Unravelling the link between insulin resistance and androgen excess

O’Reilly, Michael (2015). Unravelling the link between insulin resistance and androgen excess. University of Birmingham. Ph.D.

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Abstract

Insulin resistance and androgen excess are the cardinal phenotypic features of polycystic ovary syndrome (PCOS). The severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated. Aldoketoreductase type 1C3 (AKR1C3) is an important source of androgen generation in human adipose tissue, and may represent a link between androgen metabolism and metabolic disease in PCOS. We performed integrated in vitro studies using a human preadipocyte cell line and primary cultures of human adipocytes, coupled with in vivo deep phenotyping of PCOS women and age- and BMI-matched controls.

We have shown that insulin upregulates AKR1C3 activity in primary female subcutaneous adipocytes. AKR1C3 mRNA expression increased with obesity. Androgens were found to increase lipid accumulation in human adipocytes. In clinical studies, androgen exposure induced relative suppression of adipose lipolysis in PCOS women, supporting a role for androgens in lipid accumulation. Androgens were detectable in adipose fluid from PCOS women, and correlated with systemic markers of androgen metabolism.

Using comprehensive in vivo, ex vivo, and in vitro techniques, we have shown regulation of adipose androgen generation through AKR1C3, with evidence of a vicious circle of hyperinsulinaemia, adipose androgen generation and lipid accumulation. These data identify AKR1C3 as a promising therapeutic target in PCOS.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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