Ignite Creation Date:
2024-05-06 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 12:52 PM
Study NCT ID:
NCT03643783
Status:
COMPLETED
Last Update Posted:
2021-03-01
First Post:
2018-08-16
Brief Title:
Impact of Plasma Soluble Prorenin Receptor in Obese and Type 2 Diabetic Patients
Sponsor:
Tulane University
Organization:
Tulane University
Study Overview
Official Title:
Impact of Plasma Soluble Prorenin Receptor in Obese and Type 2 Diabetic Patients
Status:
COMPLETED
Status Verified Date:
2021-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Obesity increases the risk for type 2 diabetes mellitus high blood pressure and mortality Obesity is a major health problem in the United States especially in the Deep South regions Obesity increases the risk for T2DM the occurrence of hypertension and mortality but the efficacy of long-term weight loss medications has been disappointing There are three options available for patients who want to lose weight lifestyle modification pills or weight loss by bariatric surgery When we compare the three options available bariatric surgery is the most effective method to lose weight at present Bariatric surgery allows patients lose the most weight be able to sustain the weight reduction over time and more importantly diabetes mellitus and other cardiovascular risk factors significantly improve Understanding the link among obesitydiabetes-hypertension is crucial in order to develop new therapeutic targets to decrease CVD morbidity and mortality There is less prevalence of coronary artery disease CAD in premenopausal women than in men but once initiated the morbidity and mortality due to CAD in women is worse than in men thus highlighting this sex difference in CVD Indeed women with diabetes exhibit a higher risk of myocardial infarction and stroke mortality than men compared to people without diabetes In obese subjects there is inappropriate activation of the systemic and adipose renin-angiotensin system The prorenin receptor is a molecule expressed in various tissues including fat tissue and part of it the soluble prorenin receptor can be secreted into the blood The prorenin receptor is part of a very important system that regulates blood pressure and fat in our body the renin-angiotensin system In this prospective observational human pilot study we will determine whether the adipose tissue is the major supplier of soluble prorenin receptor levels in the plasma of obese patients and the relationship between blood soluble prorenin receptor and diabetes mellitus obesity high blood pressure and other important cardiovascular risk factors Outcomes from this study will allow a better understanding of the complex factors that link obesity diabetes mellitus and other cardiovascular risk factors and designing better therapeutic alternatives to improve patients health particularly in obese diabetic women
Detailed Description:
Human blood samples will be collected prospectively from 50 obese patients who are enrolled and planning to undertake bariatric surgery in the Outpatient Bariatric Surgery Clinic at Tulane University HSC Christopher G Ducoin MD MPH Chair of Bariatric Surgery Clinic and Surgeon and Shauna Levy MD Bariatric Surgeon Specialist Type of bariatric surgery used in each patient will be recorded Because it has been shown that after 6 months of bariatric surgery there is about 50-60 BW loss 15-18 we plan to obtain two tubes of blood samples with 5 mL of blood each Blood will be drawn during the pre-Op visit and during 3 visits following the bariatric surgery 1 week 2-3 days 1 month 2 weeks and 6 months 1 - 2 months Blood samples will be used for plasma measurements of glycaemia HbA1c lipids profile LDL HDLtriglycerides and sPRR Time of drawing of blood sample will be recorded due to potential effects of circadian rhythms to the RAS Quantification of plasma sPRR by ELISA will be performed in Dr Minolfa Prietos laboratory located at Tulane University School of Medicine Patient biological samples will be identified by a code that will link the sample to the patient After conclusion of the study samples will be used exclusively for obesity and T2DM related conditions research Background Factors will include sex age race ethnicity health insurance status and personal medical history will assess presence of any of the following conditions diabetes mellitus or hypertension including any of the following treatments antihypertensive drugs -ACEi AT1R blockers diuretics or calcium antagonists use of oral contraceptives or hormone replacement previous surgeries type date last menstruation date including any menstrual irregularity congestive heart failure CHF peripheral vascular disease PVD pulmonary hypertension PHTN or ischemic heart disease obstructive sleep apnea OSA asthma deep vein thrombosispulmonary embolism DVTPE gastroesophageal reflux disease GERD liver disease dyslipidemia polycystic ovarian syndrome depression alcohol use substance abuse andor tobacco use Physical exam will include BW BMI waist circumference height office BP DBP and SBP measured at the Outpatient Clinic with the patient in a sitting position after resting for at least 5 min and pulse rate Patient biological samples will be identified by a code linking the sample with the patient Plasma samples for ELISA measurements will be assayed in duplicate in a blinded fashion ELISA kits are commercial available and manufactured by IBL America Inc This assay is routinely performed in the PIs laboratory and has been validated using appropriate standards provided by the manufacturers We will use duplicate or triplicate samples when assayed Biological controls such as buffer as blank will be used as technical controls Because ELISA kits will be obtained from commercial