Determinants of Type 2 Diabetes Risk in Middle-aged Black South African Men and Women

June 13, 2019 updated by: Julia Goedecke, University of Witwatersrand, South Africa

Determinants of Type 2 Diabetes Mellitus Risk in Middle-aged Black South African Men and Women: Dissecting the Role of Sex Hormones, Inflammation and Glucocorticoids

There is little known about menopause in African women, whose phenotype differs to Caucasian women, and no data is available on middle-aged black South African men. Accordingly, the study aims 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.

Research questions and hypotheses:

  1. Does the decrease in sex hormones that occur with ageing increase circulating cortisol and/or inflammatory markers, and directly and/or indirectly via increases in central fat mass, decrease insulin sensitivity in middle-aged black South African men and women?

    Hypothesis: The mechanism underlying the decrease in insulin sensitivity (outcome) associated with the decline in sex hormones (exposure) that occurs with ageing is mediated via an increase in centralization of body fat (mediator), which is due to an increase in inflammation and cortisol production.

  2. How does HIV alter the relationship between sex hormones, inflammation and cortisol levels, and subsequently body fat distribution and insulin sensitivity?

    Hypothesis: HIV infection will exacerbate the effects of the decline in sex hormones with ageing, leading to further increases in inflammation and cortisol production, and a consequent increase in the centralization of body fat and decrease in insulin sensitivity.

  3. Does adipose tissue glucocorticoid and inflammatory gene expression differ between pre- and post-menopausal women, with and without HIV, and how do these relate to body fat distribution and insulin sensitivity and secretion?

Hypothesis: Adipose tissue estrogen receptor beta (ERβ), 11-beta hydroxysteroid dehydrogenase type 1 (11HSD1) activity and pro-inflammatory markers will be higher in post- compared to pre-menopausal women, which will be exacerbated by HIV infection. This will be associated with down-regulation of subcutaneous adipose tissue (SAT) adipogenic genes, increased visceral adipose tissue (VAT), a decrease in insulin sensitivity and secretion, and consequently an increased risk for type 2 diabetes (T2D).

Study Overview

Detailed Description

The study will be performed in two parts:

Part 1 - Using a longitudinal design, a sample of 500 black women at different stages of the menopausal transition, and 500 middle-aged men living in Soweto Johannesburg, South Africa, who were included in previous studies between 2011 and 2014, will be recruited. Socio-demographics, health and menopausal status will be assessed using questionnaires; physical activity and sedentary behaviour will be measured using accelerometry; dietary intake will be estimated using a food frequency questionnaire; body composition and body fat distribution will be assessed using dual energy x-ray absorptiometry (DXA); fasting blood samples will be drawn for the determination of cardio-metabolic risk (glucose, insulin, lipids), cluster of differentiation 4 (CD4) count, as well as sex hormones, inflammatory markers and cortisol concentrations. An oral glucose tolerance test will be performed to measure insulin sensitivity and secretion. Statistical analyses will include multilevel mediation modelling.

Part 2 - Using a cross-sectional design, a sub-sample of 100 women from Part 1 will be selected and divided into four groups including 25 pre-menopausal HIV-negative women and 25 age-matched pre-menopausal HIV-positive women (ARV-Naïve); 25 post-menopausal HIV-negative and 25 age-matched post-menopausal HIV-positive women (ARV-Naïve). The women will undergo a frequently sampled intravenous glucose tolerance test to measure insulin sensitivity and secretion, and adipose tissue biopsies will be taken from the gluteal and abdominal SAT depots for the analysis of gene and protein expression relating to inflammation, sex hormones, glucocorticoid metabolism and adipogenesis. Statistical analyses will include multilevel mediation modelling.

Study Type

Observational

Enrollment (Actual)

1025

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Gauteng
      • Johannesburg, Gauteng, South Africa, 2013
        • SAMRC/WITS Developmental Pathways of Health Research Unit, University of Witwatersrand

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

A sample of 500 black women at different stages of the menopausal transition, and 500 middle-aged men living in Soweto Johannesburg, South Africa. The women are a sub-sample of 1007 women on whom baseline data was collected between 2011 and 2014 as part of the Study of Women Entering and in Endocrine Transition. The 500 women will be selected using a random process, to allow their profile to mirror that of the overall sample.

The men are a sub-sample of 962 black men on whom similar data was collected in 2014 as part of a larger African genomics study (www.h3africa.org). The 500 men will be randomly selected following the same approach applied to the female cohort.

Description

Inclusion Criteria:

Part 1:

  • Women on whom baseline data was collected between 2011 and 2014 as part of the Study of Women Entering and in Endocrine Transition.
  • Men on whom baseline data was collected in 2014 as part of a larger African genomics study (www.h3Africa.org).

Part 2: A sub-sample of women from Part 1 of the study:

  • Pre-menopausal women age-matched within the age range 35-45 years;
  • Post-menopausal women age-matched within the age range 55-65 years;
  • All women: BMI 25-40 kg/m2

Exclusion Criteria:

Part 1:

- Failed to consent to participate in the study.

Part 2:

  • Diabetes, thyroid dysfunction, inflammatory, hepatic and renal diseases;
  • Use of hormone replacement therapy; hormonal contraceptives, oral cortisone, anti-inflammatory drugs or antiretroviral therapy;
  • Peri-menopausal;
  • Currently pregnant or lactating;
  • Tobacco use.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin sensitivity and secretion
Time Frame: 4-6 years
Part 1: insulin sensitivity and secretion estimated from an oral glucose tolerance test; Part 2: insulin sensitivity and secretion estimated using a frequently sampled intravenous glucose tolerance test
4-6 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Body fat distribution
Time Frame: 4-6 years
Body fat depots measured using dual energy x-ray absorptiometry
4-6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Julia H Goedecke, PhD, Medical Research Council, South Africa
  • Principal Investigator: Lisa K Mickelsfield, PhD, University of Witwatersrand, South Africa

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

January 23, 2017

Primary Completion (ACTUAL)

July 31, 2018

Study Completion (ACTUAL)

July 31, 2018

Study Registration Dates

First Submitted

January 17, 2018

First Submitted That Met QC Criteria

January 17, 2018

First Posted (ACTUAL)

January 24, 2018

Study Record Updates

Last Update Posted (ACTUAL)

June 14, 2019

Last Update Submitted That Met QC Criteria

June 13, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The principal investigators are prepared to share all individual patient data (IPD) with the wider scientific community, and will make the data available after all the results have been published.

IPD Sharing Time Frame

Starting 6 months after publication of the data.

IPD Sharing Access Criteria

Access will be assessed on a case-by-case basis by the principal investigators of the study.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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