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

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).

Conditions

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

Sponsors & Collaborators

• Medical Research Council, South Africa

  collaborator OTHER

• GlaxoSmithKline

  collaborator INDUSTRY

• University of Oxford

  collaborator OTHER

• University Hospital, Umeå

  collaborator OTHER

• University of Witwatersrand, South Africa

  lead OTHER

Principal Investigators

• Julia H Goedecke, PhD · Medical Research Council, South Africa

• Lisa K Mickelsfield, PhD · University of Witwatersrand, South Africa

Eligibility

Min Age

35 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-01-23

Primary Completion

2018-07-31

Completion

2018-07-31

Countries

• South Africa

Study Locations