Trial Information

Insulin and the Polycystic Ovary Syndrome

Insulin resistance is present in women with PCOS. Women with PCOS are at high risk for
developing type 2 diabetes, presumably due to the insulin resistance that accompanies the
syndrome. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG)
mediators of insulin action, and evidence suggests that a deficiency in a specific
D-chiro-inositol (DCI)-containing IPG may contribute to insulin resistance in individuals
with impaired glucose tolerance or type 2 diabetes mellitus. A deficiency in DCI may also
contribute to the insulin resistance in women with PCOS. In PCOS, three separate studies
have shown that administration of DCI, the precursor to DCI-IPG, to women with PCOS improved
glucose intolerance while reducing circulating insulin, improved ovulatory function, and
decreased serum androgens. Serum triglycerides, HDL cholesterol and blood pressure improved
in some of the studies as well. Collectively, these findings strongly suggest that
administration of DCI improved insulin sensitivity in women with PCOS, and that a deficiency
in DCI may contribute to the insulin resistance of this disorder.

Previous studies of our group demonstrated that women with PCOS, when compared to normal
women, had a (i) greater than 5-fold increase in the renal clearance of DCI, (ii) 50%
reduction in the circulating concentration of DCI, and (iii) decreased insulin-stimulated
release of DCI-IPG during an oral glucose tolerance test (OGTT). Moreover, insulin
sensitivity (as determined by frequently sampled intravenous glucose tolerance test
[FSIVGTT]) correlated inversely with renal clearance of DCI. In addition, it appears that
obesity needs to be present for the abnormality in renal clearance of DCI to be present in
PCOS, and obesity does not seem to have an effect in DCI renal clearance in normal women.

Our hypothesis is that obesity modulates the renal clearance of DCI in women with PCOS, but
not in normal women. A corollary of this hypothesis is that an increased urinary DCI
clearance leads to a reduction in circulating DCI and insulin-stimulated DCI-IPG release,
and aggravates insulin resistance in women with PCOS. To test our hypothesis, we propose to
study the following specific aims:

Specific Aims:

Specific Aim 1: Determine if DCI renal clearance in obese women with PCOS is increased
compared to age- and weight-matched, obese normal women.

In this aim, we will determine if obese women with PCOS have (i) increased renal clearance
of DCI, (ii) decreased circulating levels of DCI, and (iii) decreased DCI-IPG release in
blood during an OGTT, as compared to age- and BMI-matched, obese normal women.

Specific Aim 2: Determine if weight loss reduces DCI renal clearance in obese women with
PCOS, but not in age- and weight-matched obese normal women.

This aim determines if weight loss reverses the abnormalities in DCI handling in PCOS. The
effects of weight loss on (i) renal clearance of DCI, (ii) circulating levels of DCI, and
(iii) DCI-IPG release in blood during an OGTT, will be compared between obese women with
PCOS and age- and BMI-matched obese normal women.

Specific Aim 3: Determine if a change (reduction) in DCI renal clearance as a result of
weight loss is correlated with a change (improvement) in insulin sensitivity in obese women
with PCOS that is independent of weight loss itself.

In our Preliminary Studies, we have determined that insulin sensitivity has a significant
inverse relationship with urinary DCI clearance. In this aim, we will determine if
decreasing DCI renal clearance by weight loss in obese women with PCOS will improve insulin
sensitivity independent of the degree of weight loss (via statistical adjustment with the
degree of weight loss as a covariate).

Specific Aim 4: Determine if an equivalent degree of weight loss in obese women with and
without PCOS is associated with (i) a greater reduction in DCI renal clearance, and (ii) a
greater improvement in insulin sensitivity in the PCOS women compared to the normal women.

To further demonstrate whether improvement in insulin sensitivity as a result of an
improvement in DCI handling is independent of weight loss itself, women will be stratified
by the degree of weight loss. For each degree of weight loss, we will determine if obese
women with PCOS have (i) a greater reduction of renal clearance of DCI and (ii) a greater
improvement in insulin sensitivity as a result of weight reduction, as compared to
weight-matched obese normal women.

If our proposed studies confirm a role for obesity in modulating DCI handling in PCOS, they
will substantially enhance our understanding of the pathogenesis of PCOS and are likely to
provide insights into novel treatment strategies directed specifically at the IPG system and
normalization of its function.