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facilitate the action of these proteins involved in the signalling process ( Pawson & Scott 1997 ). The glucagon-like peptide-1 (GLP-1) receptor is a member of the G-protein-coupled receptor subfamily ( Dillon et al. 1993 , Thorens 1993 , Thorens
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ABSTRACT
Injections and infusions of oxytocin into conscious dogs caused an increase in plasma concentrations of glucose, insulin and glucagon. When blood glucose was clamped at a raised level the injection of oxytocin still increased insulin and glucagon concentrations in plasma. Infusion of somatostatin suppressed plasma concentrations of glucagon and insulin but did not prevent oxytocin-induced increments in blood glucose. Injection of oxytocin still caused a marked release of glucagon, whereas the insulin response was greatly diminished. When endogenous insulin and glucagon secretion was suppressed by infusion of somatostatin and glucose levels were stabilized by concomitant infusions of glucagon and insulin, injections of oxytocin did not alter blood glucose concentrations. It is concluded that the increase in blood glucose following the administration of oxytocin is secondary to the release of glucagon and that oxytocin exerts a direct stimulatory effect on glucagon and possibly insulin secretion.
J. Endocr. (1986) 108, 293–298
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Abstract
We have found [125I]glucagon-like peptide (GLP)-1(7–36)amide specific binding activity in rat liver and isolated hepatocyte plasma membranes, with an Mr of approximately 63 000, estimated by cross-linking and SDS-PAGE. The specific binding was time- and membrane protein concentration-dependent, and equally displaced by unlabelled GLP-1(7–36)amide and by GLP-1(1–36)amide, achieving its ID50 at 3×10−9 m of the peptides. GLP-1(7–36)amide did not modify the basal or the glucagon (10−8 m)-stimulated adenylate cyclase in the hepatocyte plasma membranes. These data, together with our previous findings of a potent glycogenic effect of GLP-1(7–36)amide in isolated rat hepatocytes, led us to postulate that the insulin-like effects of this peptide on glucose liver metabolism could be mediated by a type of receptor probably different from that described for GLP-1 in pancreatic B-cells or, alternatively, by the same receptor which, in this tissue as well as in muscle, uses a different transduction system.
Journal of Endocrinology (1995) 146, 183–189
Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Introduction Glucagon-like peptide 1 (GLP-1) is a proglucagon-derived peptide hormone that is synthesized and secreted by intestinal L-cells in response to the ingestion of nutrients and circulates to the pancreas where it stimulates
Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Department of Vascular Biology, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, UK
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Introduction Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the enteroendocrine L-cells of the small intestine in response to food intake ( Kieffer & Habener 1999 , Drucker 2001 ). GLP-1 plays an important role in
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Abstract
The effect of glucagon on ACTH secretion was studied in anaesthetized rats injected with either saline (0·1 ml i.m.) or glucagon (0·02 mg/kg i.m.). For the first 90 min after glucagon injection, plasma ACTH fell by 50% from the basal value of 23 ±4 pmol/l (mean ± s.e.m.) to 11 ±2 (P=0·011), after which an abrupt return to baseline occurred (120 min value: 26 ± 2 pmol/l). In saline injected rats, the baseline ACTH value was not significantly different from either the 90 min value or the 120 min value (27 ±3 vs 21 ± 4 and 24 ± 3 pmol/l respectively; P>0·10). Plasma glucose after glucagon peaked at 11·6 ± 1·1 mmol/l by 15 min but subsequently fell rapidly, attaining the baseline by 60 min. Insulin levels increased sharply after glucagon, from 381 ±78 pmol/l to 3172 ±668 pmol/l at 15 min, and plateaued at approximately 1000 pmol/l thereafter. No changes in glucose or insulin were seen in saline injected rats. The magnitude of suppression of ACTH after glucagon was not affected either by sustained hyperinsulinaemia (≃ 1400 pmol/l), induced with continuous glucose infusion to maintain plasma glucose>12 mmol/l, or by pretreatment with the long-acting somatostatin analogue octreotide (50 μg/kg s.c.). However, the return to baseline between 100 and 120 min was prevented both by hyperinsulinaemia induced with sustained hyperglycaemia, and by octreotide. It is postulated that glucagon may inhibit ACTH secretion either by a direct effect on the hypothalamus or indirectly through insulin, which is known to stimulate endogenous somatostatin release.
Journal of Endocrinology (1995) 145, 51–58
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SUMMARY
Acid-ethanol extracts of different regions of the gut in man, dog, rabbit and pig were assayed for glucagon-like activity by the glycogenolytic response of liver slices.
Glucagon-like activity was present in the extracts of human stomach, including the pyloric region, and in the duodenum, jejunum and ileum. No activity was found in liver, spleen and blood. The stomach of the dog yielded higher activities than that of the human. Pig tissues contained little activity.
The properties of the active substance in the human gastro-intestinal tract were those of a peptide or protein in that it was non-diffusible during dialysis, precipitated by ammonium sulphate and destroyed by chymotrypsin. Glucagon behaves in a similar way in these respects.
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The effects of two [d-Cys14]-analogues of somatostatin on basal plasma levels of glucagon, insulin and glucose were determined in unanaesthetized rats to re-examine a glucagon-selective action of these peptides which has been claimed by others. Somatostatin, [d-Cys14]-somatostatin and [d-Trp8, d-Cys14]-somatostatin caused a short-lasting, dose-dependent decrease of plasma glucagon and insulin but they had no significant influence on plasma glucose. Glucagon and insulin reached the nadir 2 min after intravenous injection of the peptides (dose range 1–10 μg/kg) or 5 min after subcutaneous administration (30 and 300 μg/kg). At the nadir, insulin was decreased to a greater extent than glucagon and the effects of all three peptides were equipotent. However, in the period after the nadir and at high doses, the time-course of some effects of the analogues on either glucagon or insulin differed from that of somatostatin. Thus, these [d-Cys14]-analogues may show partial kinetic dissociation of effects on glucagon and insulin but they are not truly selective inhibitors of glucagon release.
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ABSTRACT
The role of microtubules in the regulation of glucagon receptors on cultured rat hepatocytes was studied. Antimicrotubular reagents, colchicine and vinblastine, did not affect the binding of 125I-labelled glucagon to hepatocytes at 4°C. At 20 and 37 °C, however, the reagents reduced the binding after 60 or 90 min of incubation. Scatchard analysis indicated that the reduction in the binding was due to loss of glucagon-receptor populations. If hepatocytes were preincubated with both unlabelled glucagon and the reagents at 37 °C, the binding of the ligand to the cells decreased markedly after a certain delay. The reagents did not inhibit the internalization of the ligand in the cells until 30 min of incubation at 37 °C. The results suggest that the microtubule system plays a role in the transport of glucagon receptors to the plasma membrane, which is followed by their internalization.
J. Endocr. (1985) 106, 125–131
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SUMMARY
An isolated rat liver perfusion system was used to study the effects of insulin and glucagon on renin substrate production. Normal livers synthesized renin substrate at a rate of 28·3 ± 3·8 (s.e.m.) ng angiotensin I equiv./g liver each h (n = 8). The addition of insulin (more than 0·1 i.u.) to the perfusion significantly enhanced the production of renin substrate which was about twofold higher than normal control values (P< 0·001). However, glucagon (20 μg) did not affect the synthesis of renin substrate. These results indicated that insulin promoted the synthesis of renin substrate by the isolated rat liver.
