Insulin Sensitivity
Conditions
Keywords
Insulin signaling and glucose disposal in muscle, Hepatic insulin sensitivity, TLR4 signaling and inflammatory gene expression, Plasma cytokine concentration, Intramyocellular diacylglycerol and ceramide content
Brief summary
The purpose of this study is to determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) prevents lipid-induced insulin resistance in lean, normal glucose tolerant (NGT) subjects.
Detailed description
E5564 = Eritoran
Interventions
DRUGEritoran
Eritoran = E5564 Eritoran is a pharmacologic inhibitor of TLR4.
DRUGD5W (5% Dextrose in water)
D5W = 5% Dextrose Water Vehicle
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participant, Care Provider, Investigator, Outcomes Assessor
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects capable of giving informed consent. * lean (BMI \<26 kg/m2) * normal glucose-tolerant subjects (completers) without a family history of Type 2 diabetes mellitus (DM) * Both genders. (50% males) * Age = 18-65 years. Older subjects are excluded because aging is a pro-inflammatory state. * All ethnic groups * Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for \>=6 months. * Lab: Hematocrit \>=34%, serum creatinine \<=1.4 mg/dL, normal electrolytes, urinalysis, and coagulation tests. Liver function tests up to 2x normal range. * Stable body weight (+/-1%) for \>=3 months. * One or less sessions of strenuous exercise/wk for last 6 months.
Exclusion criteria
* Presence of diabetes or impaired glucose tolerance based on ADA criteria; * Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects on a stable dose of statin (\>3months) are eligible. * Non-steroidal anti-inflammatory drugs or systemic steroid use for more than 1 week within 3 months. * Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsies. * History of heart disease (New York Heart Classification greater than class II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers. * Poorly controlled blood pressure (systolic BP\>160, diastolic BP\>90 mmHg). * Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Eritoran on Muscle Insulin Sensitivity | 72 hours | Muscle insulin sensitivity = muscle insulin sensitivity is determined by euglycemic hyperinsulinemic clamp procedure. M value (mg glucose / kg of body weight / minute) calculated from the clamp is measured. Higher M value indicates better insulin sensitivity. There is no established reference range. |
| Effect of Eritoran on Hepatic Insulin Sensitivity | 72 hours | Hepatic insulin sensitivity = is determined by euglycemic hyperinsulinemic clamp procedure. Endogenous glucose production or EGP (mg/kg/min) calculated from the clamp is measured. Lower EGP indicates better hepatic insulin sensitivity. There is no established reference range. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | 72 hours | TLR4 expression on the peripheral blood monocytes is determined by flow cytometry using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. |
| Effect of Eritoran on Plasma Cytokine Concentration | 72 hours | TNF-alpha levels (tumor necrosis factor-alpha) are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range. |
| Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content | 72 hours | Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lean Subjects Ten lean subjects were randomized to receive 3 infusions in different order. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Lean Subjects |
|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 1 |
| BMI | 23.8 kg/m^2 STANDARD_DEVIATION 2.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Fasting plasma glucose | 5.5 mg/dL STANDARD_DEVIATION 0.3 |
| HbA1c | 5.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 7 / 10 | 10 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Effect of Eritoran on Hepatic Insulin Sensitivity
Hepatic insulin sensitivity = is determined by euglycemic hyperinsulinemic clamp procedure. Endogenous glucose production or EGP (mg/kg/min) calculated from the clamp is measured. Lower EGP indicates better hepatic insulin sensitivity. There is no established reference range.
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D5W (5% Dextrose in Water) + Saline | Effect of Eritoran on Hepatic Insulin Sensitivity | 2.2 mg/kg/min | Standard Error 0.1 |
| D5W (5% Dextrose in Water) + Intralipid | Effect of Eritoran on Hepatic Insulin Sensitivity | 2.3 mg/kg/min | Standard Error 0.1 |
| Eritoran + Intralipid | Effect of Eritoran on Hepatic Insulin Sensitivity | 2.2 mg/kg/min | Standard Error 0 |
Primary
Effect of Eritoran on Muscle Insulin Sensitivity
Muscle insulin sensitivity = muscle insulin sensitivity is determined by euglycemic hyperinsulinemic clamp procedure. M value (mg glucose / kg of body weight / minute) calculated from the clamp is measured. Higher M value indicates better insulin sensitivity. There is no established reference range.
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D5W (5% Dextrose in Water) + Saline | Effect of Eritoran on Muscle Insulin Sensitivity | 11.9 mg/kg/min | Standard Error 0.6 |
| D5W (5% Dextrose in Water) + Intralipid | Effect of Eritoran on Muscle Insulin Sensitivity | 10.2 mg/kg/min | Standard Error 0.7 |
| Eritoran + Intralipid | Effect of Eritoran on Muscle Insulin Sensitivity | 9.8 mg/kg/min | Standard Error 0.6 |
p-value: 0.02ANOVA
Secondary
Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content
Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes.
Time frame: 72 hours
Population: Data were not collected due to lack of funding.
Secondary
Effect of Eritoran on Plasma Cytokine Concentration
TNF-alpha levels (tumor necrosis factor-alpha) are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range.
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D5W (5% Dextrose in Water) + Saline | Effect of Eritoran on Plasma Cytokine Concentration | 1.6 pg/ml | Standard Error 0.2 |
| D5W (5% Dextrose in Water) + Intralipid | Effect of Eritoran on Plasma Cytokine Concentration | 2.0 pg/ml | Standard Error 0.3 |
| Eritoran + Intralipid | Effect of Eritoran on Plasma Cytokine Concentration | 2.0 pg/ml | Standard Error 0.1 |
Secondary
Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes
TLR4 expression on the peripheral blood monocytes is determined by flow cytometry using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Time frame: 72 hours
Population: Data from 1 subject were not collected due to instrument failure. Therefore, data from 9 subjects were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D5W (5% Dextrose in Water) + Saline | Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | 1.1 AU | Standard Error 0.1 |
| D5W (5% Dextrose in Water) + Intralipid | Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | 1.2 AU | Standard Error 0.2 |
| Eritoran + Intralipid | Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | 1.1 AU | Standard Error 0.1 |