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
To determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) will reduce inflammation and improve glucose metabolism in insulin resistant (obese and T2DM) subjects.
Detailed description
E5564 = Eritoran
Interventions
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) with normal glucose-tolerant subjects without a family history of type 2 DM * obese (BMI 30-37 kg/m2) with normal glucose-tolerant subjects * Type 2 DM subjects base on ADA criteria, who have HbA1c \<8.5% and control with diet or sulfonylureas. * 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
* Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects on a stable dose of statin (\>3 months) 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 in Peripheral Blood Monocytes | 72 hours | TLR4 expression in 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 TLR4 Expression in Muscle Tissue | 72 hours | TLR4 expression in muscle tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no 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. |
| Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration | 72 hours | TNF-alpha levels are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range. |
| Effect of Eritoran on TLR4 Expresison in Adipose Tissue | 72 hours | TLR4 expression in the adipose tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Obese Group Subjects with BMI \>30 kg/m2 were enrolled to receive two infusions, the order of which was randomly assigned. | 11 |
| Type 2 Diabetic Subjects Subjects with BMI \>30 kg/m2 and 2-hour Oral Glucose Tolerance Test \>200mg/dL | 3 |
| Lean/Healthy Subjects with BMI \<26 kg/m2 and normal glucose tolerant | 1 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout (3-4weeks Between Infusions) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| Washout (3-4weeks Between Infusions) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Obese Group | Total | Lean/Healthy | Type 2 Diabetic Subjects |
|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 6 | 53 years STANDARD_DEVIATION 12.4 | 19 years STANDARD_DEVIATION 0 | 55 years STANDARD_DEVIATION 15.6 |
| BMI | 32.1 kg/m^2 STANDARD_DEVIATION 1.8 | 31.5 kg/m^2 STANDARD_DEVIATION 4 | 19 kg/m^2 STANDARD_DEVIATION 0 | 33.5 kg/m^2 STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 11 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Fasting plasma glucose | 5.1 mg/dL STANDARD_DEVIATION 0.8 | 5.4 mg/dL STANDARD_DEVIATION 0.9 | 4.5 mg/dL STANDARD_DEVIATION 0 | 6.9 mg/dL STANDARD_DEVIATION 0.7 |
| HbA1c | 5.4 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.2 | 5.6 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.5 | 5.3 Percentage of glycated hemoglobin STANDARD_DEVIATION 0 | 6.3 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 15 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 3 | 0 / 3 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 9 / 11 | 9 / 11 | 1 / 3 | 2 / 3 | 0 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 3 | 0 / 3 | 0 / 1 | 0 / 1 |
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
Population: Data from T2DM subjects and Lean subject were not collected for primary outcome measure because of insufficient number of participants in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on Hepatic Insulin Sensitivity | 2.0 mg/kg/min | Standard Error 0.2 |
| Obese Group - Eritoran | Effect of Eritoran on Hepatic Insulin Sensitivity | 1.9 mg/kg/min | Standard Error 0.1 |
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
Population: Data from T2DM subjects and Lean subject were not collected for primary outcome measure because of insufficient number of participants in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on Muscle Insulin Sensitivity | 8.0 mg/kg/min | Standard Error 0.9 |
| Obese Group - Eritoran | Effect of Eritoran on Muscle Insulin Sensitivity | 10.6 mg/kg/min | Standard Error 1.1 |
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 TNF-alpha (Tumor Necrosis Factor-alpha) Concentration
TNF-alpha levels are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range.
Time frame: 72 hours
Population: Data from T2DM subjects and Lean subject were not analyzed because the number of participants was insufficient in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration | 2.4 pg/ml | Standard Error 0.3 |
| Obese Group - Eritoran | Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration | 2.3 pg/ml | Standard Error 0.2 |
Secondary
Effect of Eritoran on TLR4 Expresison in Adipose Tissue
TLR4 expression in the adipose tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Time frame: 72 hours
Population: The total number of obese subjects enrolled is 9. However, we were only able to obtain fat biopsies from 4 subjects. In addition, data from T2DM subjects and Lean subject were not analyzed for this secondary outcome measure because of insufficient number of participants in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on TLR4 Expresison in Adipose Tissue | 1 AU | Standard Deviation 0.11 |
| Obese Group - Eritoran | Effect of Eritoran on TLR4 Expresison in Adipose Tissue | 1.22 AU | Standard Deviation 0.07 |
Secondary
Effect of Eritoran on TLR4 Expression in Muscle Tissue
TLR4 expression in muscle tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Time frame: 72 hours
Population: The total number of obese subjects enrolled is 9. However, we were only able to obtain muscle biopsies from 7 subjects. In addition, data from T2DM subjects and Lean subject were not collected for this secondary outcome measure because of insufficient number of participants in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on TLR4 Expression in Muscle Tissue | 1 AU | Standard Error 0.11 |
| Obese Group - Eritoran | Effect of Eritoran on TLR4 Expression in Muscle Tissue | 1.16 AU | Standard Error 0.16 |
Secondary
Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes
TLR4 expression in 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 T2DM subjects and Lean subject were not analyzed because the number of participants was insufficient in the 2 groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Group - Placebo | Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes | 1.1 AU | Standard Error 0.1 |
| Obese Group - Eritoran | Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes | 1.2 AU | Standard Error 0.1 |