Ntuli, Philisiwe2025-10-152024Ntuli, Philisiwe. (2024). Association of catestatin with insulin resistance disparity in normoglycaemic Black and White South African women [Master`s dissertation, University of the Witwatersrand, Johannesburg]. WIReDSpace. https://hdl.handle.net/10539/47047https://hdl.handle.net/10539/47047A research report submitted in fulfillment of the requirements for the Master of Science in Medicine, in the Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, 2024Background: Unexplained ethnic disparities exist in insulin resistance (IR) worldwide, affecting negatively more women of African ancestry than their white female counterparts. Insulin resistance is a pathological condition preceding the development of Type 2 diabetes (T2D), which in 2016 was the second leading cause of death in South Africa. The studies evaluating IR disparities in South Africa are very sparse, focussing mainly on obesity and fat distribution. However, IR has multifactorial aetiology and disparities have been reported irrespective of Body Mass Index (BMI) or age. Additional studies are therefore needed. From rodent-based and in-vitro studies it becomes clear that glycoprotein Chromogranin A (CgA) and its cleavage products catestatin (CST; found in pancreatic β-cells, having insulin- sensitising effects) and pancreastatin (PST; derived from pancreatic α-cells, having anti-insulin effects) are involved in the regulation of glucose metabolism. We hypothesise that women of African ancestry may have low CST levels due to dysregulated CgA cleavage, yielding in an increased proportion of deregulatory PST. Therefore, we aim to determine whether circulatory levels of CST (or CgA; CgA/CST ratio) differ between healthy normoglycaemic black and white South African women independently of obesity and whether they are significantly involved in the regulation of IR. Methods: “Apparently healthy” black (n=67) and white (n=54) women volunteers below 50 years of age from Gauteng province were enrolled in the study, following the enrolment criteria. Anthropometric measurements including weight, height, waist (WC) and hip (HC) circumferences and blood pressure (BP) were recorded. All participants underwent shortened oral glucose tolerance test (OGTT) to evaluate their glycaemic status except for externally enrolled white women (n=47). Samples were collected for measurements of glucose (fasting and 30-minutes), insulin (fasting and 30-minutes) and C-peptide (fasting) which were analysed by an automated Roche Cobas analyser. Other samples collected at fasting for CgA, CST, Interleukin 6 (IL-6), leptin, monocyte chemotactic protein-1 (MCP-1) and adiponectin were analysed by individual enzyme-linked immunosorbent assay (ELISA) kits. Surrogate indices for IR (HOMA-IR), early insulin secretion (Insulinogenic index; IGI), -cell function (Disposition index; DIo) and hepatic insulin clearance (HIC) were calculated. vi Indices of adiposity (BMI, waist to hip ratio (WHR), waist to height ratio (WHtR) and a body shape index (ABSI)) were calculated from obtained measurements. Demographic information and socio-economic status (SES) were evaluated by questionnaires. Results: Black women were younger 26 (21; 32) than white women 30 (24; 35) and had higher BMI than white women (26.9 (22.4; 31.4) kg/m2 vs 23.5 (20.8; 25.9) kg/m2 respectively). Although normoglycaemic, white women had higher basal glucose levels (4.8 ± 0.3 mmol/L vs. 4.7 ± 0.3 mmol/L). No ethnic differences were found for fasting insulin or HOMA-IR. The only difference was attributable to adiposity in obese (OB) vs non-obese (NOB) black women. Similarly, no ethnic differences were observed for DIo and IGI. However, NOB black women had reduced (p<0.001) HIC in comparison with NOB white women. Black NOB women had reduced CST and elevated CgA (and CgA/CST ratio) than white NOB women, all with p<0.001. No associations of CST, CgA or CgA/CST were observed in white women. Catestatin correlated inversely with HIC (p=0.045) and positively with leptin (p=0.010) in black women. Correction for confounders removed this significance. CgA and the CgA/CST ratio correlated negatively with HOMA-IR and fasting insulin and positively with HIC. Only after removal of the strongest determinants, positive associations for CgA (p<0.001) and the ratio (p=0.009) remained in the model for HIC. Conclusion: In the study population of normoglycaemic, normotensive and apparently healthy black and white women, we have not found elevated insulin levels or higher IR in the black ethnic group. However, we demonstrated for the first time the ethnic differences in CST with reduced levels and elevated levels of CgA and the CgA/CST ratio in black women vs white women. This difference is independent of obesity; we have not identified its reason but a genetic origin cannot be excluded. There were no direct regulatory effects of CST (CgA or CgA/CST) on IR. However, the study results indicate that HIC is the most closely associated variable of glucose- insulin dynamics with CST (CgA and CgA/CST ratio) in the black women in our study. The effects of CST on IR and glucose regulation may be indirect. The study found a positive correlation with leptin and CST-leptin interaction has been described previously in the literature. The binding of CST to insulin receptor results in reduction of obesity and this, in turn, can reduce IR and improve insulin and glucose levels.en© 2024 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg.UCTDnormoglycaemic Black and White South African womenAssociation of catestatin with insulin resistance disparity in normoglycaemic Black and White South African womenDissertationUniversity of the Witwatersrand, JohannesburgSDG-3: Good health and well-being