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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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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 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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The plasma insulin response to glucose and arginine was increased in intact female rats implanted with progesterone. This change was not mediated by increased energy intake since the insulin response to glucose was similarly enhanced in progesterone-treated rats pair-fed with controls. In contrast, similar levels of pancreatic glucagon were observed in the plasma of both control and experimental rats during arginine stimulation. Thus the molar ratio of insulin to glucagon may be increased in the plasma of progesterone-treated rats following a mixed meal. This change may represent a physiological adaption to a demonstrable resistance to the peripheral actions of insulin in non-adipose soft tissue. The hyperglycaemic and lipolytic actions of exogenous glucagon were also impaired in progesterone-treated rats. It is suggested that an increase in the molar ratio of insulin to glucagon will favour hepatic lipogenesis and the peripheral deposition of fat.
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SUMMARY
The intravenous injection of glucagon (0·4 mg/kg) 12–30 min before the administration of a diabetogenic dose of alloxan (60 mg/kg) prevents the development of alloxan diabetes in dogs.
The protection obtained with glucagon is abolished by a subcutaneous injection of insulin (2 i.u./kg) administered 2 hr previously.
The possible mechanism of this protection and of its antagonism by insulin is discussed.
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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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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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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.
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SUMMARY
Maternal blood glucose, foetal blood glucose and liver carbohydrate levels were estimated after foetuses were injected with glucagon through the uterine wall on days 19½, 20½ and 21½ of gestation in the rat.
Glucagon had a hyperglycaemic effect in the foetus on all the days studied but the response was greater and more rapid on day 21½ of gestation. Glucagon was shown to decrease liver glycogen on day 20½ and 21½ but again the response was more rapid and more pronounced on day 21½.
The normal levels of foetal liver glycogen were similar to those previously found but the normal foetal blood glucose values are lower than previous results. Decrease in liver glycogen observed in the control group of foetuses on day 21½ of gestation together with a loss in foeto-maternal blood glucose relationship on that day of gestation suggest that on day 21½ the foetal rat develops the ability to mobilize hepatic glycogen and thereby to alter its blood glucose level independently from the mother.
The significance of the low blood glucose levels found in the foetus is discussed.
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An inverse age-related pattern of GH secretion has been identified in immature ducks between 2 and 9 weeks of age, the plasma level of GH falling progressively from 30–40 ng/ml at 2 weeks of age to the adult level (< 10 ng/ml) by 9 weeks of age. This decrease in GH secretion was not accompanied by any age-related changes in the concentrations of plasma immunoreactive insulin or glucagon-like immunoreactivity or in plasma glucose or free fatty acid level.
In 4- to 6-week-old ducklings the intravenous infusion of insulin (2·5 or 10 mu./kg per min for 30 min) and glucagon (0·1 or 0·5 μg/kg per min for 30 min) induced some inhibition of GH secretion, independently of changes in blood glucose level. These results suggest that although insulin and especially glucagon have direct effects on GH secretion in the duck, maturational differences in pancreatic function are unlikely to be causally related to the decrease in GH secretion during growth.
