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Claes Hellerström

ABSTRACT

Metabolic effects of D-glucosamine on the pancreatic islet B-cells were evaluated by measurements of the oxygen uptake of isolated and surviving islets. The tissue specimens, which were obtained from obese-hyperglycaemic mice and consisted of more than 90% B-cells, were incubated in Cartesian divers with Krebs-Ringer phosphate medium at +37° C. Addition of glucosamine to the incubation medium caused a significant inhibition of the endogenous islet respiration and an even more pronounced inhibition of the oxygen uptake in the presence of D-glucose. When islets were pre-incubated with glucosamine and subsequently supplied with glucose, there was a relatively slight elevation of the oxygen consumption rate, indicating a partial block of the stimulating effect of glucose on the islet respiration. The results support the view that the diabetogenic effect of glucosamine is caused in part by a direct interference with the glucose utilization in the pancreatic B-cell, resulting in a diminished insulin release.

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Claes Hellerström

ABSTRACT

A technique for the dissection of fresh pancreatic islets of different mammalian species is described. Besides being suitable for microchemical analyses, the isolated islets seem of potential value for direct studies of the metabolism of the islet cells. The method has proved to be useful for the isolation of relatively large amounts of islet tissue for analytical purposes.

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Birger Petersson and Claes Hellerström

Abstract. Cysteamine (CSH; β-mercaptoethylamine) is known to deplete pancreatic somatostatin without affecting the insulin or glucagon content. It may therefore be useful for studies of intra-islet regulation of hormone release. In the present study injection of CSH (60 mg/kg body weight) to mice decreased the somatostatin content of their isolated pancreatic islets to 50% in 1 h and 30% in 4 h as compared to islets of non-injected controls. Exposure of isolated mouse islets to CSH (100 μg/ml) for either 0.5 h followed by incubation in control medium for 3.5 h, or continuously for 4 h, decreased the somatostatin content to about 40% of the controls. There was no change in the islet content of insulin or glucagon. Islets pretreated with CSH (100 μg/ml) for 1 h in vitro showed a decreased glucose stimulation of both oxygen consumption and glucose oxidation. Measurements of insulin release after a similar preincubation of the islets indicated an increased basal release and an attenuated glucose stimulation. It is concluded that CSH rapidly decreases islet somatostatin both in vivo and in vitro. This depletion may lead to a loss of tonic inhibition by islet somatostatin on basal insulin release. It is, however, more plausible that the increased basal insulin release reflected a direct effect of CSH on the islet β-cells.

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Claes Hellerström and Bo Hellman

ABSTRACT

Microtitrimetric assays of dipeptidase activity were performed in isolated pancreatic islet tissue from mice. Considerable enzyme activity was found in both the endocrine and exocrine pancreas of normal mice, the enzyme level of the exocrine parenchyma being significantly higher. In obesehyperglycaemic mice with free access to food, isolated islets of Langerhans had a much higher enzyme activity than in normal animals. The increased islet dipeptidase activity in the obese-hyperglycaemic animals may, at least in part, be accounted for by their higher proportion of B cells. The intense insulin synthesis and renewal of B cells in these animals have been considered as alternative explanations. Histochemical staining for leucine aminopeptidase revealed a moderate enzyme reaction in both the endocrine and exocrine pancreatic tissue of normal and obese-hyperglycaemic mice.

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Claes Hellerström and Bo Hellman

ABSTRACT

Repeated subcutaneous injections of crystalline glucagon resulted in a rapid loss of body weight in 5 weeks old rats allowed free access to food. In spite of the large glucagon doses employed (0.3–0.4 mg per rat a day) there was no glycosuria or morphological evidence of an increased insulin secretion from the B cells in the islets of Langerhans. While the nuclear areas of both the islet B and A1 cells decreased by 4.4%, a more pronounced and highly significant nuclear atrophy was noted in the A2 cells. After 5 days' treatment with glucagon the nuclear size ratio A2/B was reduced from 0.94 to 0.91 (t = 2.69; P < 0.02). As a consequence of the regressive changes in the A2 cells the nuclei of these cells were smaller than those of the A1 cells in all 10 glucagon treated rats analysed. The finding of a considerable nuclear atrophy of the A2 cells lends support to the hypothesis that these cells produce glucagon.

