Determinants of type 2 diabetes mellitus risk in middle-aged black South African men and women
Lead Research Organisation:
University of the Witwatersrand
Department Name: UNLISTED
Abstract
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Technical Summary
Background: Globally, T2D is estimated to account for 5.1 million deaths, or 8.4% of all-cause deaths in adults. While the prevalence of diabetes in sub-Saharan Africa (SSA) is relatively low (5.7%), the projected rate of increase over the next 20 years exceeds that of other regions, with the prevalence in SSA expected to double by 2035. Black Africans with T2D have higher rates of associated co-morbidities, referred to as multi-morbidity, and are 2-3 times more likely to die from these diseases than their white counterparts. Within South Africa (SA), there is a high prevalence of T2D, particularly in black African urban-dwelling populations, which has increased significantly over the past 20 years, most likely driven by the increasing prevalence of obesity, particularly in black SA women (39.9%). Indeed, a high BMI accounted for 93.8% of deaths in SA women due to diabetes in 2000. Notably, SA also has an additional challenge of a high burden of infectious diseases, with a national HIV prevalence of 12.2%. Aim: The aim of the study is to examine the changes in sex hormone levels over the menopausal transition in women, and in men of the same age, and explore the effects on body fat distribution and insulin sensitivity and secretion, dissecting the specific roles of glucocorticoids and inflammatory mediators, in the context of HIV. Methods: Baseline data was collected on 1007 black women (age: 49.1±5.7 years; BMI: 33.3±7.3 kg/m2) from 2011-2014 and 962 black men (age: 49.3±12.6 years; BMI: 25.1±5.9 kg/m2); between 2014 and 2015, as part of the SWEET (Study of Women Entering and in Endocrine Transition) and AWI-Gen (Africa Wits-INDEPTH partnership for Genomics Studies on body composition and cardiometabolic disease risk – www.h3africa.org) studies. The proposed study will consist of two parts. Part 1: Using a longitudinal design, follow up data will be collected to measure changes in sex hormones, circulating cortisol and inflammatory markers, to assess their role in mediating changes in body fat distribution and insulin sensitivity, and to examine the influence of HIV status on this relationship. Part 2: Using a cross-sectional design, differences in adipose tissue oestrogen receptors, glucocorticoid metabolism and inflammation will be examined in black South African pre- and post-menopausal women, with and without HIV, and the association with body fat distribution and insulin sensitivity will be explored.
Organisations
- University of the Witwatersrand (Lead Research Organisation)
- Chalmers University of Technology (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- University of Stellenbosch (Collaboration)
- University of Oxford (Collaboration)
- University of Queensland (Collaboration)
- Umea University (Collaboration)
- Heidelberg University (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- University of Bonn (Collaboration)
- University of Bristol (Collaboration)
Publications
Chikowore T
(2024)
Variability of polygenic prediction for body mass index in Africa.
in Genome medicine
Dlamini SN
(2021)
Glucocorticoids associate with cardiometabolic risk factors in black South Africans.
in Endocrine connections
Dlamini SN
(2021)
Associations Between CYP17A1 and SERPINA6/A1 Polymorphisms, and Cardiometabolic Risk Factors in Black South Africans.
in Frontiers in genetics
Dlamini SN
(2022)
Targeted proteomics of appendicular skeletal muscle mass and handgrip strength in black South Africans: a cross-sectional study.
in Scientific reports
Goedecke JH
(2024)
Sex hormone-binding globulin, testosterone and type 2 diabetes risk in middle-aged African women: exploring the impact of HIV and menopause.
in medRxiv : the preprint server for health sciences
Goedecke JH
(2022)
Pathophysiology of type 2 diabetes in sub-Saharan Africans.
in Diabetologia
Kufe C
(2022)
Increased risk for type 2 diabetes in relation to adiposity in middle-aged black South African men compared to women
in European Journal of Endocrinology
Kufe CN
(2022)
Physical behaviors and their association with type 2 diabetes mellitus risk markers in urban South African middle-aged adults: an isotemporal substitutionapproach.
in BMJ open diabetes research & care
Madanhire T
(2023)
The Impact of Human Immunodeficiency Virus and Menopause on Bone Mineral Density: A Longitudinal Study of Urban-Dwelling South African Women.
in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Masemola M
(2024)
Regional adiposity and insulin sensitivity - interactions with menopause and HIV in middle-aged Black African women.
in The Journal of clinical endocrinology and metabolism
Mendham AE
(2022)
Physical Behaviors and Their Association With Adiposity in Men and Women From a Low-Resourced African Setting.
in Journal of physical activity & health
Micklesfield LK
(2022)
Physical Activity Behaviors of a Middle-Age South African Cohort as Determined by Integrated Hip and Thigh Accelerometry.
