Tandi E. Matsha

Diabetes Mellitus and Inflammation

Type 2 diabetes mellitus (T2DM) is increasingly common worldwide. Related complications account for increased morbidity and mortality, and enormous healthcare spending. Knowledge of the pathophysiological derangements involved in the occurrence of diabetes and related complications is critical for successful prevention and control solutions. Epidemiologic studies have established an association between inflammatory biomarkers and the occurrence of T2DM and complications. Adipose tissue appears to be a major site of production of those inflammatory biomarkers, as a result of the cross-talk between adipose cells, macrophages, and other immune cells that infiltrate the expanding adipose tissue. The triggering mechanisms of the inflammation in T2DM are still ill-understood. Inflammatory response likely contributes to T2DM occurrence by causing insulin resistance, and is in turn intensified in the presence of hyperglycemia to promote long-term complications of diabetes. Targeting inflammatory pathways could possibly be a component of the strategies to prevent and control diabetes and related complications.

the 30-year cardiovascular risk profile of south africans with diagnosed diabetes, undiagnosed diabetes, pre-diabetes or normoglycaemia: the Bellville, south africa pilot study

Abstract The aim of this pilot study was to assess the 30-year risk for cardiovascular disease (CVD) in the South Africa population of mixed-ancestry in individuals with non-diabetic hyperglycaemia, and undiagnosed and self-reported diabetes. Participants were drawn from an urban community of the Bellville South suburb of Cape Town. In total, 583 subjects without a history of CVD were eligible for lifetime CVD risk estimation. Gender-specific prediction for CVD risk was calculated using the 30-year CVD interactive risk calculator. High CVD risk (> 20%) was evident in normoglycaemic and younger subjects (under 35 years). The significant predictors of CVD were sibling history of diabetes, and triglyceride, low-density lipoprotein cholesterol and glycated haemoglobin levels (p < 0.001). The high lifetime risk in normoglycaemic and younger subjects may be considered a warning that CVD might take on epidemic proportions in the near future in this country. We recommend the inclusion of education on CVD in school and university curricula.

HbA1c of 6.5% to Diagnose Diabetes Mellitus — Does It Work for Us? — The Bellville South Africa Study

Background HbA1c has been the gold standard for glycaemic control follow-up for decades. In 2009, a level of 6.5% (48 mmol/mol) was proposed as diagnostic for diabetes. We test this cut-off in our community. Methods Participants (946) from a community-based study were screened for diabetes using either a fasting blood glucose or oral glucose tolerance test (OFTT). The HbA1c cut-off of 6.5% was tested for each group. A receiver operator characteristic (ROC) curve for both groups was generated to establish an optimal cut-off. Results Our study included 224 (23.7%) males and 722 (76.3%) females. Using fasting blood glucose alone, 117 (14%) were diagnosed with diabetes −50% had an HbA1c value of ≥6.5% (48 mmol/mol). Using an OGTT, 147 (18%) were diagnosed with diabetes −46% had an HbA1c value of ≥6.5% (48 mmol/mol). ROC curves found a level of 6.1% (43 mmol/mol) to be optimal in both groups (AUC 0.85 and 0.82 respectively). The sensitivities were 80% and 75% and the specificities 77% and 78% respectively. Conclusions A cut off of 6.5% (48 mmol/mol) is a good diagnostic tool with its high specificity; however the low sensitivity limits its use. We found a level of 6.1% (43 mmol/mol) to be optimal. This emphasizes the need for evidenced based values to be established in various population groups.

Exploring Leukocyte O-GlcNAcylation as a Novel Diagnostic Tool for the Earlier Detection of Type 2 Diabetes Mellitus

