UBC Theses and Dissertations
On the mechanism of action of glucose-dependent insulinotropic polypeptide Dahl, Marshall Andrew
The interaction of the intestinal insulinotropic hormone GIP (Glucose-dependent Insulinotropic Polypeptide or Gastric Inhibitory Polypeptide) with the stimulus-secretion coupling mechanism of glucose-induced insulin secretion was investigated using the isolated, perfused, rat pancreas technique. The action of GIP in potentiating insulin secretion which had been initiated by a number of metabolic compounds other than glucose (D-glycer-aldehyde, 2-ketoisocaproate, L-leucine + L-glutamine) and the concentration-dependent nature of this action led to the formulation of the hypothesis that the insulinotropic effect of GIP required prior oxidation of these insulin-stimulating metabolites. It was therefore likely that the mechanism whereby GIP potentiated glucose-induced insulin secretion required an interaction located at a level involving effects secondary to glucose degradation in the B-cell. This effect may have required an intact N-terminus on the GIP molecule since a GIP₃-₄₂ homologue, which lacked the N-terminal Tyrosine-Alanine, possessed greatly diminished insulinotropic activity. Additional biological actions of GIP were suggested by the stimulation by the hormone of pancreatic somatostatin release and of the release of lipoprotein lipase-like activity from isolated rat adipocytes. A technique using reversed phase high pressure liquid chromatography (HPLC) was developed allowing the purification and fodination-state analysis of a pure bioactive ¹²⁵I-GIP molecule. Preliminary investigations of receptor binding activity of this purified ¹²⁵I-GIP to isolated rat adipocytes were also performed.
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