Glucagon-like peptide (7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis released rapidly after meals despite the fact that GLP-1 secreting cells (L-cells) occur predominantly in the distal gut. The importance of these colonic L-cells for postprandial GLP-1 was determined in healthy control subjects and in ileostomy patients with minimal small bowel resection (<5 cm). Subjects were fed a high complex carbohydrate test meal (15.3 g starch) followed by two carbohydrate-free, high fat test meals (25 g and 48.7 g fat respectively). Circulating levels of glucose, insulin, glucagon, glucose insulinotrophic peptide (GIP) and GLP-1 were measured over a 9-h postprandial period. For both subject groups the complex carbohydrate test meal failed to elicit a rise in either GIP or GLP-1. However, both hormones were elevated after the fat load although the GLP-1 concentration was significantly reduced in the ileostomist group when compared with controls (P=0.02). Associated with this reduction in circulating GLP-1 was an elevation in glucagon concentration (P=0.012) and a secondary rise in the plasma glucose concentration (P=0.006). These results suggest that the loss of colonic endocrine tissue is an important determinant in the postprandial GLP-1 concentration. Ileostomists should not be assumed to have normal enteroinsular function as the colon appears to have an important role in postprandial metabolism.
MD Robertson, G Livesey, LM Morgan, SM Hampton and JC Mathers
P Plaisancié, V Dumoulin, J-A Chayvialle and J-C Cuber
Glucagon-like peptide-1 (GLP-1) is released from endocrine cells of the distal part of the gut after ingestion of a meal. GLP-1 secretion is, in part, under the control of hormonal and/or neural mechanisms. However, stimulation of the colonic L cells may also occur directly by the luminal contents. This was examined in the present study, using an isolated vascularly perfused rat colon. GLP-1 immunoreactivity was measured in the portal effluent after luminal infusion of a variety of compounds which are found in colonic contents (nutrients, fibers, bile acids, short-chain fatty acids (SCFAs)). Oleic acid (100 mm) or a mixture of amino acids (total concentration 250 mm), or starch (0·5%, w/v) did not increase GLP-1 secretion over basal value. A pharmacological concentration of glucose (250 mm) elicited a marked release of GLP-1 which was maximal at the end of infusion (400% of basal), while 5 mm glucose was without effect on secretion. Pectin evoked a dose-dependent release of GLP-1 over the range 0·1–0·5% (w/v) with a maximal response at 360% of basal when 0·5% pectin was infused. Cellulose or gum arabic (0·5%) did not modify GLP-1 secretion. The SCFAs acetate, propionate or butyrate (5, 20 and 100 mm) did not induce a significant release of GLP-1. Among the four bile acids tested, namely taurocholate, cholate, deoxycholate and hyodeoxycholate, the last one was the most potent at eliciting a GLP-1 response with a maximal release at 300% and 400% of the basal value when 2 and 20 mm bile acid were administered respectively. In conclusion, some fibres and bile acids are capable of releasing colonic GLP-1 in rats and may contribute to the secretory activity of colonic L cells.
Journal of Endocrinology (1995) 145, 521–526
A Acitores, N Gonzalez, V Sancho, I Valverde and ML Villanueva-Penacarrillo
Glucagon-like peptide-1 (GLP-1), an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties, has insulin-like effects on glucose metabolism in extrapancreatic tissues participating in overall glucose homeostasis. These effects are exerted through specific receptors not associated with cAMP, an inositol phosphoglycan being a possible second messenger. In rat hepatocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), protein kinase C (PKC) and protein phosphatase 1 (PP-1) has been shown to be involved in the GLP-1-induced stimulation of glycogen synthase. We have investigated the role of enzymes known or suggested to mediate the actions of insulin in the GLP-1-induced increase in glycogen synthase a activity in rat skeletal muscle strips. We first explored the effect of GLP-1, compared with that of insulin, on the activation of PI3K, PKB, p70s6 kinase (p70s6k) and p44/42 mitogen-activated protein kinases (MAPKs) and the action of specific inhibitors of these kinases on the insulin- and GLP-1-induced increment in glycogen synthase a activity. The study showed that GLP-1, like insulin, activated PI3K/PKB, p70s6k and p44/42. Wortmannin (a PI3K inhibitor) reduced the stimulatory action of insulin on glycogen synthase a activity and blocked that of GLP-1, rapamycin (a 70s6k inhibitor) did not affect the action of GLP-1 but abolished that of insulin, PD98059 (MAPK inhibitor) was ineffective on insulin but blocked the action of GLP-1, okadaic acid (a PP-2A inhibitor) and tumour necrosis factor-alpha (a PP-1 inhibitor) were both ineffective on GLP-1 but abolished the action of insulin, and Ro 31-8220 (an inhibitor of some PKC isoforms) reduced the effect of GLP-1 while completely preventing that of insulin. It was concluded that activation of PI3K/PKB and MAPKs is required for the GLP-1-induced increment in glycogen synthase a activity, while PKC, although apparently participating, does not seem to play an essential role; unlike in insulin signaling, p70s6k, PP-1 and PP-2A do not seem to be needed in the action of GLP-1 upon glycogen synthase a activity in rat muscle.
