Glucose Metabolism in High-Risk Prostate Cancer Patients throughout the Acute Disease Trajectory
Di Sebastiano, Kathleen
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Background: Hyperglycemia and insulin resistance are associated with obesity, physical inactivity, and poor diet, and may be related to hyperinsulinemia, disrupted lipid and adipokine signaling, and pro-inflammation. The independent and/or combination of these metabolic perturbations may increase prostate cancer risk, exacerbate during acute treatment, and worsen in survivorship. The interactions between prostate cancer, treatment, dysregulation of glucose metabolism, and the associated metabolic sequelae are complex and should be evaluated in an integrative manner to discern these relationships. The purpose of this thesis is to employ an integrative approach to examine glucose metabolism and related features at diagnosis and during the acute treatment trajectory (up to the first 6 months of treatment) of prostate cancer patients. Objectives: The objectives of this thesis were to: 1) characterize glucose and associated parameters (insulin, C-peptide, IGF-1, IGFBP-3) in relation to lipid measures (triglycerides, cholesterols), adipokines (adiponectin, leptin), body composition, physical activity, diet, and inflammation (CRP, IL-1β, IL-4. IL-6, IL-8, IL-10, TNF-α) prior to prostate cancer treatment, 2) examine potential changes in this comprehensive metabolic profile during the acute prostate cancer treatment trajectory (~6 months following radiation therapy), and 3) develop a cell culture model to examine the cellular mechanisms contributing to potential alterations in glucose metabolism observed during the treatment trajectory. Methods: In Study 1, fasting glucose, insulin, C-peptide, IGF-1, IGFBP-3, cholesterol, triglycerides, leptin, adiponectin, CRP were measured along with traditional moderators glucose metabolism (body composition, nutrition intake, habitual physical activity) to characterize interrelated metabolic features in men undergoing prostate biopsy. High-risk prostate cancer patients demonstrate the greatest C-peptide and leptin concentrations, as well as the greatest visceral adiposity in Study 1. In Study 2, more comprehensive evaluations, including an oral glucose tolerance test (OGTT), were prospectively performed on a separate group of high-risk prostate cancer patients prior to radiation therapy (baseline), as well as 7 weeks and 33 weeks following baseline. Patients were compared to a group of young healthy males and a group of age- and BMI-matched males to assess age- and cancer-related differences in glucose metabolism. To understand the underlying mechanisms of poor metabolic outcomes in high-risk prostate cancer patients, a novel cell culture model was developed in Study 3 where human skeletal muscle myoblasts (HSkMM) were incubated with human serum from prostate cancer patients across the acute treatment trajectory to examine glucose uptake. Results: At the time of the prostate biopsy (or time of diagnosis for the prostate cancer patients) in Study 1, prostate cancer patients diagnosed with aggressive cancer (Gleason ≥4+3) demonstrated greater insulin secretion assessed by C-peptide concentrations compared with patients that had less aggressive cancers (Gleason ≥4+3: 2.8±1.1 ng/mL vs Gleason 3+3 1.4±0.6 mg/mL vs Gleason 3+4: 1.3±0.8 mg/mL; p=0.002). Insulin concentrations and HOMA-IR tended to be greater in patients with the most aggressive cancer compared to the others. Greater insulin secretion, measured by C-peptide concentrations, was related to greater visceral adiposity, higher leptin and leptin:adiponectin ratio, suggesting these metabolic perturbations may relate to obesity. In Study 2, high-risk prostate cancer patients demonstrated impaired glucose tolerance by 2 hours of an OGTT prior to treatment (Normal: <7.8mM, Patients: 8.62±2.87mM), which improved at 7 weeks post-baseline (6.78±1.48 mM) and was maintained 33 weeks following baseline (5.69±2.14mM, p=0.007). Insulin, C-peptide, IGF-1, IGFBP-3, adipokines, triglycerides, cholesterols, inflammatory markers, physical activity, and nutrition intake did not change during the study trajectory. In Study 3, we evaluated the effects of serum from prostate cancer patients and matched males on differentiated HSkMM, which showed significantly reduced glucose uptake compared with young males; however there were no differences between prostate cancer patients and matched males, suggesting an age-related decrease in glucose uptake. Conclusions: At diagnosis, prostate cancer patients demonstrated a cluster of glucose-related metabolic perturbations that may contribute to prostate cancer aggressiveness. Significant improvements in glucose metabolism were observed during acute treatment, despite the lack of change in traditional moderators of glucose metabolism, suggesting cancer-related effects on host glucose metabolism. New models are needed to elucidate the mechanisms driving these metabolic changes and to, ultimately, reduce the risk of cancer recurrence, diabetes, and cardiovascular disease in prostate cancer survivors.