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Bo Hellman and Claes Hellerström

ABSTRACT

Histochemical methods for the detection of glucose-6-phosphatase (G-6-Pase), adenosine triphosphatase (ATPase) and amylo phosphorylase were applied to the islets of Langerhans in mice with hereditary obesity and hyperglycaemia (AO-mice) and in their lean litter mates (AN-mice).

While the G-6-Pase activity was high in the hyperactive B cells of the AO-mice, it was only moderate in the AN-mice. In both types of mice ATP-hydrolyzing enzymes were observed in the islet capillaries and periinsular connective tissue, while the reaction in the islet cells was negative. From a study of the substrate specificity it was found that the enzyme activity was not dependent on specific ATPase, but probably mainly on less specific polyphosphatases. The reaction for amylo phosphorylase was negative in the islets of both the AN- and the AO-mice.

The high G-6-Pase activity in the islets of the AO-mice is discussed in the light of the hypothesis that the activity of this enzyme represents an essential controlling factor in the insulin output of the B-cells.

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Bo Hellman and Claes Hellerström

ABSTRACT

By studying the Islets of Langerhans in man in thin Bouin fixed paraffin sections, first after impregnation with silver, and subsequently after removal of the silver, stained with Gomori's chrome-haematoxylin or aldehyde-fuchsin, it was possible to assess the specificity of the argyrophil reaction.

Reports in the literature that some of the B cells were also silver impregnated could not be confirmed. On the other hand, the argyrophil reaction was not characteristic for all the A cells, since a minority of them were not blackened. In agreement with these observations, the considerably higher frequency of silver cells over A cells, previously reported in connection with comparative differential cell counts on the same human pancreas material, was shown to be only apparent.

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Claes Hellerström and Bo Hellman

ABSTRACT

By using a modification of Davenport's alcoholic silver nitrate method for impregnating nerves, it was possible to obtain a distinct argyrophil reaction on thin paraffin sections from rat pancreas which had been fixed either in formalin or Bouin's solution. Since this was followed by a removal of silver with subsequent granule staining according to Gomori, it became clear that the distinctly blackened cells comprised only some of the A cells.

Some post-mortem change seemed to be an essential prerequisite of the argyrophil reaction, since this almost completely failed to appear after fixation in an ice-cold Bouin's solution. The reducing material was considerably resistent to acids; strongly blackened islet cells could be observed even after refixation in hydrochloric acid at a p H of 0.5. Although a preoxidation, e. g. with an acid solution of potassium permanganate, is essential for the differentiation of the islet cells with the modern granule stains, such treatment results in the argyrophil reaction becoming weaker or not appearing at all. Actual blackening, except in the case of those A cells, which could be distinguished as silver cells even after a short time, could not be produced by lengthening the impregnation time, but instead, the argyrophil reaction tended to decrease after a certain optimal period.

The observation that among those cells, which by granule staining were classified as A cells, a separate fraction with distinctly blackened cytoplasm could be distinguished, led to the suggestion that the blackened cells should be called A1 cells and the remaining ones, A2 cells.

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Bo Hellman and Claes Hellerström

In assessing the functional state of the islet cells it must be taken into account that these cells do not form a homogeneous group from a functional point of view, but on the contrary each type of cell seems to produce its own substance, insulin or glucagon, which has completely different effects on the carbohydrate metabolism. Insulin production can undoubtedly be attributed to the B-cells, and it has been maintained that glucagon is formed by the A-cells.

The latter view is supported by the fact that glucagon activity has been demonstrated in both mammalian pancreatic tissue, when the B-cells have been destroyed by alloxan (Sutherland & DeDuve, 1948, Gaede et al., 1950) and in certain fish in which the endocrine tissue in question is quite separate from the exocrine (Cavallero et al., 1952). Glucagon was also obtained from a pancreas in which the exocrine portion had atrophied after ligation of

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Décio L Eizirik, Anna Skottner and Claes Hellerström

Eizirik DL, Skottner A, Hellerström C. Insulin-like growth factor I does not inhibit insulin secretion in adult human pancreatic islets in tissue culture. Eur J Endocrinol 1995;133:248–50. ISSN 0804–4643

Insulin-like growth factor I (IGF-I) has been found to increase insulin sensitivity and suppress insulin secretion, thereby having a potential interest as a therapeutic agent for non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to investigate the direct actions of IGF-I (400 ng/ml) on human pancreatic islets, or on rat pancreatic islets, during a 48 h period in tissue culture. