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M Wimmer, C Tag, D Schreiner, and HW Hofer

High concentrations of protein tyrosine phosphatase (PTP) were found with secretory vesicles of glucagon-producing INR1G9 cells by electron microscopic immunocytochemistry, using a polyclonal antiserum specific for the PTP1B/T-cell (TC)PTP subfamily of PTP. Since TCPTP protein and mRNA were below the detection limit in the cells but significant amounts of PTP1B and mRNA were recognised by a specific monoclonal antibody and a mRNA probe we conclude, that the PTP associated with the vesicles is PTP1B. Only reverse transcriptase (RT)-PCR with primers specific for PTP1B yielded a product of the expected nucleotide sequence. Thus, we conclude that the PTP associated with the vesicles is PTP1B. The presence of vanadate for 48 h attenuated PTP1B expression and caused reduction of steady-state levels of the phosphatase. These conditions also led to a continuing increase in the steady-state rate of glucagon release by the cells. This rate and tyrosine phosphatase levels showed an inverse relationship, suggesting a suppressive role of PTP1B on the regulated secretion of glucagon by INR1G9 cells.

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A. J. KENNY and R. R. SAY


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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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.

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The regulation of insulin biosynthesis, and insulin and glucagon secretion have been investigated in a human islet cell adenoma, by incubation of tumour fragments.

Both biosynthesis and secretion of insulin were strongly stimulated by incubation of islet tumour cells in the presence of increasing glucose concentrations in the range 2–8 mmol/l. However, 20 mm-glucose or 20 mm-glucose plus isobutyl methylxanthine (IBMX), both of which provide potent secretagogues for normal B cells, failed to stimulate proinsulin biosynthesis and secretion from the tumour cells. Overall rates of secretion, expressed as a proportion of total insulin content, were up to 20-fold higher than those expected for normal pancreatic tissue.

Glucagon secretion from the tumour was stimulated by low glucose concentrations; normal A cells also respond in this way under these conditions. However, no stimulation of glucagon secretion occurred in the presence of IBMX. There was therefore a major alteration in the regulation both of insulin and glucagon secretion, in that release of neither hormone was stimulated by cyclic AMP.

Ultrastructural examination showed the tumour to be rather heterogeneous. A and B cells with normal storage granule content and structure were seen, as well as a rather larger number of B cells containing some granules of atypical appearance. The insulin content of the tumour (13 i.u./g wet wt) was consistent with 6–8% of the tumour cells being B cells.

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Raylene A Reimer

Introduction Glucagon-like peptide-1 (GLP-1) is a gut hormone released from intestinal L-cells in response to food ingestion ( Kieffer & Habener 1999 ). In addition to potentiating glucose-dependent insulin secretion, GLP-1

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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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J. Watanabe, S. Kanamura, K. Kanai, M. Asada-Kubota, and M. Oka


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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CENEXA—Centro de Endocrinología Experimentaly Aplicada, CONICET—Universidad Nacional de La Plata, Facultad de Ciencias Médicas, Calle 60 y 120, 1900 La Plata, Argentina

(Received 10 March 1978)

Circadian variations in the serum concentration of immunoreactive insulin in the mouse (Gagliardino & Hernández, 1971) and the effect of fasting and feeding on this rhythm (Pessacq, Rebolledo, Mercer & Gagliardino, 1976) have already been described. However, no information is available on circadian variations in the level of glucagon in the blood of experimental animals and the present experiments were performed to investigate changes in the concentrations of glucagon in the plasma and glycogen and cyclic AMP in the liver of the female mouse over a 24 h period.

Female mice (C3HS strain), 19–21 weeks old, were kept at a constant temperature (25 ± 1·0 °C) under a schedule of 12 h light : 12 h darkness (lights on 06.00–18.00 h) and allowed free

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*Laboratoire de Physiologie du Développement, Tour 23/33, Université Paris VII, 2 Place Jussieu, 75005 Paris, France and †Unité de Recherches de Diabétologie et d'Etudes Radio-Immunologlques des Hormones Protéiques, U.55 (INSERM), Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France

(Received 1 November 1977)

Experimental prolonged gestation in the rat results in a reduction in the amounts of insulin and glucagon accumulated in the pancreas, a low level of insulin in the plasma and a sharp depletion of hepatic glycogen stores (Portha, Rosselin & Picon, 1976). Moreover, in the liver of the postmature foetus the activities of the main glyconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, are increased (Portha, Le Provost, Picon & Rosselin, 1978). The present study was undertaken to investigate the effects of glucagon in the circulation on these processes.

Gestation was prolonged by s.c. administration of progesterone to the mother (2·5 mg/rat) once daily on days 20·5, 21·5

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L Friis-Hansen, KA Lacourse, LC Samuelson, and JJ Holst

The maturation of many peptide hormones is attenuated in carboxypeptidase E (CPE)-deficient fat/fat mice, leading to a slowly developing, adult-onset obesity with mild diabetes. To determine the contribution of the hormones generated from the proglucagon precursor to this phenotype, we studied the tissue-specific processing of glucagon and glucagon-like peptide-1 (GLP-1) in these mice. In all tissues examined there was a great reduction in mature amidated GLP-1. Furthermore, a lack of CPE attenuates prohormone convertase processing of proglucagon in both the pancreas and the intestine. These findings suggest that defects in proglucagon processing together with other endocrine malfunctions could contribute to the diabetic and obesity phenotype in fat/fat mice.