vendors authentication by the vendors includes certifications of reactivity purity applications These methods and outcomes have been previously reported Internal controls standards curve of various concentrations of sPRR will be included in each plate reading for comparison purposes To reduce bias samples will be randomly assayed wherever possible and include positive standard controls with known concentrations for comparisons purposes Both a data handling plan outliers report of missing data and a statistical analysis plan Statistical analysis plan endpoints primary and secondary inclusion for multiple testing will be used Our lab has authenticated sPRR ELISA and compared with measurements published by others To ensure the detection of meaningful and realistic differences the sample numbers are based on the requirement to perform each assay Power and Sample size calculations To ensure reproducibility all protocols will be reported including all of the experimental conditions in detail After conclusion of the study samples will be used exclusively for obesity and DM related research Aim 1 Determine whether plasma levels of sPRR decrease in obese patients after bariatric surgery Scientific Premise and Rationale In obese rats PRR and renin are augmented two-fold in adipose tissue Preliminary data from mice with T2DM-induced by high fat diet showed presence of a phenotype characterized by obesity increased SBP glucose intolerance marked insulin resistance and increased levels of sPRR in plasma by 18-wks on the dietary regimen These mice also showed increased PRR expression in adipocytes from visceral fat Our preliminary study showed that plasma sPRR levels are higher in lean men than lean women In contrast plasma sPRR levels were higher in obese diabetic women than in men Furthermore we found that obese patients with T2DM exhibited a positive correlation between plasma sPRR and BMI in women but not in men This aims seeks to test the hypothesis that adipose tissue is the major supplier of plasma sPRR in obese patients
Experimental Design quantifications will be done in plasma samples obtained from 50 obese patients undergoing bariatric surgery Plasma samples will be drawn before bariatric surgery pre-Op visit and at each of 2 follow-up visits 1 month 1 - 2 weeks and at 6 months 1-2 months for the assessment of plasma sPRR by ELISA Prietos Lab Tulane University See Power Analysis These samples will be obtained from patients of the Bariatric and Minimal Invasive Surgery Clinic of Christopher G Ducoin MD at Tulane HSC Collaborator Comparisons will be established with human biological de-identified plasma samples from lean control patients that have already been collected and are available as part of the Tulane Obesity-Endocannabinoids Study Tina Thethi MD Collaborator After patients consent agreement the patient will be examined in the Bariatric and Minimal Invasive Surgery Clinic for vital signs BP SBP and DBP taken by sphygmomanometry waist-to-hip ratio and BMI Fasting blood samples will be drawn by vein puncture for glycaemia HbA1c lipids profile LDL HDL triglycerides and sPRR Background factors and personal medical history will be taken as described in the Study Design section Power Analysis and Statistical Considerations All the outcomes at each time point will be summarized as mean and standard deviation SD The repeated measures analysis of variance and paired test will be conducted to evaluate the change across the time points The historical data suggest that about 10 patients receive bariatric surgery per month in the Outpatient Bariatric Clinic at Tulane University we expect that at least 50 eligible patients will be recruited in the first 6 months of this project
Aim 2 Define whether changes in plasma levels of sPRR correlate with improvement of T2DM parameters in obese patients subsequent to weight loss after bariatric surgery Scientific Premise and Rationale Obesity and T2DM are major risk factors for CVD
Activation of RAS is implicated in the pathogenesis of CV risk factors Often T2DM is improved immediately after bariatric surgery and even further with the sustained substantial BW loss However it remains unknown whether adipose tissue is the major supplier of sPRR in the plasma of obese patients and if plasma sPRR contributes to T2DM and CV complications in these patients Use of sPRR inhibitors would constitute a novel therapeutic approach to manage obesity in women and CV complications We will test the hypothesis that decreases in levels of plasma sPRR after bariatric surgery is associated with the improvement in glycemic control and lipid profile in obese patients Analysis and Statistical Considerations Multiple linear regression models will be used to measure the association between sPRR glycaemia HbA1c lipids profile LDL HDL triglycerides Comparisons will be established with values before and 2 visits after surgery The proposed n50 will be sufficient to fit models with up to 7 predictors and to have 80 power to detect a significant association between sPRR and any one predictor if at least 1225 of the total variability of sPRR is accounted for by the predictor Unadjusted and adjusted correlations and associated P values will be reported
