or reduce iNOS expression may be necessary for the prevention or inhibition of β-cell damage. Glucagon-like peptide-1 (GLP-1) and its potent agonist exendin-4 (EX-4) have received great attention because of their insulinotropic and β
Jung-Hoon Kang, Seo-Yoon Chang, Hyun-Jong Jang, Dong-Bin Kim, Gyeong Ryul Ryu, Seung Hyun Ko, In-Kyung Jeong, Yang-Hyeok Jo, and Myung-Jun Kim
U Ritzel, U Leonhardt, M Ottleben, A Ruhmann, K Eckart, J Spiess, and G Ramadori
Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.
M-J Kim, J-H Kang, Y G Park, G R Ryu, S H Ko, I-K Jeong, K-H Koh, D-J Rhie, S H Yoon, S J Hahn, M-S Kim, and Y-H Jo
Introduction Glucagon-like peptide-1 (GLP-1) has been of much interest due to its β-cell-proliferating effect and role as an incretin hormone in synergizing with glucose to enhance insulin release ( Ørskov 1992 , Egan et al. 2003
J Schirra, P Leicht, P Hildebrand, C Beglinger, R Arnold, B Goke, and M Katschinski
Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.
Sarah L Craig, Victor A Gault, Gerd Hamscher, and Nigel Irwin
relates to preventing degradation and subsequent loss of bioactivity of the endogenous intestinal-derived incretin hormones, glucagon-like peptiede-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ( Deacon 2019 ). Thus, GLP-1 and GIP
cDNAs from these species further revealed that it encodes not only glucagon but also two glucagon-like peptide hormones, namely glucagon-like peptide-1 (GLP-1) and GLP-2 ( Lund et al . 1982 ). Glucagon is produced and released from the pancreatic α
Srividya Vasu, Mary K McGahon, R Charlotte Moffett, Tim M Curtis, J Michael Conlon, Yasser H A Abdel-Wahab, and Peter R Flatt
various glucagon-like peptide-1 (GLP-1 mimetics) have been strongly promoted over the past few years ( Kahn et al. 2014 , Irwin & Flatt 2015 ). This approach has several potential advantages over development of small-molecule drugs, providing greater
MD Robertson, G Livesey, LM Morgan, SM Hampton, and JC Mathers
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.
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.
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