Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women.

AIMS/HYPOTHESIS: Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes. METHODS: This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210). RESULTS: We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient -0.35; 95% CI -0.44, -0.25) and men (coefficient -0.09; 95% CI -0.15, -0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men. CONCLUSIONS/INTERPRETATION: We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.

Physical Activity Behaviors of a Middle-Age South African Cohort as Determined by Integrated Hip and Thigh Accelerometry.

PURPOSE: Descriptive studies of objectively measured physical activity behaviors in African populations are rare. We developed a method of combining hip and thigh accelerometery signals to quantify and describe physical behaviors in middle-age South African men and women. METHODS: We integrated signals from two triaxial accelerometers worn simultaneously during free-living, in a subsample of the Middle-age Soweto Cohort ( n = 794; mean (SD) age, 53.7 (6.3) yr). Acceleration time series from the accelerometers were combined and movement-related acceleration was derived using Euclidean Norm Minus One (in milligrams), to determine total movement volume (mean Euclidean Norm Minus One) and nonmovement time (<28 m g ), light-intensity physical activity (LPA; 28-85 m g ), and moderate- to vigorous-intensity physical activity (MVPA; >85 m g ); thigh pitch angle and a sleep diary were used to divide nonmovement time (in minutes per day) into sleep, awake sitting/lying, and standing. Sociodemographic factors were self-reported, and weight and height were measured. RESULTS: Mean (SD) wear time was 128 (48) h. Movement volume was 15.0 (6.5) m g for men and 12.2 (3.4) m g for women. Men spent more time in MVPA and sitting/lying, whereas women spent more time standing. Age was inversely associated with movement volume, MVPA, and LPA. When compared with their normal-weight counterparts, men who were overweight or obese spent less time in MVPA, whereas women who were overweight or obese spent less time in LPA and more time sitting/lying. Socioeconomic status was inversely associated with total movement volume, MVPA, and time spent sleeping, and positively associated with time spent sitting/lying, in both men and women. CONCLUSIONS: Integrating signals from hip and thigh accelerometers enables characterization of physical behaviors that can be applied in an African population.

Physical behaviors and their association with type 2 diabetes mellitus risk markers in urban South African middle-aged adults: an isotemporal substitutionapproach.

INTRODUCTION: To examine the associations between physical behaviors and type 2 diabetes mellitus (T2DM) risk markers in middle-aged South African men and women. RESEARCH DESIGN AND METHODS: This cross-sectional study included middle-aged men (n=403; age: median (IQR), 53.0 (47.8-58.8) years) and women (n=324; 53.4 (49.1-58.1) years) from Soweto, South Africa. Total movement volume (average movement in milli-g) and time (minutes/day) spent in different physical behaviors, including 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. All participants completed an oral glucose tolerance test, from which indicators of diabetes risk were derived. Associations between physical behaviors and T2DM risk were adjusted for sociodemographic factors and body composition. RESULTS: Total movement volume was inversely associated with measures of fasting and 2-hour glucose and directly associated with insulin sensitivity, basal insulin clearance, and beta-cell function, but these associations were not independent of fat mass, except for basal insulin clearance in women. In men, replacing 30 min of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 1.2-1.4 mmol/L lower fasting glucose and 12.3-13.4 mgl2/mUmin higher insulin sensitivity. In women, substituting sitting/lying with the same amount of standing time or LPA was associated with 0.5-0.8 mmol/L lower fasting glucose. Substituting 30 min sitting/lying with the same amount of standing time was also associated with 3.2 mgl2/mUmin higher insulin sensitivity, and substituting 30 min of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 0.25-0.29 ng/mIU higher basal insulin clearance in women. CONCLUSION: MVPA is important in reducing T2DM risk in men and women, but LPA appears to be important in women only. Longitudinal and intervention studies warranted to provide more specific PA recommendations.

Increased risk for type 2 diabetes in relation to adiposity in middle-aged Black South African men compared to women.

Aims: Despite a higher prevalence of overweight/obesity in Black South African women compared to men, the prevalence of type 2 diabetes (T2D) does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and/or beta-cell function and also sex-specific associations with total and regional adiposity. Methods: This cross-sectional study included 804 Black South African men (n = 388) and women (n = 416). Dual-energy X-ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C-peptide index) and clearance (C-peptide/insulin ratio) were estimated from an oral glucose tolerance test. Results: After adjusting for sex differences in the 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). Further, the association between total adiposity and T2D risk was also greater in men than women (relative risk ratio (95% CI): 2.05 (1.42-2.96), P < 0.001 vs 1.38 (1.03-1.85), P = 0.031). Conclusion: With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta-cell function, Black African men are at greater risk for T2D than their female counterparts.