The overall objective of this research proposal is to define specific mechanisms of action through which Gastric Inhibitory Polypeptide (GIP) contributes to glucose homeostasis and related processes. Using a combination of in vitro and in vivo animal bodies, we seek to further characterize the interaction of GIP and the beta-cell, in terms of the dose-response relationship of GIP to insulin release, and the influence of the glucose-dependency of this relationship. Specific studies are planned to characterize the importance of transport specific mechanisms in the GIP beta-cell interaction, and the relationship between membrane-linked events versus cytoplasmic metabolism of glucose on the mediation of the beta-cell response to GIP. Since it has been shown that GIP has suppressive effects on hepatic glucose production, we also wish to investigate the role of GIP in the control of hepatic glucose metabolism, in terms of the effects of GIP on gluconeogenic and glycogenolytic pathways, the possible inhibition of GIP of the glucagon-mediated control of these processes, and the possible neural mediation of the hepatic effect (s) of GIP. Since it has been demonstrated that GIP may affect peripheral glucose metabolism as well as mesentric blood flow, we further seek to examine the peripheral actions of GIP, in terms of the role of GIP in the enhancement of insulin-mediated glucose disposal, and the regulatory effects of GIP on splanchnic and pancreatic blood flow. Methodologic approaches will utilize the isolated perfused rat pancreas preparation, chronic and acute catheterization techniques in intact dogs, and animal studies employing the glucose-clamp technique for the control of ambient glucose and insulin levels. Measurement of hepatic and peripheral glucose metabolism in selected studies will be performed using tracer techniques utilizing (3-H3)- glucose infusion. Organ- and region-specific blood flow determinations will be performed using the radiolabeled microsphere technique. Observation drawn from various in vitro and in vivo studies will be used to assess the relative importance of the pancreatic and extra-pancreatic effects of GIP in the control of glucose homeostasis.
