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

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Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women
Diabetologia ( IF 8.4 ) Pub Date : 2022-09-17 , DOI: 10.1007/s00125-022-05788-1
Amy E Mendham _{1,

2} , Lisa K Micklesfield ₁ , Fredrik Karpe _{3,

4} , Andre Pascal Kengne ₅ , Tinashe Chikowore ₁ , Clement N Kufe _{1,

6} , Maphoko Masemola ₁ , Nigel J Crowther ₇ , Shane A Norris _{1,

8} , Tommy Olsson ₉ , Sölve Elmståhl _{10,

11} , Tove Fall ₁₂ , Lars Lind ₁₃ , Julia H Goedecke _{1,

2,

5}

Affiliation

South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Health through Physical Activity, Lifestyle and Sport Research Centre, International Federation of Sports Medicine (FIMS), International Collaborating Centre of Sports Medicine, Division of Physiological Sciences, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
National Institute for Health and Care Research, Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK.
Biomedical Research and Innovation Platform and Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa.
Epidemiology and Surveillance Section, National Institute for Occupational Health, National Health Laboratory Service, Johannesburg, South Africa.
Department of Chemical Pathology, National Health Laboratory Service and University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa.
School of Human Development and Health, University of Southampton, Southampton, UK.
Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden.
Department of Clinical Sciences in Malmö, Division of Geriatric Medicine, Lund University, Lund, Sweden.
Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

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.

Graphical abstract

中文翻译：

靶向蛋白质组学确定非洲黑人男性和女性血糖异常、β 细胞功能和胰岛素敏感性的潜在生物标志物

目标/假设

我们使用靶向蛋白质组学方法，旨在在南非黑人队列中识别和验证与葡萄糖代谢受损 (IGM) 和 2 型糖尿病相关的循环蛋白。此外，我们评估了经过验证的蛋白质与 2 型糖尿病的病理生理通路之间的性别特异性关联。

方法

这项横断面研究包括中年索韦托队列 (MASC) 中的南非黑人男性 ( n =380) 和女性 ( n =375)。采用双能X射线吸收法测定脂肪量和内脏脂肪组织，采集空腹静脉血样本进行葡萄糖、胰岛素和C肽分析以及靶向蛋白质组学，共测定184种预选蛋白质生物标志物. 对没有糖尿病的参与者进行了 OGTT，并评估了外周胰岛素敏感性（松田指数）、HOMA-IR、基础胰岛素清除率、胰岛素分泌（C 肽指数）和 β 细胞功能（处置指数）。参与者被归类为具有正常葡萄糖耐量（NGT；n = 546）、IGM（n=116) 或 2 型糖尿病 ( n =93)。MASC 中与血糖异常（IGM 或 2 型糖尿病）相关的蛋白质在瑞典 EpiHealth 队列（NGT，n = 1706；空腹血糖受损，n = 550；2 型糖尿病，n = 210）中得到验证。

结果

我们在 MASC 中鉴定了 73 种与血糖异常相关的蛋白质，其中 34 种在 EpiHealth 队列中得到验证。在这些经过验证的蛋白质中，有 11 种与胰岛素动力学的各种测量值相关，其中最多的蛋白质与 HOMA-IR 相关。在性别特异性分析中，IGF 结合蛋白 2 (IGFBP2) 与女性（系数 –0.35；95% CI –0.44，–0.25）和男性（系数 –0.09；95% CI –0.15， –0.03)。金属蛋白酶抑制剂 4 (TIMP4) 与更高的胰岛素分泌（系数 0.05；95% CI 0.001，0.11；相互作用p =0.025）和 β 细胞功能（系数 0.06；95% CI 0.02，0.09； p对于交互= 0.013）仅在女性中。相比之下，在男性中观察到 IGFBP2 与使用 OGTT 确定的胰岛素敏感性之间更强的正相关（系数 0.38；95% CI 0.27，0.49）（相互作用p = 0.004）。后验分析表明 TIMP4 和胰岛素动力学之间的关联不受肥胖介导。相反，除胰岛素分泌外，IGFBP2 与胰岛素动力学之间的大部分关联均由男性和女性的脂肪量指数或内脏脂肪组织介导。在男性中，脂肪质量指数是 IGFBP2 和胰岛素敏感性（总效应介导 40.7%；95% CI 37.0, 43.6）以及 IGFBP2 和 HOMA-IR（总效应介导 39.1%；95% CI 31.1, 43.5）之间的最强中介。

结论/解释

我们验证了 34 种与 2 型糖尿病相关的蛋白质，其中 11 种与 2 型糖尿病病理生理学指标相关，例如外周胰岛素敏感性和 β 细胞功能。这项研究强调了不同血统、不同生活方式和社会人口特征的人群之间相似的生物标志物。确定的非洲特异性生物标志物需要在非洲队列中进行验证，以识别风险标志物并增加我们对非洲人群 2 型糖尿病病理生理学的理解。

图形概要

更新日期：2022-09-18

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