Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor

Knudsen, Lotte Bjerre; Pridal, Lone

doi:10.1016/s0014-2999(96)00795-9

Cited by 228 publications

(150 citation statements)

References 18 publications

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“…The antiapoptotic effect induced by exendin-4 was indeed abolished by the GLP1 receptor antagonist, thus suggesting GLP1 receptor-dependent action of the peptide. Interestingly, the major metabolite GLP1 (9-36), which possesses no affinity to the classical GLP1 receptor (Knudsen & Pridal 1996, Ban et al 2008, failed to reduce palmitate-induced apoptosis in HCAECs, adding further credence in favor of the view that the protective effect of exendin-4 is mediated through the known GLP1 receptor in these cells. It was previously reported that most effects of GLP1 are mediated through activation of cAMP/PKA signaling (Brubaker & Drucker 2004).…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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“…This effect was shown to be dependent on the GLP-1 receptor protein and exendin-4, a specific GLP-1 receptor agonist, had similar effects on T-cell migration. However, while GLP-1 ) is the physiologic agonist of the GLP-1 receptor and increases plasma concentrations of insulin after food intake, the metabolite GLP-1(9-36) is an antagonist of the GLP-1 receptor and metabolically inactive [10,11]. The effects of the metabolite GLP-1(9-36) on human CD4-positive lymphocyte migration are unknown.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes

Marx

Burgmaier

Heinz

et al. 2010

Cell. Mol. Life Sci.

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Introduction: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering GLP-1(7-36) to the metabolically inactive GLP-1(9-36), are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis.

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“…Subsequent studies have recently shown that the major degradation product of GIP metabolism, GIP , acts as a GIP receptor antagonist in acute studies in vivo (Gault et al 2002). Parallel studies using the sister incretin hormone, GLP-1, have also shown that the truncated GLP-1(9-36) amide degradation product can act as a GLP-1 receptor antagonist (Knudsen & Pridal 1996, Green et al 2004b). Interestingly, GLP-2(3-33), which also arises from proglucagon processing in the intestine, may act as a competitive GLP-2 receptor antagonist (Thulesen et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Parker

Lavery

Irwin

et al. 2006

Journal of Endocrinology

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Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and AbstractGlucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

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Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor

Cited by 228 publications

References 18 publications

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

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