The relationship between pre–diabetic hyperglycemia and markers of nitric oxide bioavailability in a cohort of Africans and Caucasians : the SABPA–study
Koegelenberg, Anna Susanna Elizabeth
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Motivation: Cardiovascular disease (CVD) is becoming an eminent health problem worldwide. Several studies have implicated that type 2 diabetes mellitus, together with other risk factors including hypertension, contributes significantly to the development of CVD. Vascular endothelial dysfunction is one of the most common characteristics of diabetes, and involves alterations such as a decrease in nitric oxide (NO) bio-availability. However, endothelial dysfunction is already present in individuals suffering from impaired fasting glucose, more commonly known as pre-diabetes. The International Diabetes Federation estimates that adults living with pre-diabetes by 2030 in sub-Saharan Africa will comprise 9.6% of the population, whereas adults living with diabetes will comprise of 4.3% of the population. The excessive amount of pre-diabetics in sub-Saharan Africa and its association with vascular endothelial dysfunction motivated this study. In order to gain a better understanding of this relationship, we wanted to explore the relationship between pre-diabetic hyperglycemia and markers of NO bio-availability in Africans and Caucasians residing in South Africa. Aim: Our aim was firstly to determine whether glucose measures (fasting glucose and glycated hemoglobin (HbA1c)) and markers of NO bio-availability (namely L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-citrulline and reactive oxygen species (ROS)) differ between African and Caucasian individuals. Secondly, we aimed to determine the relationship of glucose measures with markers of NO bio-availability; blood pressure and renal function. Thirdly we aimed to establish whether these associations are ethnic-specific. Methodology: This study forms part of the SABPA (Sympathetic Activity and Ambulatory Blood Pressure in Africans) study which included a total of 409 urbanised African and Caucasian teachers between the ages of 25 and 65 years. Exclusion criteria were an elevated ear temperature, psychotropic substance dependence or abuse, the use of α- and β-receptor blockers, being blood donors or having been vaccinated during the previous three months. For this substudy participants were excluded due to missing data on HbA1c and markers of NO bioavailability (n=16), participants infected with the human immunodeficiency virus (HIV) (n=19), participants with HbA1c levels greater than or equal to 6.5% (n=29), and participants using diabetes medication (n=5). The overall sample of this study therefore consisted of 340 participants divided into African (n=148) and Caucasian (n=192) sub-groups. All participants signed informed consent forms. The Ethics Review Board of the North-West University approved the study. General health questionnaires were used to determine medication use and lifestyle habits. Anthropometric measurements such as weight, height, and waist circumference were determined. Ambulatory blood pressure measurements (ABPM) and physical activity were monitored during a normal working day. Blood samples were taken after subjects were requested to fast overnight. Biochemical analyses of HbA1c, glucose, Larginine, ADMA, L-citrulline, SDMA, ROS, ferric reducing antioxidant power (FRAP), urea, lipid profile (high-density lipoprotein cholesterol, total cholesterol), γ-glutamyl transferase (GGT), cotinine, high sensitivity C-reactive protein (CRP), and creatinine were performed. HIV testing was performed with First Response HIV Card Test 1-2.0 (PMC Medical, India Pvt Ltd) and confirmed with Pareekshak HIV Triline (UCB Pharma). Results: In our study we found higher levels of L-arginine (p<0.001) in Africans. L-citrulline (p=0.053) levels tended to be higher in Africans who also presented with higher levels of HbA1c (p<0.001), blood pressure (p<0.001) and albumin-to-creatinine ratio (ACR) (1.04 [0.35; 3.95] vs. 0.34 [0.09; 1.88] for Africans and Caucasians, respectively). The Caucasians presented higher levels of SDMA (p<0.001) whereas the groups had similar ADMA and ROS levels. Another finding was the disparate manner in which components of the NO biosynthesis pathway correlated with glucose and HbA1c in both the Africans and Caucasians. In Africans alone, L-citrulline was independently associated with fasting glucose (R2=0.21; β=0.19; p=0.017) and HbA1c (R2=0.21; β=0.19; p=0.018) whereas in Caucasians alone, ADMA was independently associated with fasting glucose (R2=0.13; β=0.39; p<0.001) and HbA1c (R2=0.06; β=0.17 p=0.03). Independent variables included: age, gender, BMI, physical activity, cotinine, GGT, CRP, triglycerides, fasting glucose or HbA1c and systolic blood pressure. Secondly, blood pressure and estimated creatinine clearance were differentially associated with glucose and HbA1c among the two ethnic groups. Independent variables for this model included: age, gender, BMI, physical activity, cotinine, GGT, CRP, triglycerides, fasting glucose or HbA1c and anti-hypertensive medication. Systolic blood pressure was positively associated with fasting glucose (borderline significant relationship p=0.06) and HbA1c (p=0.04) in Caucasians. Glucose was also positively associated with diastolic blood pressure in Caucasians (p=0.008). In Africans alone, estimated creatinine clearance was negatively associated with glucose (borderline significant relationship p=0.088) and HbA1c (p=0.019). A further analysis also showed an independent relationship between estimated creatinine clearance and L-citrulline (R2=0.55; β=-0.20; p=0.0015) in Africans. Conclusion: Regardless of the unfavourable cardiovascular, glucose and renal profile in Africans, they demonstrated a more favourable profile regarding markers of NO bio-availability. Still the main finding remained the lack of associations between markers of NO bio-availability and hyperglycemia in both ethnic groups, with the exception of a positive independent association between L-citrulline and glucose measures in Africans and a positive independent association between ADMA and glucose measures in Caucasians. In the African group, the relationship was probably driven by an unfavourable renal profile, which is characterised by an ACR that is approximately three times higher in Africans than Caucasians. In the Caucasian group, who presented a more favourable cardiovascular profile, our findings support the literature in which hyperglycemia had a significant positive independent association with both ADMA and blood pressure.
- Health Sciences