Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

Abstract

Parlevliet ET, Heijboer AC, Schröder-van der Elst JP, Havekes LM, Romijn JA, Pijl H, Corssmit EP. Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 294: E142-E147, 2008. First published October 30, 2007 doi:10.1152/ajpendo.00576.2007.-We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 Ϯ 460, P Ͻ 0.01; 2.5 nmol, 1,828 Ϯ 684, P Ͻ 0.01; 0.75 nmol, 2,322 Ϯ 303, P Ͻ 0.05; control: 2,790 Ϯ 222 mmol ⅐ l Ϫ1 ⅐ 120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 Ϯ 14.7 vs. 39.9 Ϯ 5.7 mol ⅐ min Ϫ1 ⅐ kg Ϫ1 , P Ͻ 0.001). During insulin infusion, insulin levels were twice as high in OXMtreated mice compared with controls (10.6 Ϯ 2.8 vs. 4.4 Ϯ 2.2 ng/ml, P Ͻ 0.01). Consequently, glucose infusion rate (118.6 Ϯ 30.8 vs. 38.8 Ϯ 26.4 l/h, P Ͻ 0.001) and glucose disposal (88.1 Ϯ 13.0 vs. 45.2 Ϯ 6.9 mol ⅐ min Ϫ1 ⅐ kg Ϫ1 , P Ͻ 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 Ϯ 15.5 vs. 15.8 Ϯ 11.4% inhibition, P Ͻ 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action. animal model; gut hormone; glucose tolerance; insulin; hyperinsulinemic euglycemic clamp POSTTRANSLATIONAL PROCESSING OF PROGLUCAGON in the intestine and the central nervous system yields glucagon-like peptide-1 (GLP-1), GLP-2, glicentin, and oxyntomodulin (OXM) (18,32,35). OXM contains 37 amino acids, including the complete glucagon sequence with a basic octapeptide carboxyterminal extension (6). OXM is released from intestinal L cells into the blood in response to food ingestion in amounts proportional to caloric content (20,30). It potently inhibits meal-stimulated gastric acid and enzyme secretion in rodents and man (19).OXM appears to be an effective regulator of appetite and body weight. Intravenous infusion of OXM suppresses appetite and reduces food intake in humans during a buffet meal (14). Furthermore, both intracerebroventricular and intraperitoneal administration of OXM reduce food intake and body weight gain during refeeding in fasted rats (15,1...

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

“…However, unlike glucagon and the other two analogues, (D-Ser 2 )glucagon-exe did not induce elevations in blood glucose. This profile of (D-Ser 2 )glucagon-exe also differs from the biological actions of native OXM, which has previously been shown to increase glucose production during a hyperinsulinaemic-euglycaemic clamp in mice [29]. Thus, (D-Ser 2 )glucagon-exe, which consists of the entire glucagon sequence, with a nine amino acid C-terminal extension, may have improved therapeutic use over OXM, similar to exendin(1-39).…”

Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice

“…In the hyperinsulinemic-euglycemic clamp studies, insulin (Actrapid, Novo Nordisk, Bagsvaerd, Denmark) was administered intravenously by primed (4.5 mU ), continuous (6.8 mU/h for 2.5 h) infusion to attain steady-state circulating insulin levels of ~4 ng/ml ( 16,18,19 ). A variable intravenous infusion of a 12.5% D-glucose solution was used to maintain euglycemia as determined at 10 min intervals via tail bleeding (<3 µl, Accu-chek, Sensor Comfort; Roche Diagnostics, Mannheim, Germany).…”

Oxintomodulina e obesidade

“…Resumidamente, sabe-se que a OXM, juntamente com outros peptídeos intestinais (GLP-1 e PYY), apresenta diversas funções, quais sejam: 1°: age no núcleo arqueado, inibindo o AgRP/NPY (neurônios orexígenos); 2°: atua via nervo vago, enviando sinais eferentes ao núcleo do trato solitário e hipotálamo estimulando a população de neurônios POMC/CART; 3°: a OXM também pode atuar diretamente no hipotálamo inibindo a ingestão alimentar; 4° após a ativação dos neurônios anorexígenos (POMC, CART e α-MSH), estes se ligam aos receptores de melanocortina 3 e 4 (MC 3 e MC 4), aumentando o gasto energético e diminuindo o consumo alimentar; 5°c ontrapondo os efeitos benéficos da OXM, mutações podem ocorrer com o gene que expressa a OXM, e inibir os receptores MC 3 e MC 4, levando à obesidade (Figura 1) 3,11,20,37,39,40 .…”

“…Parlevliet et al 40 , ao avaliarem os efeitos da administração aguda de OXM via intraperitoneal sobre o metabolismo da glicose de camun- …”