Background: Turner syndrome (TS) is caused by the absence or fragmentation of the 2^nd sex chromosome. An increased risk of diabetes mellitus (DM) has consistently been noted, but the specific phenotype and genetic etiology of this trait are unknown.

Methods: In a prospective study, we examined the prevalence of DM in adult participants in an intramural NIH TS study. Results were analyzed with respect to karyotype, age, BMI and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups.

Results: Type 2 DM was present in 56/224 (25%) of women with TS; type 1 DM was found in only one (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0% vs. 17.3%, p=0.004). Euglycemic women with TS (n=72; age 33±12; BMI 23±3) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group.

Conclusion: Type-2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X chromosome, but is even more greatly increased among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.