Expected Results Pitfalls and Alternative Approach Aim 1 To our knowledge no previous study has defined the relationship among plasma sPRR-obesity-T2DM or has established the correlations between plasma sPRR and BMI WHR or HbA1c We expect that plasma sPRR levels will be higher in obese than in lean control samples and that compared with control plasma sPRR levels will be higher in T2DM obese patients We anticipate that plasma sPRR levels will be positively associated with obesity in T2DM obese women but not in male counterparts after adjusting for background factors suggesting that increases in plasma sPRR in women might be due to hyperandrogenemia Aim 2 will define whether changes in plasma sPRR correlate with the improvement of T2DM and lipid profile in obese patients after bariatric surgery Based on our strong preliminary data we anticipate that the outcomes will allow better understanding of the role of sPRR and metabolic risk factors in obese patients Potential pitfalls Because patients undergoing bariatric surgery are more commonly women if recruitmentenrollment of men results to be low we will justify the analysis with women to men frequency data ratio of 4119 Alternative Approach We expected that the outcomes allow comparing the impact of the direct effects of the bariatric surgery vs the long-term effects probably related to weight loss on plasma sPRR and insulin resistance If recruitment is less than expected we will reach out to other local bariatric surgery centersincluding Ochsner Clinic
Experimental Design quantifications will be done in plasma samples obtained from 50 obese patients undergoing bariatric surgery Plasma samples will be drawn before bariatric surgery pre-Op visit and at each of 2 follow-up visits 1 month 1 - 2 weeks and at 6 months 1-2 months for the assessment of plasma sPRR by ELISA Prietos Lab Tulane University See Power Analysis These samples will be obtained from patients of the Bariatric and Minimal Invasive Surgery Clinic of Christopher G Ducoin MD at Tulane HSC Collaborator Comparisons will be established with human biological de-identified plasma samples from lean control patients that have already been collected and are available as part of the Tulane Obesity-Endocannabinoids Study Tina Thethi MD Collaborator After patients consent agreement the patient will be examined in the Bariatric and Minimal Invasive Surgery Clinic for vital signs BP SBP and DBP taken by sphygmomanometry waist-to-hip ratio and BMI Fasting blood samples will be drawn by vein puncture for glycaemia HbA1c lipids profile LDL HDL triglycerides and sPRR Background factors and personal medical history will be taken as described in the Study Design section Power Analysis and Statistical Considerations All the outcomes at each time point will be summarized as mean and standard deviation SD The repeated measures analysis of variance and paired test will be conducted to evaluate the change across the time points The historical data suggest that about 10 patients receive bariatric surgery per month in the Outpatient Bariatric Clinic at Tulane University we expect that at least 50 eligible patients will be recruited in the first 6 months of this project
Aim 2 Define whether changes in plasma levels of sPRR correlate with improvement of T2DM parameters in obese patients subsequent to weight loss after bariatric surgery Scientific Premise and Rationale Obesity and T2DM are major risk factors for CVD
Activation of RAS is implicated in the pathogenesis of CV risk factors Often T2DM is improved immediately after bariatric surgery and even further with the sustained substantial BW loss However it remains unknown whether adipose tissue is the major supplier of sPRR in the plasma of obese patients and if plasma sPRR contributes to T2DM and CV complications in these patients Use of sPRR inhibitors would constitute a novel therapeutic approach to manage obesity in women and CV complications We will test the hypothesis that decreases in levels of plasma sPRR after bariatric surgery is associated with the improvement in glycemic control and lipid profile in obese patients Analysis and Statistical Considerations Multiple linear regression models will be used to measure the association between sPRR glycaemia HbA1c lipids profile LDL HDL triglycerides Comparisons will be established with values before and 2 visits after surgery The proposed n50 will be sufficient to fit models with up to 7 predictors and to have 80 power to detect a significant association between sPRR and any one predictor if at least 1225 of the total variability of sPRR is accounted for by the predictor Unadjusted and adjusted correlations and associated P values will be reported
Expected Results Pitfalls and Alternative Approach Aim 1 To our knowledge no previous study has defined the relationship among plasma sPRR-obesity-T2DM or has established the correlations between plasma sPRR and BMI WHR or HbA1c We expect that plasma sPRR levels will be higher in obese than in lean control samples and that compared with control plasma sPRR levels will be higher in T2DM obese patients We anticipate that plasma sPRR levels will be positively associated with obesity in T2DM obese women but not in male counterparts after adjusting for background factors suggesting that increases in plasma sPRR in women might be due to hyperandrogenemia Aim 2 will define whether changes in plasma sPRR correlate with the improvement of T2DM and lipid profile in obese patients after bariatric surgery Based on our strong preliminary data we anticipate that the outcomes will allow better understanding of the role of sPRR and metabolic risk factors in obese patients Potential pitfalls Because patients undergoing bariatric surgery are more commonly women if recruitmentenrollment of men results to be low we will justify the analysis with women to men frequency data ratio of 4119 Alternative Approach We expected that the outcomes allow comparing the impact of the direct effects of the bariatric surgery vs the long-term effects probably related to weight loss on plasma sPRR and insulin resistance If recruitment is less than expected we will reach out to other local bariatric surgery centersincluding Ochsner Clinic
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None