Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

Holst, Jens J.

doi:10.1007/s00125-005-0107-1

Cited by 211 publications

(162 citation statements)

References 94 publications

(60 reference statements)

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“…When given exogenously, GLP-1 improves glucostasis in type-2 diabetes patients, primarily by stimulating endogenous insulin secretion. * For manuscript correspondence contact: Nigel H. Greig Room 2C13, Gerontology Research Center, 5600 Nathan Shock Dr. Baltimore MD 21224 Phone: 410-558-8278;Fax: 410-558-8695 E-mail: Greign@grc.nia.nih.gov Despite its promise, the use of GLP-1 as a therapeutic agent for the treatment of type-2 diabetes is critically undermined by its extremely short half-life (1.5 minutes in rodents and humans (Estall & Drucker, 2006;Holst 2006)) Exendin-4 (Ex4), a naturally occurring, more stable analogue of GLP-1, shares 53% sequence homology with GLP-1 (Figure 1), although it is the product of a uniquely non-mammalian gene. It binds at the GLP-1 receptor with greater affinity than GLP-1 (specifically due to the PSS sequence at the beginning of the 9-amino acid tail), is more potent at maintaining plasma insulin levels than GLP-1, and has a half-life of approximately 120 minutes in rodents (Wang et al, 1997;Greig et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Perry

Holloway

Weerasuriya

et al. 2007

Experimental Neurology

166

135

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Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic β-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

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Section: Introductionmentioning

confidence: 99%

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Perry

Holloway

Weerasuriya

et al. 2007

Experimental Neurology

166

135

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“…Together with glucose-dependent insulinotrophic peptide (GIP), it is responsible for up to 50% of normal insulin release following a meal [1]. As incretin hormones enhance glucose-stimulated insulin release, but do not on their own initiate insulin secretion, their action in vivo is glucosedependent [2]. The new GLP-1-based glucose-lowering therapies, comprising GLP-1 analogues and agents that inhibit GLP-1 degradation, take advantage of this property to offer safer therapies for type 2 diabetes [3].…”

Section: Introductionmentioning

confidence: 99%

“…GIP, calcitonin generelated peptide [CGRP], gastrin-releasing peptide), and neurotransmitters (e.g. acetylcholine, γ-amino butyric acid) [2,5,7].…”

Section: Introductionmentioning

confidence: 99%

Cyclic AMP triggers glucagon-like peptide-1 secretion from the GLUTag enteroendocrine cell line

et al. 2007

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Aims/hypothesis To investigate the pathways by which cyclic AMP (cAMP) stimulates glucagon-like peptide-1 (GLP-1) secretion, using the GLUTag enteroendocrine cell line. Materials and methods GLP-1 release from GLUTag cells was measured in response to agents that increase cAMP, and single cells were studied by fluorescence calcium imaging and electrophysiology to evaluate the underlying pathways. Results Pituitary adenylate cyclase-activating polypeptide increased cAMP levels and stimulated GLP-1 release from GLUTag cells. Agents that increase cAMP levels, including forskolin plus 3-isobutyl-1-methylxanthine (fsk/IBMX), triggered a rise in the intracellular calcium concentration and enhanced the response to glucose by increasing both the number of cells responding to glucose and the magnitude of calcium responses in individual cells. Importantly, fsk/IBMX also stimulated GLP-1 release and intracellular calcium elevation even in the absence of nutrients. fsk/IBMX triggered membrane depolarisation and the firing of action potentials, associated with a +14 mV shift in the voltage-dependence of activation of hyperpolarisation-activated currents and the closure of a background potassium conductance. Conclusions/interpretation We show here that cAMP elevation directly triggers GLP-1 release and enhances the secretory response to other stimuli like glucose, by modulating hyperpolarisation-activated currents and the background potassium current. cAMP-elevating pathways and the cAMPmodulated conductances in L cells present important targets for the development of therapeutic GLP-1 secretagogues.

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“…THE INTEGRATED ENDOCRINE RESPONSES TO FOOD INGESTION are dependent on both the size and the composition of a meal and include the postprandial release of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and the islet hormones insulin and glucagon (3,5,21,32). Most studies have focused on responses to an oral glucose tolerance test, after which levels of GIP, GLP-1, and insulin rise, whereas glucagon levels are suppressed (4,18,20,24).…”

mentioning

confidence: 99%

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Carr

Larsen²,

Winzell

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

162

126

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and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20 -25 yr (n ϭ 12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P Ͻ 0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P Ͻ 0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r 2 ϭ 0.86; P ϭ 0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.insulin; glucagon; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; incretins; man THE INTEGRATED ENDOCRINE RESPONSES TO FOOD INGESTION are dependent on both the size and the composition of a meal and include the postprandial release of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and the islet hormones insulin and glucagon (3,5,21,32). Most studies have focused on responses to an oral glucose tolerance test, after which levels of GIP, GLP-1, and insulin rise, whereas glucagon levels are suppressed (4,18,20, 24). It is also known that fat and protein ingestion stimulate GLP-1 and GIP secretion (10,14,20,27). Less is known, however, regarding relationships between the incretin responses and changes in insulin and glucagon levels after meal or noncarbohydrate macronutrient ingestions.GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which cleaves the two NH 2 -terminal amino acids of the peptides, making them largely inactive (9). Accurate estimation of the relationship between incretin hormone secretion and islet hormones therefore requires measurement of both the total and the active intact forms of the two incretins. How this is related to macronutrient ingestion is not known. Indeed, we recently showed in mice that protein ingestion increased intact incretin hormone levels compared with carbohydrate ingestion, and this was associated with reduced intestinal DPP-4...

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Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

Cited by 211 publications

References 94 publications

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Cyclic AMP triggers glucagon-like peptide-1 secretion from the GLUTag enteroendocrine cell line

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

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