BADERC-Nelly Pitteloud

Nelly Pitteloud, M.D.

Modulation of Insulin Action by Testosterone in Men

Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disease now reaching epidemic proportions. While epidemiologic studies consistently demonstrate an inverse relationship between insulin resistance and testosterone (T) in men, data on causality are lacking. In addition, it is unclear whether T might modulate insulin action by a direct effect mediated through the androgen receptor or an indirect effect mediated by aromatization to estradiol (E2). Thus, the overall goal of this proposal (5R01DK071168) is to define the role of gonadal sex steroids in modulating insulin action in men. The present study, by combining carefully designed physiologic experiments with state of the art genetic and imaging studies, affords the opportunity to determine, if and how, T modulates insulin sensitivity in men. It is currently estimated that 20% of men over 60 yr have low T levels. Therefore, if low T levels are shown to play a role in the pathogenesis of insulin resistance, T may well represent an important therapeutic modality for both the primary and secondary prevention of the metabolic syndrome and/or type 2 diabetes in men.

References:

1. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, Amory JK, Pitteloud N, Seminara SB. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2009
Chen H, Xu CF, Ma J, Eliseenkova AV, Li W, Pollock PM, Pitteloud N, Miller WT, Neubert TA, Mohammadi M. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc Natl Acad Sci U S A. 2008;105:19660-5.
Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata T, Sato N, Claahsen-van der Grinten HL, van der Donk K, Seminara S, Bergman JE, Brunner HG, Crowley WF Jr, Hoefsloot LH. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. 2009;75:65-71.
Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008;118:2822-31.
Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc. 2008;119:29-37.
Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab. 2008;93:3551-9.
Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. The relative role of gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-stimulating hormone secretion in men. J Clin Endocrinol Metab. 2008;93:2686-92.
Boepple PA, Hayes FJ, Dwyer AA, Raivio T, Lee H, Crowley WF Jr, Pitteloud N. Relative roles of inhibin B and sex steroids in the negative feedback regulation of follicle-stimulating hormone in men across the full spectrum of seminiferous epithelium function. J Clin Endocrinol Metab. 2008;93:1809-14.
Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 2008;93:784-91.
Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007;104:17447-52.
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 ;357:863-73.
Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92:4254-9.
Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457-63.






			Nelly Pitteloud, M.D. Modulation of Insulin Action by Testosterone in Men Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disease now reaching epidemic proportions. While epidemiologic studies consistently demonstrate an inverse relationship between insulin resistance and testosterone (T) in men, data on causality are lacking. In addition, it is unclear whether T might modulate insulin action by a direct effect mediated through the androgen receptor or an indirect effect mediated by aromatization to estradiol (E2). Thus, the overall goal of this proposal (5R01DK071168) is to define the role of gonadal sex steroids in modulating insulin action in men. The present study, by combining carefully designed physiologic experiments with state of the art genetic and imaging studies, affords the opportunity to determine, if and how, T modulates insulin sensitivity in men. It is currently estimated that 20% of men over 60 yr have low T levels. Therefore, if low T levels are shown to play a role in the pathogenesis of insulin resistance, T may well represent an important therapeutic modality for both the primary and secondary prevention of the metabolic syndrome and/or type 2 diabetes in men. References: 1. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, Amory JK, Pitteloud N, Seminara SB. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2009 Chen H, Xu CF, Ma J, Eliseenkova AV, Li W, Pollock PM, Pitteloud N, Miller WT, Neubert TA, Mohammadi M. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc Natl Acad Sci U S A. 2008;105:19660-5. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata T, Sato N, Claahsen-van der Grinten HL, van der Donk K, Seminara S, Bergman JE, Brunner HG, Crowley WF Jr, Hoefsloot LH. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. 2009;75:65-71. Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008;118:2822-31. Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc. 2008;119:29-37. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab. 2008;93:3551-9. Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. The relative role of gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-stimulating hormone secretion in men. J Clin Endocrinol Metab. 2008;93:2686-92. Boepple PA, Hayes FJ, Dwyer AA, Raivio T, Lee H, Crowley WF Jr, Pitteloud N. Relative roles of inhibin B and sex steroids in the negative feedback regulation of follicle-stimulating hormone in men across the full spectrum of seminiferous epithelium function. J Clin Endocrinol Metab. 2008;93:1809-14. Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 2008;93:784-91. Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007;104:17447-52. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 ;357:863-73. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92:4254-9. Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457-63.