• Verderame, Michael (PI)
  • Dunaif, Andrea (PI)
  • Dunaif, Andrea (PI)
  • Dunaif, Andrea (PI)
  • Dunaif, Andrea (PI)
  • Dunaif, Andrea (PI)

Project: Research project

Project Details


Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in
women of reproductive age. It is associated with profound insulin
resistance resulting in a markedly increased risk for non-insulin
dependent diabetes mellitus (NIDDM) at a strikingly early age (3rd-4th
decades). The overall hypothesis of this research is that insulin
resistance in PCOS is the result of several distinctive defects in insulin
receptor-mediated signaling. Further, we propose that each defect has a
unique genetic basis compared to defects producing insulin resistance
associated with typical NIDDM, with obesity, or with the rare syndromes of
extreme insulin resistance. We have found a novel abnormality of insulin-
receptor signaling (increased insulin-independent insulin receptor serine
phosphorylation and decreased insulin-stimulated insulin receptor tyrosine
phosphorylation) in association with insulin resistance in approximately
50% of PCOS women. This defect is present in the major insulin target
tissue, muscle, and persists in cultured cells suggesting a genetic
abnormality. The Specific Aims of this proposal are, thus: 1) To determine
the role of insulin receptor serine phosphorylation in the pathogenesis of
insulin resistance in PCOS. We hypothesize that increased insulin-
independent insulin receptor serine phosphorylation inhibits insulin-
induced receptor-mediated signaling in PCOS. This will be investigated by
examining the effects of dephosphorylation on the kinase activity of
insulin receptors partially-purified from muscle and from fat, using
serine specific (e.g. phosphatase type-2A) as well as nonspecific (e.g.
alkaline phosphatase) phosphatases. 2) To determine whether there are
post-insulin receptor signaling defects in PCOS. In PCOS there is a marked
shift to the right in the insulin dose-response curve for glucose uptake
in fat and in muscle as well as a decrease in adipocyte GLUT4 content.
However, approximately 30% of such insulin resistant PCOS women have
normal insulin receptor phosphorylation, and we hypothesize that these
women have downstream signaling defects. Moreover, we hypothesize that 50%
of PCOS women with defects in insulin receptor phosphorylation will also
have decreased insulin-receptor mediated downstream signaling. This will
be investigated by assessing insulin stimulation, in vivo and in intact
adipocytes, of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity.
Glucose uptake and GLUT4 content will also be determined. The ED50
insulin and Vmax for glucose use and for PtdIns 3-kinase activation will
be examined. 3) To determine whether defects in insulin action in PCOS are
genetic. If insulin resistance in PCOS is a genetic defect, first degree
relatives should be affected. This will be investigated by determining
total body and cellular insulin action in brothers of PCOS probands. We
will screen for mutations in the insulin receptor and IRS-1 genes of PCOS
women with denaturing gradient gel electrophoresis or single stranded
conformation polymorphisms. Lean and obese PCOS women, brothers of PCOS
women and age-, weight-, ethnicity- and sex-matched normal control
subjects will participate in these studies.
Effective start/end date1/1/907/31/01




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