Insulin resistance, a key factor in the pathogenesis of
polycystic ovary syndrome (PCOS), is associated with a reduction in activation of muscle
glycogen synthase. A 5-bp insertion-deletion polymorphism in the (AU)AT-rich
element (ARE) within the 3'-untranslated region of the gene encoding the muscle-specific
glycogen-targeting subunit of
protein phosphatase 1 (PPP1R3) has been associated with
insulin resistance and
type 2 diabetes. The present study was undertaken to examine the relationship of the ARE polymorphism with clinical and hormonal characteristics of women with PCOS. We studied 186 women with PCOS who had undergone a standard 75-g oral
glucose tolerance test and measurement of serum
androgen and SHBG levels. Among the largest cohort of nondiabetic subjects (Caucasian, n = 112), the presence of the deletion allele (ARE-2) was associated with
insulin resistance and hyperandrogenemia. There was no association of the ARE polymorphism with body mass index or
blood glucose concentration during the oral
glucose tolerance test. Subjects who were homozygous for the insertion allele (ARE-1/1) had a mean
insulin area under the curve (99,116 +/- 6,625 pmol/liter.min) that was significantly lower than that in either the heterozygous (ARE-1/2) (132,195 +/- 12,340 pmol/liter.min) or homozygous (ARE-2/2) (164,661 +/- 24,219 pmol/liter.min) deletion groups. In addition, ARE-1/1 subjects had significantly lower serum concentrations of
dehydroepiandrosterone sulfate compared with ARE-2/2 subjects (4.2 +/- 0.3 vs. 6.6 +/- 0.7 micromol/liter) and a trend toward lower levels of free
testosterone (78.8 +/- 6.5 vs. 114.1 +/- 30.8 pmol/liter). Studies of diabetic and nondiabetic PCOS women of other racial and ethnic backgrounds will be necessary to assess the impact of this and other variants in PPP1R3 upon the phenotype and natural history of women with PCOS.