A. Faulkner and H. T. Pollock
The effects of i.v. glucagon-like peptide-1-(7–36)amide (GLP-1; 10 μg) on starved sheep given an i.v. glucose load (5 g) were studied. Plasma insulin concentrations rose significantly more after glucose administration in fed than in starved sheep. Giving GLP-1 to starved sheep increased the insulin response to the glucose load. The rise in plasma insulin concentrations in starved sheep given GLP-1 was similar to that observed in fed sheep. Plasma glucose concentrations returned to normal values more quickly in the starved sheep given GLP-1 than in starved sheep not given gut hormone. Plasma concentrations of free fatty acid, urea and α-amino nitrogen decreased more quickly following glucose administration in starved sheep given GLP-1 than in those not given GLP-1. The data suggest a role for GLP-1 in regulating plasma insulin concentrations and hence metabolism in ruminant animals. The possible role of gut hormones in ruminants is discussed.
Journal of Endocrinology (1991) 129, 55–58
N Dachicourt, P Serradas, D Bailbe, M Kergoat, L Doare and B Portha
The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.
Raylene A Reimer, Gary J Grover, Lee Koetzner, Roland J Gahler, Michael R Lyon and Simon Wood
newer antidiabetic agent that increases circulating levels of active glucagon-like peptide 1 (GLP1) by inhibiting dipeptidyl peptidase 4 (DPP4) activity ( Ahren 2007 ). Given that treatment with single antihyperglycemic agents often fails to achieve
Andreas Nygaard Madsen, Gitte Hansen, Sarah Juel Paulsen, Kirsten Lykkegaard, Mads Tang-Christensen, Harald S Hansen, Barry E Levin, Philip Just Larsen, Lotte Bjerre Knudsen, Keld Fosgerau and Niels Vrang
the novel human GLP-1 analog liraglutide for 28 days. Materials and Methods Animals All experiments were conducted in accordance with internationally accepted principles for the care and use of laboratory animals, and were approved by the Danish
Petra Kaválková, Miloš Mráz, Pavel Trachta, Jana Kloučková, Anna Cinkajzlová, Zdeňka Lacinová, Denisa Haluzíková, Marek Beneš, Zuzana Vlasáková, Václav Burda, Daniel Novák, Tomáš Petr, Libor Vítek, Terezie Pelikánová and Martin Haluzík
laboratory methods, and LDL cholesterol was calculated in the Department of Biochemistry of the General University Hospital, Prague, Czech Republic. Plasma active GLP1, GIP, leptin and insulin were measured by commercial multiplex assay (Human Metabolic
L B Hays, B Wicksteed, Y Wang, J F McCuaig, L H Philipson, J M Edwardson and C J Rhodes
secretory activity by radioimmunoassay in both static and perifusion incubation experiments as described previously at either basal (2.8 mM) or stimulatory (16.7 mM) glucose ( ± 10 nM GLP-1 or 5μM glyburide as indicated) ( Donelan et al. 2002
D. J. O'Halloran, G. C. Nikou, B. Kreymann, M. A. Ghatei and S. R. Bloom
Glucagon-like peptide (GLP)-1 (7–36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7–36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7–36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7–36)-NH2 as a physiological inhibitor of gastric acid secretion in man.
Journal of Endocrinology (1990) 126, 169–173