in Medicine and science in sports and exercise
Seipone ID
(2024)
SHBG, Free Testosterone, and Type 2 Diabetes Risk in Middle-aged African Men: A Longitudinal Study.
in Journal of the Endocrine Society
| Description | This was the first longitudinal study in Africans to determine waist-circumference thresholds for predicting diabetes risk in men and women. Results showed that current international waist-circumference cut-points do not perform well in black South Africans, particularly women. The study also a stronger association between adiposity and diabetes risk in men than women, which means that with increasing adiposity, Black African men are at greater risk for T2D than their female counterparts. Several African-specific proteins were identified to be associated with impaired glucose metabolism and type 2 diabetes and when validated these biomarkers may be used to improve sex-specific models for type 2 diabetes prediction in African populations. |
| Exploitation Route | The researchers proposed alternative cut-points, which are the same in men and women; these cut-points will simplify messaging around NCD risk and will facilitate risk stratification. Validated biomarkers that are African-specific may be used to predict type 2 diabetes in African populations. |
| Sectors | Healthcare |
| Description | Our findings have been used to leverage additional funding for follow-up data collection in the same cohort from an under-resourced setting in South Africa. This will provide the opportunity to identify known and novel risk factors (eg. waist circumference, physical activity) and biomarkers (eg. proteomics and metabolomics) for incident cardiometabolic diseases such as diabetes and hypertension. These will be validated in other African populations and compared to European populations, and once validated they can be included in clinical practice for the early detection of disease risk in African populations. In addition the dietary data will be linked to these biomarkers to identify targeted future interventions for the prevention of diabetes. This has also provided the opportunity to measure the prevalence and predictors of liver fat in the MASC cohort, and to measure single cell RNA sequencing in the adipose tissue samples collected in the original study. |
| First Year Of Impact | 2021 |
| Description | Competitive Programme for Rated Researchers |
| Amount | R2,200,000 (ZAR) |
| Funding ID | 99108 |
| Organisation | South African National Research Foundation (NRF) |
| Sector | Public |
| Country | South Africa |
| Start | 01/2016 |
| End | 12/2018 |
| Description | European Research Area Network for Personalised Medicine (ERA PerMed) Transnational Research on "Prevention in Personalised Medicine |
| Amount | € 938,002 (EUR) |
| Organisation | European Commission |
| Sector | Public |
| Country | Belgium |
| Start | 04/2023 |
| End | 04/2025 |
| Description | Prevalence and predictors of liver fat in Africans. |
| Amount | R2,920,000 (ZAR) |
| Funding ID | CPRR240321210274 |
| Organisation | National Research Foundation |
| Sector | Public |
| Country | South Africa |
| Start | 03/2025 |
| End | 02/2027 |
| Description | Understanding the impact of HIV infection and its treatment on the effect menopause has on the musculoskeletal health of African women |
| Amount | £197,182 (GBP) |
| Organisation | University of Bristol |
| Department | Global Challenges Research Fund |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 09/2019 |
| End | 07/2021 |
| Title | Abdominal and gluteal adipose tissue biopsies |
| Description | Adipose tissue biopsies are completed at the abdominal SAT and gluteal depots. After administration of local anaesthesia (5-10 ml of 1% lignocaine, Intramed, Port Elizabeth, South Africa), a 14g needle attached to a 60 ml syringe, is inserted into the fat depot and adipose tissue samples extracted. This technique yields ~300 mg of fat from each depot. Samples are washed with saline and aliquoted into 40% formalin and wax embedded for histology, or snap frozen in liquid nitrogen and stored at -80 °C for subsequent analyses of gene and protein expression. |
| Type Of Material | Biological samples |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | Data collection is now complete. |
| Title | Objective measurement of physical activity and sedentary behaviour |
| Description | The PhD student on this project has attended the Physical Activity measurement seminar at the MRC Epidemiology Unit in Cambridge. He has used this to collect physical activity and sedentary time using accelerometry on all participants in this study and has spent time in Cambridge learning how to process this data. To update this record, further discussions have happened with Soren Brage and colleagues from the MRC Epidemiology Unit in Cambridge, who will write a manuscript describing the methodology used to combine data from two accelerometers to measure physical activity and sedentary behaviour. This is a new and novel methodology that has been developed. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | Data is still being processed and will then be analysed. |
| Title | Set-up of the method for the measurement of serum steroid concentrations in South Africa. |
| Description | The method for the measurement of serum steroid concentrations was set up for the first time at the National Health Laboratory Services in Johannesburg. The method uses liquid-liquid extraction to extract steroids from serum samples, which are subsequently run on the Xevo TQ-S liquid chromatography mass spectrophotometer (Waters, Milford, MA),. This is a method originally developed by Agilent Technologies, but has been refined for the extraction of steroids from smaller sample volumes. |
