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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03408678
• Other study ID #: M160604
• Status: Completed
• Start date: January 23, 2017
• Est. completion date: July 31, 2018

Study information

• Verified date: June 2019
• Source: University of Witwatersrand, South Africa
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1025
• Est. completion date: July 31, 2018
• Est. primary completion date: July 31, 2018
• Gender: All
• Age group: 35 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Hiv
• Insulin Resistance
• Menopause

Locations

Country	Name	City	State
South Africa	SAMRC/WITS Developmental Pathways of Health Research Unit, University of Witwatersrand	Johannesburg	Gauteng

Sponsors (5)

Lead Sponsor	Collaborator
University of Witwatersrand, South Africa	GlaxoSmithKline, Medical Research Council, South Africa, University Hospital, Umeå, University of Oxford

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Insulin sensitivity and secretion	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	Body fat distribution	Body fat depots measured using dual energy x-ray absorptiometry	4-6 years