Insulin and the Polycystic Ovary Syndrome--Weight Reduction Study
Condition: Polycystic Ovary Syndrome; Obesity
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional

Summary: 
      The polycystic ovary syndrome is the leading cause of female infertility in the United
      States. The disorder affects approximately 6-10% of women of reproductive age. It is widely
      accepted that "insulin resistance" may be responsible for the infertility of this syndrome.
      Women are insulin resistant when their bodies do not respond to insulin's action to handle
      sugar as they normally should. Because of this insulin resistance, women with the polycystic
      ovary syndrome are also at high risk for developing type 2 diabetes. We have previously shown
      that D-chiro-inositol (DCI), a substance naturally found in our body that helps insulin's
      action, is lacking in women with the polycystic ovary syndrome. Not having enough DCI may
      lead to insulin resistance. The purpose of this study is to determine if weight loss helps to
      replenish the body with DCI and help to promote insulin's action.
    

Detailed description: 
      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.
    

Intervention name(s): Weight loss
Intervention type(s): Behavioral
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment