Duodenal Cholescytokinin Triggers a Gut-Brain-Liver Axis To Regulate Glucose Production

Duodenal Cholescytokinin Triggers a Gut-Brain-Liver Axis To Regulate Glucose Production Recent studies indicated that Recent studies indicated that an acute rise in duodenal lipids trigger a gut-brain-liver axis to lower hepatic glucose production (GP) in rodents. However the downstream mechanisms in the duodenum remain unknown. Here we tested the hypothesis that duodenal gut-peptide hormone cholescytokinin (CCK) is sufficient and necessary for lipids to lower GP. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of duodenal administrations on glucose metabolism independent of changes in circulating gluco-regulatory hormones in vivo. Here we demonstrated that duodenal administration of CCK-8, a pharmacological activator of CCK-A receptors, rapidly lowered GP from 10.3 ± 0.6 (duodenal saline) to 6.0 ± 0.4 mg/kg.min (P<0.01 vs. saline) in the absence of changes in portal and peripheral CCK levels during the clamps. Co-infusion of CCK-A receptor inhibitor MK-329 or anesthetic tetracaine with duodenal CCK-8 abolished this inhibition of GP to 10.0 ± 0.3 and 9.4 ± 0.7 respectively, suggesting that duodenal CCK activates CCK-A receptors to lower GP through a neuronal network. We then inhibited N-methyl-d-aspartate (NMDA) receptors in the nucleus of the solitary tract (NTS) with inhibitor MK-801 to assess whether neurotransmission in the NTS relays afferent neuronal signals triggered by duodenal CCK. Direct administration of MK-801 into the NTS blocked the ability of duodenal CCK-8 to lower GP (10.9 ± 0.8). Hepatic vagotomy as well negated the ability of duodenal CCK-8 to lower GP (12.4 ± 0.5), indicating that the hindbrain relays signals induced by duodenal CCK to the liver to lower GP. Finally, co-infusion of CCK-A receptor inhibitor MK-329 (at the dose that blocked CCK-8) was sufficient to inhibit the ability of duodenal lipids to lower GP (9.9 ± 0.5). In summary, these findings indicate that duodenal CCK is sufficient and necessary for lipids to trigger a gut-brain-liver axis to lower GP in normal rodents. We hypothesize CCK-A receptors in the duodenum could serve as a molecular therapeutic target to lower GP and restore glucose homeostasis in obesity and diabetes. GRACE W. C. CHEUNG, ANDREA KOKOROVIC, CAROL K. L. LAM, MADHU CHARI, TONY K. T. LAM 154-OR Toronto, ON, Canada, Toronto, Canada Integrated Physiology - Other Hormones