Insulin Resistance
Conditions
Brief summary
This study will help us understand the possible beneficial effects of insulin in inflammation. Inflamamtion is considered to be the cause of atherosclerosis and heart disease.
Detailed description
Obesity and type 2 diabetes are major health problems in the United States and the world. Both conditions are characterized by increased inflammation and oxidative stress and are associated with increased risk of cardiovascular disease. Our previous work shows that insulin exerts a prompt and powerful anti-inflammatory effect, on circulating blood cells and in plasma in healthy subjects and in critically ill patients. Toll like receptors (TLRs) recognize bacterial and viral products like endotoxin and viruses and are major determinants of the inflammatory response against foreign pathogens. In view of the recent data showing that TLRs recognize a range of molecules and proteins that are not of pathogenic source like saturated lipids and that TLRs are involved in the pathogenesis of atherosclerosis which leads to cardiovascular disease and insulin resistance which leads to type 2 diabetes (DM) we hypothesized that insulin infusion suppresses TLRs expression. Our preliminary data show that insulin infusion for 4 hours reduces the levels of many TLRs and thus might protect from inflammation induced conditions We therefore propose to investigate, in more detail, the effect of infusing different doses of insulin on TLRs mRNA and protein levels and its activity in obese and DM subjects over a longer infusion period and a larger number of subjects in circulating white blood cells and in fat tissue. Also we will be comparing the baseline levels of TLRs and TLRs related proteins as well as their modulation by insulin between normal, obese and DM subjects.
Interventions
DRUGinsulin infusion
insulin to be infused at 3.5 units/hour along with Dextrose 12.5% at a rate to achieve blood glucose levels between 80-120mg/dl
Dextrose 12.5% will be infused at a rate to maintain blood glucose level 80-120mg/dl
DRUGSaline Infusion
Saline will be infused at 100ml/hr
Sponsors
University at Buffalo
American Diabetes Association
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All subjects in each cohort (normal weight, obese and obese with type 2 diabetes) received the 3 interventions (insulin, followed by dextrose, and then Saline) in a fixed sequence.
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Lean Group: 1. Age: 20 to 65 years of age inclusive 2. Sex: male or female 3. Normal fasting plasma glucose (65-100 mg/dl) 4. Normal BMI (20-25) Obese Group: 1. Age: 20 to 65 years of age inclusive 2. Sex: male or female 3. Normal fasting plasma glucose (65-100 mg/dl) 4. BMI\> 30 DM Group: 1. Type 2 Diabetes Mellitus 2. Age: 20 to 65 years of age inclusive 3. Sex: male or female 4. BMI \>30 5. Hba1c \< 8% 6. If on statins, angiotensin converting enzyme inhibitor, angiotensin receptor blocker or low dose aspirin, should be on a stable dose for one month.
Exclusion criteria
1. Pregnancy 2. Congestive heart failure 3. Heart Rate \<50 beats /minute 4. Sick Sinus Syndrome 5. Second or third degree heart block 6. Blood pressure \<80 mm systolic or \> 160/100 mmHg 7. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass surgery or coronary angioplasty) in the previous three months 8. Hepatic disease (transaminase \> 3 times normal) 9. Renal impairment (serum creatinine \> 1.5) 10. History of drug or alcohol abuse within past one year 11. Participation in any other concurrent clinical trial 12. Potassium (K+) values \<3.5 meq/l to \> 5.5 meq/l) 13. Any other life-threatening, non-cardiac disease 14. Use of an investigational agent or therapeutic regimen within 30 days of study 15. Type 2 diabetics on thiazolidinediones and/ or insulin 16. Subjects on steroids, NSAIDS or antioxidants 17. Patients taking exenatide or sitaglipin or loop diuretics 18. Anemia (Hemoglobin level less than 12gm/dl in females and 13gm/dl in males) 19)Allergy to lidocaine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Suppression of Toll Like Receptor (TLR) 2 mRNA by Insulin | 24 hours | percent change from baseline (0hrs) in TLR2 mRNA in mononuclear cells (MNC) following up to 24 hrs of 3.5U/hr insulin infusion (II) adjusted to the similar average change following up to 24hr infusion of dextrose (DI) and saline (SI) control groups. The correction is calculated as follows: Corrected percent change from baseline following II= change from baseline following II - (average change from baseline following DI and SI)\*100. Changes from baseline are calculated as: (expression at 24hrs-expression at 0hr)/expression at 0hr. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in TLR4 mRNA in MNC | 24 hours | percent change from baseline (0hrs) in TLR4 mRNA in mononuclear cells (MNC) following up to 24 hrs of 3.5U/hr insulin infusion (II) adjusted to the same change following up to 24hr infusion of dextrose (DI) and saline (SI) control groups in this order. The correction is conducted as follows: Corrected percent change from baseline following II= change from baseline following II - (average change from baseline following DI and SI)\*100. Changes from baseline are calculated as: (expression at 24hrs-expression at 0hr)/expression at 0hr. 2- For each PCR measurement of specific target gene, relative expression of 3 housekeeping genes (beta-actin, ubiquitin C and cyclophilin A) from the same cDNA is assessed, and normalization factor (based on the 3 genes) is calculated and entered into PCR software to automatically adjust/normalize target gene expression |
| Change in CD14 Expression in MNC | 24hrs | percent change from baseline (0hrs) in CD14 mRNA in mononuclear cells (MNC) following up to 24 hrs of 3.5U/hr insulin infusion (II) adjusted to the similar average change following up to 24hr infusion of dextrose (DI) and saline (SI) control groups in this specific order. The correction is conducted as follows: Corrected percent change from baseline following II= change from baseline following II - (average change from baseline following DI and SI)\*100. Changes from baseline are calculated as: (expression at 24hrs-expression at 0hr)/expression at 0hr. For each PCR measurement of specific target gene, relative expression of 3 housekeeping genes (beta-actin, ubiquitin C and cyclophilin A) from the same cDNA is assessed, and normalization factor (based on the 3 genes) is calculated and entered into PCR software to automatically adjust/normalize target gene expression. |
| Fasting TLR2 mRNA Expression Levels in the 3 Cohorts | baseline/fasting | Comparison of TLR2 mRNA expression in MNC in fasting condition. Fasting TLR2 mRNA expression is measured using real-time PCR at baselines of the 3 visits (II, DI, SI visits) is averaged and reported as arbitrary units. For each PCR measurement of specific target gene, relative expression of 3 housekeeping genes (beta-actin, ubiquitin C and cyclophilin A) from the same cDNA is assessed, and normalization factor (based on the 3 genes) is calculated and entered into PCR software to automatically adjust/normalize target gene expression. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORParesh Dandona, MBBS
The Research foundation of SUNY at Buffalo
Participant flow
Pre-assignment details
All subjects in each cohort received insulin, followed by dextrose, and then Saline, in a fixed sequence.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 50 YEARS STANDARD_DEVIATION 12 |
| Body Mass Index (BMI) | 38.2 Kg/m^2 STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 10 | 0 / 19 |
| other Total, other adverse events | 0 / 13 | 0 / 10 | 0 / 19 |
| serious Total, serious adverse events | 0 / 13 | 0 / 10 | 0 / 19 |
Outcome results
None listed