Tocopherol metabolites in diabetes and hypertension

Principal Investigator:  Kenneth Hensley, Ph.D. Assistant Member, Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation

Abstract:

Objectives:   To investigate and to develop clearer understanding of tocopherol metabolites in comparison with known pathocorrelates  in sera from type 2 diabetic subjects with and without hypertension , non-diabetic hypertensive  and healthy normotensive subjects.

Rationale:  Hypertension is a frequent complication of diabetes and a major contributor to morbidity and mortality in diabetic and non-diabetic populations. Our recent findings suggest that metabolites of natural gamma tocopherol (gT) act within the renin-angiotensin-aldosterone system (RAAS) to promote natriuresis and suppress inflammation. Clearer understanding of tocopherol metabolism in hypertensive complications could lead to improvements in the clinical management of hypertension especially within the diabetic context, and could inform the revision of current tocopherol supplementation practices that rely exclusively upon a-tocopherol (aT, vitamin E). 

Hypotheses:  Gamma tocopherol metabolite (gCEHC) has a role in the feedback regulation of the RAAS. Plasma gCEHC levels are  upregulated by aldosterone and inhibited by hyperglycemia, thus will be decreased in diabetes and elevated in hypertension, and associated with high serum aldosterone, CRP, eicosanoids and specific cytokines.

Specific Aims: 

Primary specific aim: To determine effects of Type 2 diabetes and hypertension on plasma g-CEHC. These will be accomplished by examining the differences in concentration of plasma g-CEHC in subjects with and without Type 2 diabetes, with and without untreated essential hypertension.  Groups will be balanced for gender, age and race.

Secondary specific aim:  To investigate the association between plasma gCEHC and aldosterone, cardiovascular risk factors markers (lipids, inflammatory markers, growth factors, endothelial markers) in the above study groups.

Twelve normotensive Type 2 Diabetic male subjects and twelve hypertensive Type 2 Diabetic male subjects will be recruited.   Also, twelve normotensive nondiabetic male subjects and twelve hypertensive nondiabetic male subjects will be recruited.  Four corresponding groups of female subjects will be recruited.  These eight groups will be considered a three factor design with a factorial arrangement of treatments (2 diabetic conditions x 2 hypertensive conditions x 2 genders).    

Subjects will attend the General Clinical Research Center (GCRC).  Each subject will receive initial counseling and explanation of the study from a study physician or research nurse, and after eligibility has been confirmed, will provide informed consent.  Detailed clinical information will be recorded by Dr. Gosmanova including full medical history, records of past and present glycemic control, diabetes complication status, medications, and a detailed physical exam.  Fasting blood samples will be obtained, PulseWave analysis will be performed, the patient will receive breakfast, and leave.  This is a single visit study.

Subject Population Information:

General, Age Range:  This is a cross-sectional study of four groups of subjects: with and without Type 2 diabetes, with and without hypertension.  Minimum age for recruitment: 18 yrs.; maximum age: 40 yrs.  Groups will be matched by age, race, and gender.

Study Population-Inclusion and exclusion criteria:

For (normotensive) Type 2 diabetic subjects:

Inclusion: Type 2 diabetes of at least 5 year’s duration but otherwise healthy; age 18-40 years; male or female (genders to be equally represented); any race or ethnic group (composition to reflect local community as closely as possible); stable glycemic control (but no limit on HbA1c), and no history of HTN (defined as systolic BP>140 and/or diastolic BP>/90). 

Exclusion: Evidence of significant cardiovascular complications, microalbuminuria (>40mg per 24hrs) or frank proteinuria,  evidence of unstable glycemic control, or history of admission for hyperglycemia or hypoglycemia in the 6 months prior to recruitment, other significant renal, hepatic, cardiovascular, or neurological disease; cancer; pregnancy.

For hypertensive Type 2 diabetic subjects:

Inclusion: Type 2 diabetes of at least 5 year’s duration and history of HTN (defined as systolic BP>140 and/or diastolic BP>90)  not on any medications for treatment of HTN; age 18-40 years; male or female (genders to be equally represented); any race or ethnic group (composition to reflect local community as closely as possible); stable glycemic control (but no limit on HbA1c).

Exclusion:  Currently taking antihypertensive medications.  Evidence of significant cardiovascular complications, microalbuminuria (>40mg per 24hrs) or frank proteinuria,  evidence of unstable glycemic control, or history of admission for hyperglycemia or hypoglycemia in the 6 months prior to recruitment, other significant renal, hepatic, cardiovascular, or neurological disease; cancer; pregnancy.

For (untreated and non-diabetic) hypertensive subjects:

Inclusion: History of Hypertension (defined as systolic BP>140 and/or diastolic BP>90), (defined as BP>140/90) but otherwise healthy and not on any medications for treatment of HTN; age 18-40 years; male or female (genders to be equally represented); any race or ethnic group (composition to reflect local community as closely as possible); 

Exclusion: Currently taking antihypertensive medications.  Evidence of significant cardiovascular, renal, hepatic, or neurological disease; cancer; pregnancy;, diabetes or, metabolic syndrome. use of prescription medicines.

For healthy control subjects:

Inclusion: Healthy (taking no medications), non-diabetic (defined as fasting plasma glucose <110 mg/dl), non-hypertensive (defined as BP<120/80) control subjects, individually matched to each diabetic and hypertensive subject for age (within three years of index case), gender, and race.

Exclusion: Evidence of HTN, diabetes, cardiovascular, renal, hepatic, or neurological disease; cancer; pregnancy;, use of prescription medicines.

Participant Compensation:

Contact Information:

Dr. Kenneth Hensley, Oklahoma Medical Research Foundation. (405) 271-7569 or Kenneth-Hensley@omrf.ouhsc.edu When inquiring, please mention the Diabetes and Hypertension Project at the General Clinical Research Center