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
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 (ERĪ²), 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).
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.
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