2011 ADA Posters 1261-2041.indd - Diabetes

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& 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
Integrated Physiology/ Obesity POSTERS Guided Audio Tour: Incretin Hormone Biology (Posters 1763-P to 1772-P), see page 13. 1763-P Chronic Administration of Ezetimibe Increases Active Glucagon-Like Peptide-1 and Prevents the Development of Type 2 Diabetes in Rats SOO JIN YANG, JUNG MOOK CHOI, LISA KIM, WON JUN KIM, SE EUN PARK, EUN JUNG RHEE, CHEOL-YOUNG PARK, WON YOUNG LEE, KI WON OH, SUNG WOO PARK, SUN WOO KIM, Seoul, Republic of Korea Ezetimibe is a cholesterol-lowering agent targeting Niemann-Pick C1like 1, an intestinal cholesterol transporter. Chronic administration of ezetimibe may ameliorate several metabolic disorders including hepatic steatosis and insulin resistance. In this study, we investigated whether chronic ezetimibe treatment prevents the development of type 2 diabetes and alters levels of glucagon-like peptide-1 (GLP-1), an incretin hormone involved in glucose homeostasis. Male LETO and OLETF rats at 12 weeks of age were treated with vehicle or ezetimibe (10 mg·kg-1 · day-1 WITHDRAWN ) for 20 weeks via stomach gavage. OLETF rats were diabetic with hyperglycemia and signifi cant decreases in pancreatic size and beta cell mass compared with lean controls. There was no difference in weight change and food intake between groups during the treatment period. However, chronic treatment of the OLETF rats with ezetimibe prevented the development of diabetes with reduced fasting serum glucose (7.2 ± 0.1 vs. 10.4 ± 0.2 mmol/l, P < 0.001) and improved glucose control during oral glucose tolerance test (28504 ± 1486 vs. 37512 ± 2052 area under the curve, P = 0.002) compared with OLETF controls. Moreover, ezetimibe treatment rescued the reduced pancreatic size and beta cell mass in OLETF rats. Consistent with the previous fi nding that diabetic patients showed high dipeptidyl peptidase-4 (DPP-4) activity and low levels of active GLP-1, DPP-4 activity was higher and active GLP- 1 tended to be lower in diabetic OLETF rats compared with lean controls. Interestingly, ezetimibe signifi cantly decreased serum DPP-4 activity (OLETF ezetimibe 309.5 ± 7.3, OLETF control 478.2 ± 29.7 % LETO control; P < 0.001) and increased active GLP-1 (OLETF ezetimibe 14.8 ± 4.2, OLETF control 5.3 ± 0.3 pmol/l; P = 0.034) in OLETF rats. These fi ndings demonstrated that chronic administration of ezetimibe prevented the development of type 2 diabetes and increased active GLP-1 levels, suggesting possible involvement of GLP-1 in the preventive effect of ezetimibe against type 2 diabetes. & 1764-P Prohormone Convertase 2 Positive Enteroendocrine Cells Are More Abundant in Patients with Type 2 Diabetes—A Potential Source of Gut-Derived Glucagon FILIP K. KNOP, KRISTINE J. HARE, JENS PEDERSEN, JAKOB W. HENDEL, STEEN S. POULSEN, JENS J. HOLST, TINA VILSBØLL, Hellerup, Denmark, Copenhagen, Denmark, Herlev, Denmark In α cells, the precursor proglucagon (from the glucagon gene) is processed by prohormone convertase (PC)2 to glucagon, whereas enteroendocrine L cells utilize PC1 in the processing of proglucagon to the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Hyperglucagonemia following oral glucose in type 2 diabetes mellitus (T2DM) is thought to arise as a consequence of dysfunctional α cells combined with β cell insuffi ciency. However, in contrast to oral glucose, iv glucose does not elicit hypersecretion of glucagon in T2DM. Therefore, we hypothesized that T2DM patients possess the potential to release glucagon directly from the gut. Ten male patients with T2DM (age: 51(41-62) years); BMI: 32(28-39) kg/m 2 ; HbA1c: 7.1(5.4-8.7)%) and 10 male healthy control subjects (age: 58(48-67) years; BMI: 31(26-36) kg/m 2 ; HbA1c: 5.5(5.2-6.0)%) underwent a 4h meal test and a jejunoscopy (including jejunal biopsies) on two separate days. Patients with T2DM exhibited exaggerated postprandial plasma glucose excursions (379±76 (mean±SEM) vs. 77±33 mM×4h, P=0.001). Postprandial insulin (30±6 vs. 27±5 nM×4h, P=0.7) and C-peptide responses (175±25 vs. 188±24 nM×4h, P=0.7) were similar in the two groups, but patients with T2DM exhibited higher postprandial glucagon responses (3.0±0.5 vs. 1.9±0.2 nM×4h, P=0.02). No differences in glucose-dependent insulinotropic polypeptide (GIP), GLP-1, GLP-2 or peptide YY responses were observed. Similar numbers of endocrine cells (all stained for PC1) from jejunal biopsies were observed in the two groups; including GIP, GLP-1, and GLP-2 positive cells. Signifi cantly more PC2 positive cells were found among T2DM patients (70±8 vs. 44±4 cells/mm 2 , P=0.01). Similar levels of PC1 and PC2 gene expression were observed in the two groups. Our results show that a high number of small intestinal endocrine cells in T2DM patients are equipped with PC2, which potentially - through processing of proglucagon to glucagon - contribute to the hyperglucagonemia of these patients; shifting the ‘pancreacentric’ view on type 2 diabetic hyperglucagonaemia towards a role for the gut in this pathophysiological trait. For author disclosure information, see page 785. INTEGRATED PHYSIOLOGY—OTHER CATEGORY HORMONES A478 & 1765-P Glucose-Dependent Insulinotropic Polypeptide—A Bifunctional Blood Glucose Stabilizer MIKKEL CHRISTENSEN, LOUISE VEDTOFTE, JENS J. HOLST, TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark, Copenhagen, Denmark Longstanding knowledge positions glucose-dependent insulinotropic polypeptide (GIP) as an incretin hormone in healthy humans, but controversy exists regarding the effects of GIP on glucagon secretion. We hypothesized that the glucagonotropic effect of GIP, like its insulinotropic effect, is glucose-dependent. Therefore, we aimed to evaluate the effect of GIP on plasma glucagon and insulin responses at three different glycemic levels. Ten healthy male subjects (age: 23±1 (mean±SEM) years; BMI: 22±1 kg/m 2 ; HbA 1 c: 5.5±0.1%) without family history of diabetes were studied on six separate days. Physiological doses of GIP or saline were administered intravenously (randomized and double-blinded) during 90 min of either insulin-induced hypoglycemia, euglycemia or hyperglycemia (randomized). During hypoglycemia plasma glucose (PG) was gradually lowered from mean fasting level of 5.0±0.1 mM (mean±SEM) to a plateau level of 2.8±0.1 mM. GIP infusion resulted in greater glucagon responses during the fi rst 30 minutes compared to saline (area under curve: 76±17 vs. 28±16 pM×30 min, P
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2011 ADA Posters 1261-2041.indd - Diabetes

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