Hematocrit ≥ 35%, serum creatinine ≤ 1.5 mg/dl, aspartate aminotransferase (AST) \< 2 X upper limit of normal, Alanine aminotransferase (ALT) \< 2 X upper limit of normal, alkaline phosphatase \< 2 X upper limit of normal, normal urinalysis \[no glucose, trace protein, trace ketones, lipase \< 50 IU/L, no bacteria, up to 1-3 white blood cells (WBC) and red blood cells (RBC) per hpf\], and normal platelets, prothrombin time (PT) and partial thromboplastin time (PTT).
2. Female subjects must be non-lactating. Female patients are eligible only if they have a negative pregnancy test throughout the study period (or postmenopausal). Postmenopausal women taking hormone replacement will be included if they have been on a stable dose for ≥6 months.
3. Subjects whose body weight has been stable (within 2%) for at least three months.

Exclusion Criteria:

1. Subjects with impaired glucose tolerance based on American Diabetes Association criteria.
2. Subjects taking drugs known to affect glucose and lipid homeostasis will be excluded. Statins will be permitted if the subject has been on a stable dose for at least three months. Subjects who have taken for more than a week non-steroidal anti inflammatory drugs (NSAIDS) within two months or systemic steroids, anabolic steroids, growth hormone or immunosuppressants within 12 months will be excluded. Subjects taking low-dose (81 mg/day or less) aspirin will be allowed.
3. Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
4. Recent systemic or pulmonary embolus, impaired renal function, poorly controlled blood pressure (systolic BP\>170, diastolic BP\>95), resting heart rate \>100, electrolyte abnormalities, neuromuscular or musculoskeletal disease.
5. Subjects who smoke.
6. Subjects who engage in a regular exercise program (zero or one exercise sessions per week are allowed).
7. Any subject who has donated blood in the previous two months.
8. Any subject with a hematocrit of less than 35.
9. Subjects who are claustrophobic.
10. Women taking oral contraceptives.
11. alcohol consumption greater than 30 grams daily.
12. baseline plasma triglyceride levels over 200 mg/dl

Primary outcomes:
measure: Muscle Insulin Sensitivity-M Value
timeFrame: 48 hr after lipid/saline infusion
Secondary outcomes:
measure: TLR4 Messenger Ribonucleic Acid (mRNA) in Muscle
timeFrame: 48 hr following lipid/saline infusion, pre-clamp
measure: Extracellular Signal-regulated Kinase (ERK) Phosphorylation in Muscle
timeFrame: 48 hr following lipid or saline infusion, pre-clamp
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Audie L. Murphy VA Hospital
state: Texas
Study officials:
affiliation: Univerisity of Texas Health Science Center at San Antonio
name: Nicolas Musi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hussey SE, Lum H, Alvarez A, Cipriani Y, Garduno-Garcia J, Anaya L, Dube J, Musi N. A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. Diabetologia. 2014 Mar;57(3):582-91. doi: 10.1007/s00125-013-3111-x. Epub 2013 Dec 14.