Insulin Resistance, Metabolic Syndrome
Conditions
Keywords
inflammation, obesity, diabetes
Brief summary
The purpose of this study is to determine whether improvement in fat and muscle metabolism after the treatment with Omacor (fish oils) provides insight into the link between obesity, fat and muscle function leading to metabolic syndrome, which is a risk factor for heart disease and diabetes.
Detailed description
The development of type 2 diabetes (T2DM) represents a complex series of events, involving abnormalities in adipose tissue lipid distribution and insulin action. Along with an increase in adipose tissue mass is an increase in inflammation brought about by macrophages that infiltrate adipose tissue. These macrophages express inflammatory cytokines such as tumor necrosis factor (TNF) and Interleukin -6 (IL-6) which are correlated with insulin resistance and metabolic syndrome, and suggest that metabolic syndrome and diabetes are conditions characterized by a state of chronic, low-grade inflammation. Thiazolidinediones (TZDs) improve insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR) , and there is much evidence that PPAR agonists also have anti-inflammatory properties. Fish oils are rich sources of Omega-3 fatty acids and there is a large literature on the potential benefits of fish oils on lowering serum triglycerides, cardiovascular protection, and immune modulation, and there is evidence that fish oils also activate PPAR . Hence, the focus of this study will be on subjects with insulin resistance and metabolic syndrome, but who do not yet have diabetes. We plan to treat insulin resistant subjects with fish oils and ask the following questions. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. Aim 1. From blood samples drawn before and after treatment, we will measure levels of circulating inflammatory cytokines. Aim 2. Adipose tissue biopsies will be performed before and after fish oil treatment. From the adipose biopsies, we will quantitate cytokine expression, macrophage number, and we will look for evidence of macrophage apoptosis. Aim 3. We will determine whether fish oil treatment increases the adipose tissue secretion and serum level of the high molecular weight form of adiponectin. Hypothesis 2. The reduction in inflammatory markers occurs through an activation of PPAR by the fish oils. Aim 4. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR inhibitor. We will determine whether fish oils stimulate the secretion of the high molecular weight adiponectin isoform from adipose tissue and whether they induce apoptosis from macrophages, and whether this process is inhibited by the PPAR inhibitor. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid, and an improvement in muscle insulin signal transduction. Aim 5. Before and after treatment with fish oils, insulin sensitivity will be measured, along with intramyocellular lipid and genes involved in insulin action and muscle lipid oxidation.
Interventions
DRUGomega-3 fatty acid
4g of omega-3 fatty acid daily by mouth for 12 weeks.
DRUGplacebo
4 inert capsules daily by mouth for 12 weeks.
Sponsors
GlaxoSmithKline
National Institutes of Health (NIH)
National Center for Research Resources (NCRR)
Philip Kern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI 27-45 kg/m2 * age 35-65 years * abnormal carbohydrate metabolism
Exclusion criteria
* triglycerides over 700 mg/dl * renal disease * liver disease * congestive heart failure * history of heart disease or stroke * chronic aspirin or NSAID use (anti-coagulant) * history of a bleeding disorder * use of statins, fibrates, ACE inhibitors, angiotensin II receptor blockers and glucocorticoids * diet heavy in omega-3 fatty acids (salmon, sardines, flaxseeds)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adipocyte Size | baseline | Prior to starting the fish oil regiment, participants will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine adipocyte size |
| Adipocyte Size After Fish Oil Treatment | week 12 | After completing the fish oil regiment, participant will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine individual adipocyte size |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Insulin Resistance | baseline | Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose levels were plotted on a time course curve and analyzed using the MIDMOD algorithm. |
| Insulin Resistance After Fish Oil Regiment | week 12 | Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose and Insulin levels will be plotted on a time course curve and analyzed using the MINMOD algorithm. |
Countries
United States
Participant flow
Recruitment details
Non-diabetic subjects with either impaired glucose tolerance, impaired fasting glucose, or at least three features of metabolic syndrome were recruited at the University of Kentucky or the University of Arkansas. Exclusion criteria included history of coronary heart disease, inflammatory disease or chronic anti-inflammatory use
Participants by arm
| Arm | Count |
|---|---|
| Fish Oil Group 4g Lovaza (omega-3 fatty acid) daily.