CONTEXT Because current tests available for the diagnosis of diabetes have shortcomings, a novel screening method for the earlier and more efficient detection of type 2 diabetes would be a significant clinical advance. OBJECTIVE The hexosamine biosynthetic pathway usually acts as a fuel sensor, and its activation leads to O-linked β-N-acetylglucosamine (O-GlcNAc) modification of target proteins (O-GlcNAcylation) in a glucose-responsive manner. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are responsible for O-GlcNAc addition and removal, respectively. Because higher hexosamine biosynthetic pathway flux is linked to insulin resistance/type 2 diabetes, we hypothesized that increased O-GlcNAcylation of leukocyte proteins can detect the onset of pre- and overt diabetes. DESIGN, SETTING AND PATIENTS Seventy-four participants from Bellville and Stellenbosch (Western Cape, South Africa) were recruited and classified as normal, prediabetic, and diabetic individuals (American Diabetes Association criteria). MAIN OUTCOME MEASURES Leukocytes isolated from study subjects were evaluated for O-GlcNAc, OGA, and O-GlcNAc transferase expression by flow cytometry and immunofluorescence microscopy. RESULTS Flow cytometric analysis of leukocyte subtypes revealed increased O-GlcNAcylation in granulocytes vs. lymphocytes (P < 0.001). Diabetic individuals displayed higher leukocyte O-GlcNAcylation (P < 0.01), whereas granulocyte analysis showed an increase for prediabetic subjects (P < 0.01). However, OGA expression increased in leukocytes of diabetic subjects and is likely an adaptation to attenuate higher O-GlcNAcylation observed (P < 0.001). CONCLUSIONS Together our data demonstrate that leukocyte (particularly granulocyte) O-GlcNAcylation could help detect pre- and overt diabetes and offer clinical value as unique markers for the earlier and more efficient detection of type 2 diabetes.

Chronic kidney diseases in mixed ancestry south African populations: prevalence, determinants and concordance between kidney function estimators

BackgroundPopulation-based data on the burden of chronic kidney disease (CKD) in sub-Saharan Africa is still very limited. We assessed the prevalence and determinants of CKD, and evaluated the concordance of commonly advocated estimators of glomerular filtration rate (eGFR) in a mixed ancestry population from South Africa.MethodsParticipants were a population-based sample of adults selected from the Bellville-South community in the metropolitan city of Cape Town. eGFR was based on the Cockroft-Gault (CG), Modification of Diet in Kidney Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) equations (with and without adjustment for ethnicity). Kidney function staging used the Kidney Disease Outcome Quality Initiative (KDOQI) classification. Logistic regressions and kappa statistic were used to investigate determinants of CKD and assess the agreement between different estimators.ResultsThe crude prevalence of CKD stage 3–5 was 14.8% for Cockcroft-Gault, 7.6% and 23.9% respectively for the MDRD with and without ethnicity correction, and 7.4% and 17.3% for the CKD-EPI equations with and without ethnicity correction. The highest agreement between GFR estimators was between MDRD and CKD-EPI equations, both with ethnicity correction, Kappa 0.91 (95% CI: 0.86-0.95), correlation coefficient 0.95 (95% CI: 0.94-0.96). In multivariable logistic regression models, sex, age and known hypertension were consistently associated with CKD stage 3–5 across the 5 estimators.ConclusionsThe prevalence of CKD stages greater than 3 is the highest reported in Africa. This study provides evidence for support of the CKD-EPI equation for eGFR reporting and CKD classification.

The growing importance of PON1 in cardiovascular health: a review

The wide acceptance of the oxidation theory of atherogenesis has prompted attention to antioxidant mechanisms, particularly the prevention of lipid oxidation by high-density lipoprotein-associated proteins like paraoxonase 1 (PON1) enzyme. PON1 is a calcium-dependent enzyme that has interested toxicologists since its discovery as an organophosphate hydrolase. There is a growing interest in the enzymes importance in cardiovascular health prompted by evidence that it may have a role in lipid metabolism and the development of atherosclerosis via its antioxidant effects. PON1 is capable of hydrolyzing homocysteine thiolactone, a metabolite of homocysteine that can impair protein function leading to endothelial dysfunction and vascular damage. Although this lactonase activity has been suggested to be PON1s native activity, the enzymes specific physiological role and substrate remain unclear. In this review, we summarize developments in the field of PON1 research relating to cardiovascular health, and highlight those that perhaps warrant further research.

