Almost 50% of the Veteran patient population will be over the age of 65 by the year 2020. Therefore, it is imperative that we better understand the mechanisms of diseases affecting our older Veterans. There is increasing evidence that prolonged low-grade inflammation, expressed by elevated levels of circulating proinflammatory cytokines, may play a role in many aging-related chronic diseases especially skeletal muscle insulin resistance and pancreatic B-cell dysfunction leading to type 2 diabetes, metabolic syndrome and cardiovascular disease. There is also evidence that sex steroid hormones play a role in these metabolic disorders. One of the significant consequences of the age- associated decrease in testosterone levels in older men is an increase in central adiposity, which may be the source of adipose tissue-derived inflammatory cytokines, or adipokines. The current proposal will test the hypothesis that the aging associated decrease in testosterone levels in older men is associated with increased insulin resistance, due to an increase in adipocyte mediators of inflammation. To test this hypothesis, using our currently established protocol, 60 healthy older Veterans will first undergo short-term medical androgen ablation and aromatase inhibition and be placed on transdermal testosterone and estrogen to establish uniform initial testosterone and estrogen levels. Subjects will then be randomized into one of 4 treatment groups for 6 weeks: 1) continuation of testosterone and estrogen; 2) continuation of testosterone only, without estrogen; 3) continuation of estrogen only, without testosterone; or 4) discontinuation of both testosterone and estrogen. Outcomes before and after 6 weeks will include: 1) circulating adipokines; 2)monocyte and adipose tissue RNA/protein expression of inflammatory markers; 3) precise measures of total, visceral, subcutaneous and ectopic skeletal muscle adiposity; and 4) insulin sensitivity.
The specific aims will be 1) to define the specific individual effects of testosterone and estrogen on key serum and tissue adipokine levels in older men; 2) to determine the individual effects of testosterone and estrogen on total, subcutaneous and visceral adiposity, as well as ectopic lipid deposition in skeletal muscle; and 3) to examine the relationships between testosterone and estrogen induced changes in adipokine levels and total and regional adiposity and insulin sensitivity. These studies will provide important new information regarding the basic cellular and molecular mechanisms of the effects of sex steroid hormones on adipose tissue function and inflammation in older men, and their relation to changes in insulin sensitivity. Novel information resulting from this study should lead to new prevention strategies, agents and interventions to decrease insulin resistance and metabolic risk in older Veterans, an outcome highly relevant to the VA patient care mission.
The goal of this research is to define the mechanisms by which the age associated changes in sex hormone levels affect insulin resistance. Insulin resistance and adiposity are well- established risk factors for aging-related disorders such as type 2 diabetes and cardiovascular disease. More than 30% of the male and female Veteran population is currently considered to be obese. Also, the prevalence of diabetes in the Veteran population is estimated to be 15-20% of those Veterans receiving outpatient care, which is greater than the prevalence in the general population. According to the VHA/DOD Clinical Practice Guideline, the burden of diabetes in the VA system is among the highest of any national health care system. Thus, improved knowledge about the nature and mechanisms of sex hormone effects on insulin resistance and adiposity could ultimately have a major beneficial impact on Veteran health care.