Role of insulin dysregulation in the development of yoshida sarcoma-induced cancer cachexia
Abstract
Cancer cachexia is a devastating syndrome present in many individuals with cancer. Characterized by weight loss, loss of appetite, and wasting of skeletal muscle and adipose tissue, cachexia is associated with an increase in both morbidity and mortality in this population. The majority of individuals with cancer will experience some degree of cachexia during the course of their disease, making cachexia a clinically relevant syndrome for which the contributing mechanisms are largely unknown. A decline in insulin function, as measured by reduced glucose tolerance and insulin sensitivity, is common in individuals with and animal models of cancer cachexia. The present series of experiments was designed to examine the role of this insulin dysregulation in the development of cancer cachexia in rats bearing the Yoshida sarcoma. In experiment 1, insulin sensitivity was measured during the tumor growth period to determine when insulin dysregulation begins, relative to changes in body composition associated with cancer cachexia (Chapter 2). In Experiment 2, control and tumor-bearing animals were treated daily with saline or Exnedin-4, a GLP-1 agonist, in order to determine whether cachexia could be prevented by improving insulin sensitivity (Chapter 3). In Experiment 3, animals were fed a chow diet or a high-fat diet prior to tumor implantation, to determine if diet-induced insulin resistance modifies the development of cachexia in rats bearing the Yoshida sarcoma (Chapter 4). Our results indicate that 1) insulin dysregulation is present in Yoshida sarcoma-bearing rats prior to the onset of cachexia, 2) prevention of insulin dysregulation via chronic Exendin-4 treatment prevents the development of some cancer cachexia symptoms, and 3) the induction of insulin dysregulation via high-fat diet feeding accelerates the development of cancer cachexia. Further research is necessary to determine the mechanisms through which insulin dysregulation develops, as alterations in insulin signaling do not appear to contribute significantly to the observed effects.
Degree
Ph.D.
Advisors
Kinzig, Purdue University.
Subject Area
Biology|Neurosciences|Endocrinology|Oncology
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