2011 ADA Posters 1261-2041.indd - Diabetes

& 1759-P
Dissecting the Intestinal Cholescystokinin Signaling Pathway(s)
That Regulate Glucose Production
BRITTANY A. RASMUSSEN, DANNA M. BREEN, GRACE W.C. CHEUNG, ANDREA
KOKOROVIC, TONY K.T. LAM, Toronto, ON, Canada
Diabetes and obesity is characterized by a disruption in glucose
homeostasis due partly to an elevation of hepatic glucose production. To
date, the mechanisms underlying the regulation of glucose production in
healthy and obese/diabetic settings remain to be elucidated. Duodenal lipid
metabolism is recently demonstrated to trigger a gut-brain-liver neuronal
axis to lower glucose production in rats in vivo. The gut derived hormone
cholecystokinin (CCK) mediates this gut lipid neuronal effect through the
activation of CCK-A receptors. However, duodenal lipid-CCK activation fails
to lower glucose production in response to high-fat feeding, suggesting
duodenal CCK resistance. To begin locating the molecular signaling defect(s)
of duodenal CCK-resistance, we fi rst discovered that high-fat feeding did
not alter duodenal CCK-A receptor expression, suggesting that duodenal
CCK resistance occurs at the signaling level of the CCK-A receptors. We
next investigated whether the activation of PKA, a downstream signaling
molecule of the CCK-A receptor, is suffi cient and necessary for duodenal CCK
to lower glucose production through a neuronal network in normal rats in
vivo. First, intraduodenal infusion of the PKA activator, Sp-CAMPS, lowered
glucose production during the pancreatic (basal insulin) euglycemic clamps.
Co-infusion of Sp-CAMPS with the PKA inhibitor H89 intraduodenally
abolished the glucose production suppression effect. Second, intraduodenal
administration of CCK-8 (the biologically active form of CCK) lowered glucose
production. Importantly, co-administration of CCK-8 with H89 abolished the
ability of duodenal CCK-8 to lower glucose production. Third, the ability of
Sp-CAMPS to lower glucose production was abolished upon intraduodenal
co-administration of the anesthetic tetracaine with Sp-CAMPS. In Summary,
these data together illustrate that duodenal PKA activation is suffi cient and
necessary to lower glucose production via a neuronal network in normal
rats. This set of preliminary data raises the possibility that high fat feeding
induces duodenal CCK resistance at the signaling level of duodenal PKA.
Supported by: CIHR
& 1760-P
Gastrointestinal-Mediated Glucose Disposal in Vagotomized Subjects
ASTRID PLAMBOECK, TINA VILSBØLL, CAROLYN DEACON, ANDRE WETTERGREN,
SØREN MEISNER, CLAUS HOVENDAL, LARS BO SVENDSEN, FILIP KNOP, JENS
HOLST, Hellerup, Denmark, Copenhagen, Denmark, Odense, Denmark
After secretion, glucagon-like peptide-1 (GLP-1) is rapidly degraded by
the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in less than 15% of
the intact biologically active peptide reaching the systemic circulation. This
has led to the hypothesis that GLP-1 acts locally before being degraded. We
aimed to evaluate the role of the vagus nerves for the effect of GLP-1 on
gastrointestinal-mediated glucose disposal (GIGD).
Eight truncally vagotomized (due to duodenal ulcer) subjects (age: 70±2
years (mean±SEM); BMI: 24±1 kg/m 2 ; fasting plasma glucose (FPG): 5.8±0.2
mM), 7 subjects previously treated for esophageal cancer with resection
of the cardia including truncal vagotomy (age: 64±2 years; BMI: 23±1 kg/
m 2 ; FPG: 5.4±0.1 mM) and 5 healthy control subjects (age: 68±2 years; BMI:
25±1 kg/m 2 ; FPG: 5.4±0.2 mM) were examined on three separate occasions:
two 4h 50-g oral glucose tolerance tests (OGTTs) ± DPP-4 inhibition and an
isoglycemic intravenous (iv) glucose infusion (IIGI).
Isoglycemia during IIGIs was obtained using 24±2 g and 28±4 g of glucose
in patients with truncal vagotomy associated with surgery for duodenal
ulcer and cardia resection, respectively (P=NS) and 17±2 g in healthy control
subjects (P