Insulin Resistance
Conditions
Brief summary
Data supports diet induced obesity leads to activation of the IKK/NF-kB inflamatory pathway and that chronic inflammation leads to insulin resistance and diabetes. In rodents, salicylates inhibit IKK/NF-kB and may improve insulin sensitivity. We will study if this is true in people.
Detailed description
Please see the following review articles on this topic: Shoelson SE, Lee J, Goldfine AB. (2006) Inflammation in insulin resistance. J. Clin. Invest. 116, 1793-1801. Goldfine AB, Fonseca V and Shoelson SE (2010) Therapeutic approaches to target inflammation in type 2 diabetes. Clin Chem. 57, 162-167. Donath MY and Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 11, 98-107. Goldfine AB and Shoelson SE (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest. 127, 83-93.
Interventions
DRUGSalsalate
Active
DRUGPlacebo
Placebo for salslate, used only in the third trial
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Joslin Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
age 18 to 65 years, inclusive; HbA1c \>6.0% (off medication-diabetic) normal hemoglobin and hematocrit, without donation of blood in the previous 2 months; without involvement in any study evaluating an investigational drug or device for the previous 2 months; normal clotting studies; female postmenopausal or surgically sterile, or using barrier or oral contraception and with a negative pregnancy test.
Exclusion criteria
pregnant or lactating women; patients with persistent ketonuria or a history of ketoacidosis (suggesting the need for insulin therapy); current of previous use of insulin for glucose control; patients with abnormal liver function defined as elevation of bilirubin, alkaline phosphatase, ALT, AST, or GGTP more than 1.5 times the upper limit of normal; patients with kidney disease (serum creatinine \> 1.5 mg/dL) macroalbuminuria (1+ protein on a standard urine dip-stick, or \> 300 mg urinary albumin/day)- (patients with microalbuminuria will be enrolled); patients with any significant diseases or conditions, including emotional or psychiatric disorders and substance abuse, including history of binge drinking, that, in the opinion of the investigator, are likely to alter the patient's ability to complete the study; patients with metabolic acidosis (abnormal anion gap); history of gastric ulcer, dyspepsia, or upper or lower GI bleed; history of allergy to aspirin, or bleeding diathesis or currently on oral anticoagulants including warfarin, heparin, aspirin or other NSAIDs; patients with major vascular event within 6 months of screening for the study (e.g., myocardial infarction stroke, coronary artery bypass graft (CABG) surgery, angioplasty, peripheral vascular surgery); patients with chronic heart disease, or a history of myocardial infarction or stroke. Symptomatic angina pectoris or cardiac insufficiency as defined by the NYHA; classification as Functional Class III or IV; patients with HbA1C \> 13% (normal range 4-6%); patients who smoke more than one pack of cigarettes daily; patients taking treatment medications known to affect insulin sensitivity (e.g. diuretics, beta-blockers); patients taking warfarin, heparin or NSAID on a chronic basis; patients with inadequately controlled serum lipid levels (total cholesterol ≥ 275 mg/dL and fasting triglycerides ≥ 450 mg/dL); patients with history of cancer within 5 years prior to screening for the study other than basal cell carcinoma; active alcohol or other substance abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose | 4 weeks | fasting glucose |
Secondary
| Measure | Time frame |
|---|---|
| Adiponectin | 4 weeks |
Participant flow
Recruitment details
This study was active between 2000-2008. The location was an accademic clinic setting in the USA.
Pre-assignment details
Subjects were instructed to monitor fasting blood glucose levels and with symptoms of hyperglycemia or hypoglycemia, and to avoid changing dietary or exercise habits.
Participants by arm
| Arm | Count |
|---|---|
| Salsalate Randomized cohorts - Active | 8 |
| Placebo Randomized cohorts - Placebo | 9 |
| Total | 17 |
Baseline characteristics
| Characteristic | Salsalate | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 17 Participants |
| Age, Continuous | 51 years STANDARD_DEVIATION 12 | 54 years STANDARD_DEVIATION 8 | 52 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 0 / 8 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
Glucose
fasting glucose
Time frame: 4 weeks
Population: Receiving one dose of study drug and with measured value
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Glucose | 7.1 mmol/L | Standard Deviation 0.3 |
| Salsalate | Glucose | 6.4 mmol/L | Standard Deviation 0.3 |
Secondary
Adiponectin
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adiponectin | 22.7 mg/ml | Standard Deviation 2.5 |
| Salsalate | Adiponectin | 10.6 mg/ml | Standard Deviation 2 |