Derivation and validation of a waist circumference optimal cutoff for diagnosing metabolic syndrome in a South African mixed ancestry population

metabolic syndrome in a South African mixed ancestry population T.E. Matsha ⁎, M.S. Hassan , G.M. Hon , D.J. Soita , A.P. Kengne , R.T. Erasmus c,1 a Department of Biomedical Technology, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa b Department of Nursing and Radiography, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa c Division of Chemical Pathology, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa d NCRP for Cardiovascular and Metabolic Diseases, South African Medical Research Council, Cape Town, South Africa e Department of Medicine, University of Cape Town, Cape Town, South Africa

Immune cell membrane fatty acids and inflammatory marker, C-reactive protein, in patients with multiple sclerosis

Measurement of fatty acids in biological fluids and cell membranes including leucocytes from multiple sclerosis patients is inconsistent. The objective of the present study was to investigate the fatty acid composition within the different membrane phospholipid fractions in peripheral blood mononuclear cells in multiple sclerosis patients, and correlate with severity of neurological outcome as measured by the Kurtzke Expanded Disability Status Scale and Functional System Scores. The fatty acid composition of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin and phosphatidylinositol phospholipids in the peripheral blood mononuclear cells of twenty-six multiple sclerosis and twenty-five control subjects were measured by GC, and C-reactive protein was measured in all subjects. The elongation product of 20 : 4n-6, 22 : 4n-6, was significantly decreased in membrane phosphatidylethanolamine and phosphatidylserine in multiple sclerosis patients (P = 0.01 and P = 0.03 respectively), and correlated inversely with severity of disease and C-reactive protein. Also an inverse correlation was observed between the C-reactive protein and membrane phosphatidylcholine and phosphatidylserine 20 : 4n-6. Cultural and ethnic differences, as well as dietary variability, especially in a diseased state have been implicated in the differences observed in the fatty acid composition in peripheral blood mononuclear cell membranes of patients with multiple sclerosis. The present results suggest that the disease state may in part explain the reported inconsistencies in fatty acid levels in multiple sclerosis patients.

Effects of diabetes mellitus on amyotrophic lateral sclerosis: a systematic review

BackgroundAmyotrophic lateral sclerosis (ALS) is an incurable motor neuron degenerative disease which onset and course may be affected by concurrent diabetes mellitus (DM). We performed a systematic review to assess the effect of DM/dysglycemic states on ALS.MethodsWe searched PubMed MEDLINE, from inception to March 2013 for original articles published in English and in French languages on DM (and related states) and ALS. We made no restriction per study designs.ResultsSeven studies/1410 citations (5 case–control and 2 cross-sectional) were included in the final selection. The number of participants with ALS ranged from 18 to 2371. The outcome of interest was ALS and DM/dysglycemic states respectively in three and two case control-studies. DM/impaired glucose tolerance status did not affect disease progression, survival, disease severity and disease duration in ALS participants but ALS participants with DM were found to be older in one study. DM/IGT prevalence was similar in both ALS and non ALS participants. This review was limited by the absence of prospective cohort studies and the heterogeneity in ALS and DM diagnosis criteria.ConclusionsThis systematic review suggests that evidences for the association of ALS and DM are rather limited and derived from cross-sectional studies. Prospective studies supplemented by ALS registries and animal studies are needed to better understand the relationship between both conditions.

The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors

The previously reported link between homocysteine and obesity, both identified as established risk factors for multiple sclerosis (MS), has not previously been studied in relation to the fat mass and obesity-associated (FTO) gene. Aim: To investigate the mechanism underlying homocysteine accumulation in MS patients. A total of 114 patients and 195 population-matched controls were analysed for the FTO rs9939609 polymorphism. Homocysteine levels were measured in a subgroup of 60 patients and 87 controls screened for multiple vascular risk factors. After adjustment for potential confounders, the risk-associated FTO rs9939609 A-allele was associated with raised homocysteine levels (p = 0.003) in patients diagnosed with MS, but not in controls. Homocysteine levels correlated positively with body mass index (BMI) (p = 0.045) and total cholesterol levels (p = 0.048). Both homocysteine (p = 0.011) and BMI (p = 0.017) were significantly reduced with higher intake of folate in the diet. Higher BMI also correlated with increased intake of saturated/trans fat (p < 0.01) and low physical activity (p < 0.006). Daily intake of at least five fruits and vegetables had a favourable lowering effect on the Expanded Disability Status Scale (EDSS) (p = 0.035), while smoking increased MS disability (p < 0.001). This study has shown for the first time that having a diagnosis of MS moderates the effect of the FTO rs9939609 polymorphism on homocysteine levels. This is consistent with the role of FTO in demethylation and epigenetic changes. Identification of FTO rs9939609 reinforces the importance of adequate fruit, vegetable and folate and restriction of saturated/trans fat intake in the diet.