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Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 65-75).

Thesis (Ph.D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 98-114) Also available in print.

Thesis (M.S.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains vii, 87 p. : ill. Includes abstract. Includes bibliographical references.

Tierärztl. Hochsch., Diss., 2003--Hannover.

The glucagon-secreting α-cell is vital for the maintenance of glucose homeostasis and prevention of hypoglycaemia. Despite its importance many aspects of α-cell physiology are disputed. Thus, in this thesis, I aimed to elucidate several features of α-cell function - exploring how autonomic signals are integrated by the cell and how diabetes leads to its dysfunction. The autonomic response to hypoglycaemia results in increased acetylcholine and adrenaline in the islet vicinity, which stimulate glucagon secretion. The mechanisms underlying these effects were investigated using live [Ca²⁺]_i imaging and patch-clamp electrophysiology. Adrenaline was found to target the α-cell via a Î2-adrenergic mechanism, inducing TPC2-mediated Ca²⁺ release from the (endo)lysosomal stores, which triggered calcium-induced calcium release from the endoplasmic reticulum (ER). Acetylcholine also induced ER Ca²⁺-release via muscarinic G_q signalling. However, a component of the effect resulted from activation of a nicotinic pathway that evoked P/Q-type Ca²⁺ channel influx. The glucagon response to hypoglycaemia is lost in diabetes. To investigate the effect of hyperglycaemia on α-cell function at low glucose, the Fh1Î2KO type 2 diabetic mouse model was used. In these mice, prolonged hyperglycaemia led to blunted glucagon secretion at low glucose. Using live pH imaging, it was shown that this was caused by hyperglycaemia increasing flux through Na⁺ coupled glucose transporters (SGLTs), disrupting Na⁺-dependent acid extrusion and inducing cytoplasmic acidification. The resulting build-up of protons was speculated to compromise mitochondrial ATP production leading to the observed glucagon secretory defects. The effects of insulin-induced hypoglycaemia on δ-cell [Ca²⁺]i activity were also investigated. Increased SGLT2 transport and low [K⁺]_o, features of insulin-induced hypoglycaemia, were both shown to increase [Ca²⁺]i activity in δ-cells, stimulating somatostatin secretion and consequently suppressing glucagon secretion. Together these data suggest that glucagon secretion at low glucose is lost due to the combined effects of hyperglycaemia-driven intrinsic dysfunction and insulin-induced somatostatin secretion.

Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).