TAC3/TACR3 Mutations Reveal Preferential Activation of GnRH Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

Objective: Diabetes in the context of severe insulin resistance (SIR) presents a major therapeutic challenge because conventional therapies including insulin and insulin sensitizers often fail to achieve adequate metabolic control. Adjunctive therapy with recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) has been shown to improve insulin sensitivity in both type 1 and type 2 diabetes and may have a role in the treatment of SIR. We report clinical and physiological outcomes after adjunctive therapy with rhIGF-I/rhIGFBP-3 in five subjects with SIR. Research Design and Methods: Five females (median age, 17 yr; range, 5-37) with SIR (two with pathogenic insulin receptor mutations) were treated with 0.5-2.0 mg/kg rhIGF-I/rhIGFBP-3 using a 16-wk dose escalation protocol. Glycosylated hemoglobin was recorded monthly, and at baseline and end of treatment all patients were evaluated using continuous glucose monitoring sensing and admitted for overnight GH profiling and insulin-modified stable-label iv glucose tolerance test. Changes in body composition were assessed using dual-energy x-ray absorptiometry and magnetic resonance imaging. Results: Treatment with rhIGF-I/rhIGFBP-3 was well tolerated, and all subjects reported clinical improvements with reduction in acanthosis nigricans. Glycosylated hemoglobin was reduced (8.5% pretreatment to 7.1%; P 0.03) with a trend toward reduction in mean continuous glucose monitoring sensing glucose (10.7 vs. 8.5 mmol/liter; P 0.08). Effects of treatment on other biochemical measures were variable, but there was a trend toward improved C-peptide responses during the iv glucose tolerance test. Conclusions: rhIGF-I/rhIGFBP-3 is well tolerated and clinically effective in subjects with SIR. TAC3/TACR3 Mutations Reveal Preferential Activation of GnRH Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood Elena Gianetti, Cintia Tusset, Sekoni D. Noel, Margaret G. Au, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka Trarbach, Leticia FG Silveira, Elaine MF Costa, Berenice Bilharinho de Mendonca, Margaret de Castro, Adriana Lofrano, Janet E. Hall, Erol Bolu, Metin Ozata, Richard Quinton, John K. Amory, Susan E. Stewart, Wiebke Arlt, Trevor R. Cole, William F. Crowley, Ursula B. Kaiser, Ana Claudia Latronico, and Stephanie B. Seminara (J Clin Endocrinol Metab, 10.1210/jc.2009-2320) ABSTRACT Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design: Sequencing of TAC3/TACR3; in vitro functional assays, neuroendocrine phenotyping. Setting: Tertiary care centers world-wide. Patients or other participants: 345 probands, 18 family members, 292 controls. Intervention: Examination of reproductive phenotypes throughout reproductive life and pre/post therapy. Main Outcome Measure: Rare sequence variants in TAC3/TACR3. T R A N S L A T I O N A L H I G H L I G H T S F R O M T H E E N D O C R I N E S O C I E T Y J O U R N A L SContext: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design: Sequencing of TAC3/TACR3; in vitro functional assays, neuroendocrine phenotyping. Setting: Tertiary care centers world-wide. Patients or other participants: 345 probands, 18 family members, 292 controls. Intervention: Examination of reproductive phenotypes throughout reproductive life and pre/post therapy. Main Outcome Measure: Rare sequence variants in TAC3/TACR3. T R A N S L A T I O N A L H I G H L I G H T S F R O M T H E E N D O C R I N E S O C I E T Y J O U R N A L S