Impact of Plasma Soluble Prorenin Receptor in Obese and Type 2 Diabetic Patients
| Status: | Recruiting |
|---|---|
| Conditions: | Obesity Weight Loss |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 9/19/2018 |
| Start Date: | September 11, 2018 |
| End Date: | March 31, 2019 |
| Contact: | Minolfa Prieto, MD PhD |
| Email: | mprieto@tulane.edu |
| Phone: | 504-988-2445 |
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 patient's health,
particularly in obese diabetic women.
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 patient's health,
particularly in obese diabetic women.
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, HDL,triglycerides) 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 Prieto's 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 thrombosis/pulmonary embolism
(DVT/PE), gastroesophageal reflux disease (GERD), liver disease, dyslipidemia, polycystic
ovarian syndrome, depression, alcohol use, substance abuse, and/or 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 PI's 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
vendor(s) 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 (Prieto's 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, M.D, Collaborator). After patient's 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 n=50 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 12.25% 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 recruitment/enrollment of
men results to be low, we will justify the analysis with women to men frequency data ratio of
4:1.19 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 centers,including Ochsner Clinic.
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, HDL,triglycerides) 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 Prieto's 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 thrombosis/pulmonary embolism
(DVT/PE), gastroesophageal reflux disease (GERD), liver disease, dyslipidemia, polycystic
ovarian syndrome, depression, alcohol use, substance abuse, and/or 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 PI's 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
vendor(s) 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 (Prieto's 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, M.D, Collaborator). After patient's 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 n=50 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 12.25% 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 recruitment/enrollment of
men results to be low, we will justify the analysis with women to men frequency data ratio of
4:1.19 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 centers,including Ochsner Clinic.
Inclusion Criteria:
- Men and women 18-70 years of age
- Scheduled to undergo bariatric surgery
- Obese (defined as BMI >=30)
Exclusion Criteria:
- History of hemorrhagic stroke or myocardium infarction in the previous 6 months.
- Women who are currently pregnant
- Diagnosed with a malignant disease
- Uncontrolled diabetes mellitus (defined as HbA1c>10.0%)
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