Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disorder that affects 16 million people in the United States. Thus, elucidation of the factors that modulate insulin action has important public health implications. The relationship between androgens and insulin resistance in the human is complex with clear evidence of sexual dimorphism. In the female, insulin resistance is associated with hyperandrogenenism, while epidemiologic studies in the male consistently demonstrate an inverse relationship between testosterone and insulin. Current data on causality are conflicting. Therefore, the overall goat of this proposal is to define precisely the causal determinants of the inverse relationship between insulin resistance and testosterone in men.
Specific aim 1 will determine if the abnormalities demonstrated in the hypothalamic-pituitary-gonadal axis of men with type 2 diabetes can be corrected by administration of an insulin sensitizing agent.
Specific aim 2 will define the dose-response relationship between increasing testosterone and insulin resistance using two experimental human models: a) normal men after induction of hypogonadism with a GnRH antagonist and again after physiologic testosterone replacement; and b) men with congenital idiopathic hypogonadotropic hypogonadism before and after androgen replacement.
Specific aim 3 will examine the impact of testosterone supplementation on insulin resistance and gtycemic control in men with type 2 diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causal determinants unequivocally defined. Given the significant cardiovascular morbidity and mortality associated with insulin resistant states such as obesity and type 2 diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important clinical significance and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK064276-01A1
Application #
6720874
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2004-02-01
Project End
2005-11-30
Budget Start
2004-02-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$86,667
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Yialamas, Maria A; Dwyer, Andrew A; Hanley, Erin et al. (2007) Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92:4254-9
Pitteloud, Nelly; Mootha, Vamsi K; Dwyer, Andrew A et al. (2005) Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care 28:1636-42
Pitteloud, Nelly; Hardin, Megan; Dwyer, Andrew A et al. (2005) Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 90:2636-41