omega-3 fatty acid: 4g of omega-3 fatty acid daily by mouth for 12 weeks. | 19 |
| Control Group placebo (4 non-active capsules daily)
placebo: 4 inert capsules daily by mouth for 12 weeks. | 14 |
| Total | 33 |
Baseline characteristics
| Characteristic | Total | Control Group | Fish Oil Group |
|---|---|---|---|
| 2 hour Glucose | 163.1 mg/dl STANDARD_DEVIATION 37.6 | 157.8 mg/dl STANDARD_DEVIATION 29 | 167.8 mg/dl STANDARD_DEVIATION 43.3 |
| Age, Continuous | 50.8 years STANDARD_DEVIATION 9.3 | 53.3 years STANDARD_DEVIATION 8.3 | 48.8 years STANDARD_DEVIATION 9.8 |
| BMI | 33.4 kg/m^2 STANDARD_DEVIATION 4.9 | 33.8 kg/m^2 STANDARD_DEVIATION 4.3 | 33.4 kg/m^2 STANDARD_DEVIATION 5.4 |
| Body fat | 44.9 percent STANDARD_DEVIATION 8.64 | 46.2 percent STANDARD_DEVIATION 10.1 | 44.4 percent STANDARD_DEVIATION 7.4 |
| Cholesterol | 206 mg/dl STANDARD_DEVIATION 42.3 | 204.7 mg/dl STANDARD_DEVIATION 44.5 | 207.1 mg/dl STANDARD_DEVIATION 41.6 |
| HbA1c | 5.8 percent STANDARD_DEVIATION 0.4 | 5.6 percent STANDARD_DEVIATION 0.4 | 6.0 percent STANDARD_DEVIATION 0.3 |
| High density lipoprotein | 49.50 mg/dl STANDARD_DEVIATION 13.63 | 47.7 mg/dl STANDARD_DEVIATION 12.2 | 53.5 mg/dl STANDARD_DEVIATION 15.21 |
| Low density lipoprotein | 125.5 mg/dl STANDARD_DEVIATION 37.5 | 122.4 mg/dl STANDARD_DEVIATION 40.8 | 125.9 mg/dl STANDARD_DEVIATION 36.8 |
| Region of Enrollment United States | 33 participants | 14 participants | 19 participants |
| Sex: Female, Male Female | 22 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 11 Participants | 5 Participants | 6 Participants |
| Triglycerides | 155.7 mg/dl STANDARD_DEVIATION 69 | 163.0 mg/dl STANDARD_DEVIATION 82.8 | 150 mg/dl STANDARD_DEVIATION 57.92 |
| Weight | 96.8 kilograms STANDARD_DEVIATION 14.9 | 92.1 kilograms STANDARD_DEVIATION 16.9 | 99.8 kilograms STANDARD_DEVIATION 12.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 14 |
| other Total, other adverse events | 0 / 19 | 0 / 14 |
| serious Total, serious adverse events | 0 / 19 | 0 / 14 |
Outcome results
Primary
Adipocyte Size After Fish Oil Treatment
After completing the fish oil regiment, participant will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine individual adipocyte size
Time frame: week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fish Oil Group | Adipocyte Size After Fish Oil Treatment | 4869 square micrometers | Standard Error 209 |
| Control Group | Adipocyte Size After Fish Oil Treatment | 4051 square micrometers | Standard Error 191 |
p-value: 0.05t-test, 2 sided
Primary
Baseline Adipocyte Size
Prior to starting the fish oil regiment, participants will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine adipocyte size
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fish Oil Group | Baseline Adipocyte Size | 4958 square micrometers | Standard Error 249 |
| Control Group | Baseline Adipocyte Size | 4489 square micrometers | Standard Error 231 |
p-value: 0.05t-test, 2 sided
Secondary
Baseline Insulin Resistance
Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose levels were plotted on a time course curve and analyzed using the MIDMOD algorithm.
Time frame: baseline
Population: all participants were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fish Oil Group | Baseline Insulin Resistance | 1.8 [mU/L]^-1 x [min]^-1] | Standard Error 0.2 |
| Control Group | Baseline Insulin Resistance | 1.8 [mU/L]^-1 x [min]^-1] | Standard Error 0.3 |
p-value: 0.5t-test, 2 sided
Secondary
Insulin Resistance After Fish Oil Regiment
Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose and Insulin levels will be plotted on a time course curve and analyzed using the MINMOD algorithm.
Time frame: week 12
Population: all participants measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fish Oil Group | Insulin Resistance After Fish Oil Regiment | 1.7 [mU/L]^-1 x [min]^-1] | Standard Error 0.3 |
| Control Group | Insulin Resistance After Fish Oil Regiment | 1.5 [mU/L]^-1 x [min]^-1] | Standard Error 0.2 |
p-value: 0.5t-test, 2 sided