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We hypothesized that with exercise training and the subsequent attenuation of hyperglycemia, β-cell adaptation to worsening insulin resistance would be maintained. Also, because classical stress-activated systems and oxidative stress are involved in hepatic insulin resistance we examined if exercise would be associated with improvements in hepatic markers of oxidative stress and inflammation. Exercise maintained fasted hyperinsulinemia and preserved normoglycemia in male Zucker diabetic fatty (ZDF) rats. β-cell function calculations indicate prolonged β-cell adaptation in exercised animals. Such improved β-cell function was associated with increased β-cell mass. Hypertrophy and replication contributed to expansion of β-cell mass; exercised animals had increased β-cell size and bromodeoxyuridine (BrdU) incorporation rates versus controls. Furthermore, we observed augmented β-cell-specific immunohistochemical staining of GLUT2 and Akt/PKB in exercised versus sedentary controls. We also observed large cytoplasmic ubiquitinated structures which form in response to oxidative stress in pancreatic tissue samples from hyperglycemic ZDF rats. In the exercised groups such aggregate numbers were reduced to numbers compared to those seen in younger non-diabetic basal ZDF animals and age-matched lean Zucker rats. With respect to the liver we investigated whether exercise alters kinases such as c-Jun NH2-terminal kinase (JNK) and IKKβ (as evidenced by IκBα levels) and related insulin receptor substrate-1 (IRS-1) serine phosphorylation which are associated with hepatic insulin resistance in obesity. On average, exercised animals ran 5250m/day which improved insulin sensitivity based on the homeostasis model assessment for insulin resistance (HOMA-IR) calculations, and maintained fed and fasted glucoregulation and glucose tolerance. Ten weeks of running decreased whole-body markers of inflammation and oxidative stress in the blood and in the liver. Exercise lowered circulating interleukin-6 (IL-6), haptoglobin, malondialdehyde (MDA) levels, and protein oxidation in the liver. Exercise reduced phosphorylated JNK (pJNK) indicating decreased JNK activity; in accordance serine phosphorylated IRS-1 was reduced in exercised rats. In conclusion, improvements in glucoregulation were associated with increased β-cell compensation at least in part due to a reduction in oxidative stress. Furthermore, we show exercise attenuates development of hyperglycemia in ZDF rats in association with decreases in plasma and hepatic markers of inflammation, oxidative stress, JNK activation, and serine phosphorylation of IRS-1.

Cell-based treatments for insulin-dependent diabetes (IDD) may provide more physiologic regulation of blood glucose levels than daily insulin injections, thereby reducing the occurrence of secondary complication associated with IDD. An autologous cell source is especially attractive for regulatory and ethical reasons and for circumventing the need for immunosuppression, which is currently standard for islet transplantation. Our approach focuses on using adult non-β-cells engineered for physiologic insulin secretion. Specifically, we utilize enteroendocrine L-cells, which naturally exhibit regulated secretion of GLP-1 in response to physiologic stimuli, and upon genetic engineering, co-secrete insulin in a regulated manner. The overall goal of this project is to develop a tissue engineered pancreatic substitute based on a recombinant enteroendocrine cell line and test the efficacy of the pancreatic substitute by implantation into diabetic mice. The specific aims of this thesis were to (1) to modify murine L-cells for regulated insulin secretion and evaluate the insulin secretion properties of the recombinant cells; (2) to incorporate insulin-secreting L-cells into an implantable construct containing small intestinal submucosa (SIS) and to evaluate insulin secretion from the construct in vitro; and (3) to test the efficacy of the tissue engineered pancreatic substitute in vivo by implanting it intraperitoneally in mice made diabetic by streptozotocin. Thus, this proposal takes a tissue engineered pancreatic substitute for IDD from in vitro development to in vivo testing.

Severe and progressive weight loss is a feature of pancreatic cancer but it has been unclear whether dietetic intervention can improve patient outcomes. This study is a post hoc analysis of the extensive data available from the multicentre BH80 Cancer Cachexia trial to examine how patients with unresectable pancreatic cancer respond to intensive dietetic intervention. The BH80 study compared an n-3 fatty acid enriched oral supplement with an isonitrogenous, isocaloric supplement given over an eight week period. Additional qualitative data was also collected and examined for the patients recruited by the Australian sites. The aims were to determine whether achieving weight stabilisation is an appropriate goal of nutrition intervention for people with unresectable pancreatic cancer; to identify determinants of weight stabilisation; and to describe nutrition-related features of patients recruited by the Australian sites, prior to and during intensive nutrition intervention. Data from 107 patients for whom weight change data over an eight week nutrition intervention period was available, was divided into weight losing (less than 1kg lost) and weight stable (less than or equal to 1 kg lost) patients. Group survival duration (Kaplan Meier log rank test) and global quality of life (EORTC QLQ-C30 global health status/quality of life) were compared. Variables including energy intake, BMI, presence of pain, nausea and vomiting, and appetite loss, C reactive protein and stage of disease were also compared to determine predictors of weight stability using logistic regression analysis. This study demonstrates that weight stabilisation is not only achievable for some patients in the short term, but it is also associated with improved outcomes. Those patients who were able to stabilise their weight after eight weeks of oral nutrition support lived longer from baseline and reported better quality of life than those who continued to lose weight. Weight stabilisation is therefore a reasonable and worthwhile goal for this patient group.

Bibliography: leaves 358-406 / xv, 406 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1985

Offprint of an article by the author inserted / Bibliography: leaves 351-384 / 384 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1985

Thesis (M.Sc. (Clinical Pathology))--Mahidol University, 1978.

Mémoire (M.Sc.B.)--Université du Québec à Chicoutimi, 1991. / Document électronique également accessible en format PDF. CaQCU