Exon duplication and divergence in the human preproglucagon gene

Bell, Graeme I.; Sánchez-Pescador, Ray; Laybourn, Paul J.; Najarian, Richard C.

doi:10.1038/304368a0

Cited by 529 publications

(239 citation statements)

References 33 publications

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“…From the time of its discovery [75] and the first reports that it could stimulate insulin secretion [48], GLP-1 was considered a candidate incretin hormone. Kreymann et al studied the potential contributions of GLP-1 and GIP to the incretin effect in healthy volunteers; GLP-1 raised insulin and suppressed basal glucagon when infused to mimic postprandial levels, whereas GIP increased glucagon [46].…”

Section: Effects Of Exogenous and Endogenous Glp-1 On Alpha Cell Funcmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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Section: Effects Of Exogenous and Endogenous Glp-1 On Alpha Cell Funcmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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“…The high degree of sequence conservation of GLP-1 and GLP-2 has suggested that these peptides have important physiological functions [4, 6,8]. This and the structural similarity to glucagon prompted us to investigate the ability of GLP-1 and GLP-2 to inhibit [1251]-monoiodoglucagon binding and to activate adenylate cyclase in liver plasma membranes.…”

Section: Abbreviationsmentioning

confidence: 99%

Human glucagon‐like peptides 1 and 2 activate rat brain adenylate cyclase

1984

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Two human glucagon-like peptides, GLP-1 and GLP-2, which are coencoded with pancreatic glucagon in the preproglucagon gene, do not significantly inhibit ['ZSI]monoiodoglucagon binding to rat liver and brain membranes and do not activate adenylate cyclase in liver plasma membranes. Nevertheless, GLP-1 and GLP-2 were each found to be potent stimulators of both rat hypothalamic and pituitary adenylate cyclase. Only 30-50 pM concentrations of each peptide elicited half-maximal adenylate cyclase stimulation. Our data suggest that GLP-1 and GLP-2 may be neurotransmitters and/or neuroendocrine effecters, which would account for their high degree of sequence conservation through vertebrate evolution. Glucagon-like peptide IGlucagon-like peptide 2 Glucagon CAMP Pituitar) Hypothalamus Liver plasma membrane

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“…The nucleotide sequences of cDNA derived from hamster [1] and ox [2] glucagon mRNA and the human preproglucagon gene [3] show that pre-proglucagon contains two further glucagon-like peptides (GLP-1 and -2) C-terminal to the glucagon sequence. The amino-acid sequence of GLP-1 is completely conserved between the three mammalian species studied and shows a high degree of homology with similar deduced amino-acid sequences in angler-fish pre-proglucagons [4].…”

Section: Introductionmentioning

confidence: 99%

How glucagon-like is glucagon-like peptide-1?

et al. 1984

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Summary. Although glucagon-like peptide-1 has the appearance of a glucagon-homologue that may be co-secreted with glucagon, synthetic glucagon-like peptide-l-(1-37) does not significantly affect plasma glucose and insulin concentrations when administered at high doses (100 and 400 ~tg) to cortisone-pretreated rabbits. This synthetic preparation thus lacks the primary metabolic effect of glucagon at the doses tested. An intra-or extra-pancreatic role of glucagon-like peptide-1 has yet to be discovered. Key words:Glucagon-like peptide-1, glucose, insulin, glucagon, bioassay.The nucleotide sequences of cDNA derived from hamster [1] and ox [2] glucagon mRNA and the human preproglucagon gene [3] show that pre-proglucagon contains two further glucagon-like peptides (GLP-1 and -2) C-terminal to the glucagon sequence. The amino-acid sequence of GLP-1 is completely conserved between the three mammalian species studied and shows a high degree of homology with similar deduced amino-acid sequences in angler-fish pre-proglucagons [4]. It is defined by delimiting pairs of basic amino-acid residues, that form potential cleavage points. GLP-1 thus has the appearance of a highly conserved biologically active peptide that may be co-secreted with glucagon, and it is possible that it has a modulating role in carbohydrate metabolism. In the first instance we have tested synthetic GLP-1 for its effect on plasma glucose and insulin concentrations in rabbits. Material and methodsSynthetic GLP-l-(1-37) was synthesized by a solid phase method [5] (Bachem, Torrance, CA, USA). It was tested for its effect on plasma glucose and insulin by a modification of the twin cross-over bioassay for glucagon [6], using crystalline glucagon (Novo Industri, Copenhagen, Denmark) as a standard. Twelve rabbits were injected (25 mg subcutaneously) on day 0 with cortisone acetate injection (British Pharmacopoeia; Cortistab, The Boots Company, Nottingham, UK). The assay was performed on days 2 and 3, the rabbits being deprived of food for 18 h before each part of the assay, but with free access to water. The peptides were dissolved immediately before each experiment in 1.6% (vol/vol) aqueous glycerine containing 0.2% (wt/vol) phenol, adjusted to pH 3 with HC1.The rabbits were randomized into four groups of three each, and they received a subcutaneous injection of 1 ml of diluent, as a control, followed after 60 min by either GLP-1 (400 gg or 100 gg) or glucagon (24 .ag or 6 ~xg) in the same volume. Blood samples (0.3 ml) were taken from a marginal ear vein at times -40, 0, 20 and 60 rain in relation to both the diluent and peptide injections. The next day, the experiment was repeated with a twin cross-over, so that rabbits that had received the higher dose of glucagon now received the lower dose of GLP-1. The blood samples were collected into fluoride-oxalate centrifuge tubes, containing dried aprotinin (200 Kallikrein Inhibitor Units; Trasylol, Bayer, Wuppertal, FRG), and centrifuged immediately at 1600 g for 10 min. The plasma was frozen on solid CO2 and st...

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Exon duplication and divergence in the human preproglucagon gene

Cited by 529 publications

References 33 publications

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Human glucagon‐like peptides 1 and 2 activate rat brain adenylate cyclase

How glucagon-like is glucagon-like peptide-1?

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