THE ROLE OF GIP IN GLUCOSE METABOLISM

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.