| Type Of Material | Biological samples |
| Year Produced | 2018 |
| Provided To Others? | No |
| Impact | It was originally planned that the measurement of serum steroids would be undertaken at the University of Edinburgh. However, due to Health and Safety issues with the South African samples, we were required to set up the technique in South Africa. This technique can now be used for future studies in South Africa, and will be used in an AMS-funded study "Determinants of type 2 diabetes risk in middle-aged black South African men and women". |
| Description | Generation of a pQTL database |
| Organisation | University of Leicester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Using the proteomic data from MASC to generate a pQTL database. |
| Collaborator Contribution | Partners are providing computational expertise in generating a pQCT database. |
| Impact | None to date. |
| Start Year | 2025 |
| Description | MENOPAUSE STUDY |
| Organisation | University of Bristol |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I am a co-investigator on a GCRF Investment grant from the University of Bristol (Dr Celia Gregson (PI)) for a study entitled: Understanding the impact of HIV infection and its treatment on the effect menopause has on the musculoskeletal health of African women. This used the DXA BMD data collected as part of the current study to look at change in BMD in black African women. |
| Collaborator Contribution | Dr Celia Gregson is the PI on the project and a clinician with expertise in musculoskeletal health. |
| Impact | This has had one output to date: doi: 10.1002/jbmr.4765 |
| Start Year | 2019 |
| Description | OPTIMA study |
| Organisation | Chalmers University of Technology |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Through this collaboration we have obtained ERAPerMed funding for a collaborative project entitled "Omics Approach for Personalized Prevention of Type 2 Diabetes Mellitus for African and European Populations". Professor Julia Goedecke is the co-ordinating PI on this multi-centre study including data from the Middle-aged Soweto Cohort which was created as part of this funded grant. |
| Collaborator Contribution | Heidelberg University and University of Bonn collaborators provide access to the RODAM study as well as dietary expertise. Umea University collaborators provide access to the SCAPIS Swedish cohort, and proteomic analysis. Chalmers University collaborators provide expertise in metabolomic analysis. |
| Impact | Protocol paper in review in BMJ Open. |
| Start Year | 2023 |
| Description | OPTIMA study |
| Organisation | Heidelberg University |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Through this collaboration we have obtained ERAPerMed funding for a collaborative project entitled "Omics Approach for Personalized Prevention of Type 2 Diabetes Mellitus for African and European Populations". Professor Julia Goedecke is the co-ordinating PI on this multi-centre study including data from the Middle-aged Soweto Cohort which was created as part of this funded grant. |
| Collaborator Contribution | Heidelberg University and University of Bonn collaborators provide access to the RODAM study as well as dietary expertise. Umea University collaborators provide access to the SCAPIS Swedish cohort, and proteomic analysis. Chalmers University collaborators provide expertise in metabolomic analysis. |
| Impact | Protocol paper in review in BMJ Open. |
| Start Year | 2023 |
| Description | OPTIMA study |
| Organisation | Umea University |
| Department | Department of Public Health and Clinical Medicine |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Through this collaboration we have obtained ERAPerMed funding for a collaborative project entitled "Omics Approach for Personalized Prevention of Type 2 Diabetes Mellitus for African and European Populations". Professor Julia Goedecke is the co-ordinating PI on this multi-centre study including data from the Middle-aged Soweto Cohort which was created as part of this funded grant. |
| Collaborator Contribution | Heidelberg University and University of Bonn collaborators provide access to the RODAM study as well as dietary expertise. Umea University collaborators provide access to the SCAPIS Swedish cohort, and proteomic analysis. Chalmers University collaborators provide expertise in metabolomic analysis. |
| Impact | Protocol paper in review in BMJ Open. |
| Start Year | 2023 |
| Description | OPTIMA study |
| Organisation | University of Bonn |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Through this collaboration we have obtained ERAPerMed funding for a collaborative project entitled "Omics Approach for Personalized Prevention of Type 2 Diabetes Mellitus for African and European Populations". Professor Julia Goedecke is the co-ordinating PI on this multi-centre study including data from the Middle-aged Soweto Cohort which was created as part of this funded grant. |
| Collaborator Contribution | Heidelberg University and University of Bonn collaborators provide access to the RODAM study as well as dietary expertise. Umea University collaborators provide access to the SCAPIS Swedish cohort, and proteomic analysis. Chalmers University collaborators provide expertise in metabolomic analysis. |
| Impact | Protocol paper in review in BMJ Open. |
| Start Year | 2023 |
| Description | Physical activity methodology |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have provided the data collected as part of this study to develop a methodology that combines 2 different accelerometers to measure physical activity and sedentary behaviour. One of our PhD students also spent time in Cambridge to learn more about this methodology. |
