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UBC Theses and Dissertations

Studies on the potential utilization of glucose-dependent insulinotropic polypeptide (GIP) in type 1 and type 2 diabetes Piteau, Shalea Joanne

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that is released from the small intestine in response to a meal and acts to potentiate glucose-induced insulin secretion from the pancreatic β-cell. Recently it has been shown that GIP stimulates β-cell growth, differentiation, and survival, and inhibits apoptosis, broadening the spectrum of anti-diabetic effects of GIP and the potential application of this peptide to type 1 diabetes. In the studies described in this Thesis, the GIP analog, [DA1a²]GIP, was demonstrated to exhibit both paradoxical diabetic and anti-diabetic effects in two animal models of experimentally-induced diabetes, the multiple low-dose streptozotocin diabetic rat and the single high dose streptozotocin diabetic rat, respectively. Increased expression of the β-cell glucose transporter GLUT2 was implicated as one of the potential underlying mechanisms in [DA1a²]GIP-mediated exacerbation of multiple low-dose streptozotocin (MLD-STZ)-induced diabetes. Importantly, treatment with the native hormone, GIP(1-42), significantly improved the diabetic phenotype relative to MLD-STZ controls. Anti-apoptotic effects of [DA1a²]GEP offered a basis for the protective effects of this peptide against single doses treptozotocin (IV STZ)-induced β-cell destruction. The findings in these studies exemplify the importance of the pleiotropic effects of GIP receptor signaling and shed light on the potential utilization of GEP therapy in type 1 diabetes. It has long been known that the incretin effect is reduced in patients with type 2 diabetes and this defect has been partially attributed to a loss of the GIP component of the enteroinsular axis since glucagons-like peptide-1 (GLP-1) maintains insulinotropic activity in these individuals. However, the mechanism responsible for the diminished response to GIP has not been fully elucidated. Previous studies have shown that GIP receptor mRNA levels are downregulated in the pancreatic β-cell of an animal model of type 2 diabetes and that this is correlated with a diminished responsiveness to GIP. It has also been demonstrated that elevated glucose levels are able to significantly reduce GIP receptor expression in vivo and in vitro. Accordingly, we hypothesized that normalization of hyperglycemia in vivo would reverse the down-regulation of GIP receptor expression and GIP insensitivity in type 2 diabetes. The causal role of hyperglycemia in loss of GIP receptor expression in the ZDF rat is strongly suggested by restoration after 2 weeks treatment with phlorizin, a drug that normalizes blood glucose without increasing plasma insulin or changing plasma free fatty acid or triglyceride levels. Furthermore, restoration of GIP receptor expression was correlated with improved pancreatic GIP sensitivity. These findings suggest that GIP receptor down-regulation in type 2 diabetes is secondary to chronic hyperglycemia and that tight glycemic control leads to restoration of GIP receptor expression and subsequently, to improved GIP sensitivity at the pancreatic islet. In summary, demonstration of the anti-diabetic effects of GIP in type 1 diabetes and recovery of biological activity of GIP in type 2 diabetes offer great potential for the use of GIP analogs in the treatment of these diseases.

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