GLP-1 [7-36] amide is a naturally produced insulinotropic peptide which modulates insulin secretion from beta cells in the post-prandial state. Pharmacological doses are required to normalize blood glucose in type 2 diabetes. It is produced as a 30-amino acid peptide but within a few minutes the first two amino acids of the N-terminus (HA) are removed by a dipeptidyl peptidase IV, rendering the remaining GLP-1 [9-36] amide inactive as an insulinotropic peptide. In the post-prandial state, at least 75% of the GLP-1 is in the [9-36] form. Our previous investigators had found that GLP-1 [7-36] amide infusions not only increased insulin secretion but increased glucose disposal in liver, independent of insulin. In order to separate effects of GLP-1 [7-36] amide from its metabolite [9-36] and in conjunction with Grady Meneilly, M.D. (Vancouver General Hospital] and Dariush Elahi, Ph.D. (University of Worcester, MA) we have been infusing GLP-1 [9-36] amide to lean and obese subjects in order to elucidate if it had only intrinsic metabolic effects. We have found that GLP-1 [9-36] amide infusions result in increased glucose uptake by liver in obese, but not lean, subjects. This mirrors what we found with GLP-1 [7-36] amide infusions. We subsequently infused a GLP-1 receptor antagonist in conjunction with GLP-1 [9-36] amide and found that glucose uptake was further increased, thus demonstrating that the action of GLP-1[9-36]amide on increasing glucose uptake is not through the known GLP-1 receptor. A manuscript is under review by J Clin Endocrinol Metab on this topic. The mechanism of action underlying the increased glucose uptake by GLP-1[9-36] amide remains unresolved and is under investigation with basic research. ? ? Recently, in conjunction with collaborators at Johns Hopkins, we have been studying the effects of hypogonadism on insulin resistance and the metabolic syndrome. Patients with prostate cancer who undergo androgen deprivation therapy as part of their treatment become not only insulin resistant but more than 50% also develop the metabolic syndrome. This clearly puts them at risk for strokes and heart attacks and therefore the treatment for the prostate cancer will increase their mortality and morbidity. This is a new and evolving field of interest and data is just now appearing from other groups confirming our findings. We are currently divising a protocol to carry out a prospective study of prostate cancer patients (some of whom will have cancer-removal surgery of the prostate, some of who will receive androgen deprivation therapy and some of whom will receive both) and follow them longitudinally. We wish to determine, 1) when and why insulin resistance manifests itself and in which group, 2) introduce therapy in a subpopulation to lessen insulin resistance ( metformin, pioglitazone, exendin-4, or GLP-1) and follow outcomes, 3) quantify the degree of insulin resistance using glucose clamps, and, 4) attempt to define the mechanism of action by which androgen deprivation leads to insulin resistance. If androgen therapy continues to be a treatment for prostate cancer, proper management strategies of androgen deprived patients will be required.
