Insulin sensitivity and response in middle-aged Black South African men and women: associations with body fat distribution, menopause and objectively measured physical behaviours

Nyuyki, Clement Kufe
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Aims: To determine whether type 2 diabetes mellitus (T2DM) risk markers are different between middle-aged Black South African men and women, and between women at different stages of the menopause transition, and to determine whether there are sex-specific associations between these markers, and body composition and physical behaviours. Methods: This cross-sectional study included 804 Black South African men (n=388) and women (n=416) with a mean age of 54.66.0 years from the Middle-aged Soweto Cohort (MASC) from Soweto, Johannesburg. Dual-energy x-ray absorptiometry was used to measure total and regional adiposity. Glycated haemoglobin (HbA1c), and fasting plasma glucose, serum insulin and C–peptide concentrations were measured, and insulin resistance was calculated using the homeostasis model assessment (HOMA-IR). All participants completed an oral glucose tolerance test, from which measures of glycaemic and insulin dynamics were determined which included insulin sensitivity (Matsuda index), secretion (C-peptide index), and clearance (C-peptide/insulin ratio), beta cell function (oral disposition index), and integrated area under the curve (iAUC) for glucose, insulin and C-peptide were calculated. Total movement volume (average movement in milli-g) and time (minutes/day) spent in different physical behaviours, namely awake sitting/lying, standing, light intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) were determined by combining the signals from two triaxial accelerometers worn simultaneously on the hip and thigh. Menopausal status was determined by self-reported final menstrual period (FMP) and women were categorised as pre-menopausal, early post-menopausal and late postmenopausal. Sex-specific associations between adiposity and markers of T2DM risk, and between physical behaviours and markers of T2DM risk, were examined by robust regressions and isotemporal substitution, respectively. Results: Men (mean± standard deviation) (54.2±6.2) were younger than women (55.0±5.8) and significantly more men currently smoked (46.1% vs. 7.2%) and consumed alcohol (30.4% vs. 4.6%) than women. Mean BMI was higher in women than men (p<0.001), and accordingly a larger proportion of the women presented with obesity (70.2% vs. 26.6%) and had higher whole body fat mass (FM) (kg and %) and fat mass index (FMI). Women also had significantly greater leg FM, while men had more central FM (trunk) and a higher VAT/SAT ratio. Unadjusted HbA1C and 2-h glucose, as well as fasting insulin and C-peptide, and iAUC for insulin were higher in women than men. HOMA-IR was higher and insulin sensitivity (Matsuda index) was lower in women compared to men, which was accompanied by a higher insulin response (IGI) characterised by higher insulin secretion (C-peptide index) and lower insulin clearance (basal and postprandial). The oral disposition index did not differ by sex. After adjusting for sex differences in fat mass index, men were less insulin sensitive and had lower beta cell function than women (p<0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (p<0.001 for interactions). When exploring the relationship between adiposity and impaired glucose metabolism (IGM) and T2DM, using normal glucose tolerance as the reference, there was a significant sex*FMI interaction such that the relative risk ratio’s for IGM and T2D were greater for men than women [relative risk ratio (95% confidence interval), IGM: 1.70 (1.27– 2.29) vs 1.23 (0.95–1.60); T2DM: 2.05 (1.42–2.96) vs. 1.38 (1.03–1.85)]. The prevalences of NGT, IGT and T2DM were similar in men and women. When exploring differences in total and regional adiposity, and glycaemic and insulin dynamics across the menopausal transition in women, BMI and all the DXA-derived measures of total and regional adiposity were similar between the menopausal groups. Although HbA1c and iAUC for glucose were significantly higher in the late post-menopausal than the premenopausal group (HbA1c: 6.4±1.4% vs. 5.8±0.9%, p=0.019 and iAUC for glucose: 169.4 mmol/L vs 137.9 mmol/L, p=0.026) this was no longer significant after adjusting for age. Fasting insulin and C–peptide, iAUC for insulin, and insulin sensitivity and clearance were not different between the groups. However, iAUC for C-peptide was higher in the early postmenopausal women compared to the pre-menopausal and the late post-menopausal women before and after adjusting for age (762.9 ng/ml vs. 552.6 ng/ml and 637.5 ng/ml, all p<0.05). Insulin secretion (4.2 ng/mmol vs. 2.3 ng/mmol, p=0.001) and beta cell function (20.5 mIU/mmol vs. 11.8 mIU/mmol, p=0.008) were higher in early than late post-menopause before and after adjusting for age.
A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Health Sciences, School of Clinical Medicine, University of the Witwatersrand Johannesburg,2022