Study to Identify Markers of Insulin Resistance During Growth Hormone Treatment for Short Stature

• to compare the effect of GH on IMCL content in the two subject groups (Turner syndrome vs. ISS) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

• to assess the relationship of IMCL to IR-associated plasma markers in each groups [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  
• to assess the relationship of IMCL to the effect of GH therapy in each groups [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

Growth hormone (GH) treatment can cause insulin resistance (IR) despite its overall favorable influence on body fat composition. IR is associated with special stores of fat in the muscle (intramyocellular lipid or IMCL), which can be measured by MRI. The researchers hypothesize that changes in IR during GH treatment will be associated with a predictable, but possibly contradictory, change in muscle fat stores. Girls receiving GH for short stature, due to Turner syndrome or idiopathic short stature (ISS), will be studied both during and without GH treatment to assess the impact of GH treatment on muscle fat stores.

Hypothesis: Girls with Turner syndrome will have increased IMCL, corresponding to their insulin resistance, when compared to girls with ISS. GH treatment may paradoxically reverse this association in girls with Turner syndrome.

Objectives: The objectives are to assess changes in IMCL during GH therapy and to increase the researchers' knowledge of GH action.

Study Design: Prepubertal girls receiving GH therapy for short stature due to Turner syndrome or ISS will be recruited to participate in a crossover study. Subjects will be studied twice: first during GH treatment and at baseline, following washout without GH for 3 months. GH treatment for up to 6 months will be provided for eligible girls not currently receiving GH. Assessments include:

• IMCL (soleus and tibialis anterior) measured non-invasively by proton magnetic resonance spectroscopy (1H-MRS)
• Body composition measured by DEXA and morphometry
• Whole body insulin sensitivity assessed by oral glucose tolerance
• Levels of plasma lipids and hormones

Endpoints: The primary endpoint is to define the effect of GH on IMCL content in girls with Turner syndrome versus girls with ISS. The secondary endpoint is to examine how GH affects IMCL content by identifying correlative changes in plasma hormones and metabolites.

Significance: This study is intended to find improved strategies for monitoring GH therapy. In addition, IMCL is anticipated to be a valuable probe for understanding GH effects on glucose homeostasis.