| Collaborator Contribution | Our partners at the MRC Epidemiology Unit, Dr Soren Brage and colleagues, developed the methodology. |
| Impact | This has resulted in 3 publications to date: doi: 10.1249/MSS.0000000000002940; doi: 10.1123/jpah.2022-0032; doi: 10.1136/bmjdrc-2022-002815 |
| Start Year | 2018 |
| Description | Professor Fredrik Karpe at the University of Oxford |
| Organisation | University of Oxford |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We invited Professor Karpe to collaborate with us on this project as he provided training and expertise in human adipose tissue metabolism. Specifically Prof Karpe's research nurse travelled to South Africa to provide training in the adipose tissue biopsy technique. Following this one of our PhD students spent time in his laboratory in Oxford to complete the sample analysis. These samples represent a middle-aged African cohort which will be able to be compared to other datasets that he has access to. |
| Collaborator Contribution | Professor Karpe's research unit provided training in human adipose tissue techniques. |
| Impact | See publication outputs for collaborative publications with Prof Karpe. |
| Start Year | 2017 |
| Description | Professor Tommy Olsson at Umea University |
| Organisation | Umea University |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Professor Olsson has a long standing collaborative relationship with Professor Goedecke, and our contribution to this collaboration is in providing him with the opportunity to further explore mechanisms underlying the high prevalence of insulin resistance in black SA women, with a specific focus on adipose tissue metabolism. |
| Collaborator Contribution | Professor Olsson has expertise in understanding obesity related disorders, notably type 2 diabetes. His research has shown that significantly amounts of stress hormones (cortisol) are released from adipose tissue and that obesity is associated with abnormal adipose tissue blood flow. His expertise in the measurement of glucocorticoids and inflammatory markers will make an enormous contribution to understanding the mechanisms associated with the development of insulin resistance and type 2 diabetes. Professor Olsson has collaborated with Professor Karpe in a series of studies on adipose tissue biology. |
| Impact | Refer to publication section for collaborative manuscripts with Professor Olsson. |
| Start Year | 2017 |
| Description | Steroid hormone analyses |
| Organisation | University of Stellenbosch |
| Country | South Africa |
| Sector | Academic/University |
| PI Contribution | As part of this study we have provided the samples and phenotype data on 1000 black South African men and women. |
| Collaborator Contribution | Our Stellenbosch partner has run all the steroid hormone analyses on the samples provided. In addition 11-oxygenated androgens have been measured at no cost to us. |
| Impact | None to date. |
| Start Year | 2020 |
| Description | University of Queensland - physical behaviours |
| Organisation | University of Queensland |
| Country | Australia |
| Sector | Academic/University |
| PI Contribution | We are sharing MASC physical behaviours data as part of a grant submission to the Australian government. |
| Collaborator Contribution | Physical behaviour data will be shared by other partners from six other countries. |
| Impact | No outputs yet. |
| Start Year | 2024 |
| Description | Feedback of AWI-Gen 2 data |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Study participants or study members |
| Results and Impact | These were feedback sessions to study participants from the AWI-Gen 2 study. These participants are now part of the Middle-aged Soweto cohort (MASC) who were included in the current grant. During the feedback sessions participants were provided with their individual results on blood pressure, waist circumference, total cholesterol, body mass index, glucose and LDL levels. The researchers explained the significance of these indicators, and their implications for health, and offered insights into potential lifestyle modifications to improve their health outcomes. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Improving Experiences of the Menopause for Women in Zimbabwe and South Africa: Co-Producing an Information Resource |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | We co-produced contextually relevant resources-booklets and poster-for women in Zimbabwe and South Africa (SA) to improve health literacy about menopause and health. Resources have been translated into several African languages and endorsed by the South African Menopause Society. These resources have been disseminated in health care clinics around Soweto (South Africa) and Harare (Zimbabwe). |
| Year(s) Of Engagement Activity | 2021 |
| Description | The Menopause Study |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | The activity was a 3- hour webinar to disseminate findings from the menopause study on which Professor Micklesfield is a co-investigator. All of the work was presented in two parts: 1. Menopausal health; 2. Musculoskeletal health in mid-life women. Presenters included students and colleagues from the University of the Witwatersrand, the Health Research Unit Zimbabwe (THRU ZIM), the University of Bristol, the University of Southampton and the MRC Unit in The Gambia. The webinar was endorsed by the National Osteoporosis Foundation of South Africa (NOFSA) and the South African Menopause Society and representatives from both organizations were part of expert panels contributing to discussions on 'Where are we now and what are the next steps: implications for policy and funding' around menopausal and musculoskeletal health. |
| Year(s) Of Engagement Activity | 2023 |