Effects Of Androgen Deficiency on Glucose Homeostasis

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Recently, in conjunction with collaborators at Johns Hopkins Medical Institutes, we have been studying the effects of hypogonadism on insulin resistance, diabetes and the metabolic syndrome (MS). Patients with prostate cancer who undergo androgen deprivation therapy (ADT) as part of their treatment plan become not only insulin resistant but more than 50% develop MS. This clearly puts them at risk for strokes and heart attacks, and, in fact, cardiovascular disease is the leading cause of death in patients with prostate cancer. The MS of ADT is not characteristic of the more usual MS, in that serum levels of adiponectin, which is secreted from fat tissue, are elevated in patients with ADT. Typically, adiponectin levels are decreased in MS due to increased secretion of cytokines that down-regulate the adiponectin gene: low circulating adiponectin levels cause reduced insulin-mediated glucose uptake in muscle and liver, that is, exacerbate insulin resistance and are a consistent feature in MS. ADT is a new and evolving field of clinical interest as more and more patients are subjected to ADT, and data is now appearing from other groups confirming our metabolic findings. We have a protocol in place to study androgen deficiency in rats subjected to low circulating levels of androgens by gonadiectomy and injections of 2 pharmacological agents that prevents gonadotropin secretion from pituitary. So far, we have found that the human adiponectin data from ADT patients is reproducible in that circulating adiponectin levels are increased in the hypogonadal animals, and interestingly, adiponectin gene expression is actually increased in fat tissue. We therefore conclude the ADT therapy leads to down-regulation of adiponectin receptors in liver and muscle, causing a positive feedback to the adiponectin gene. We are currently studying how adiponectin receptors might be regulated because androgen regulation of adiponectin receptors has not been previously reported. We are confident that our findings will be also applicable to ADT in patients with prostate cancer.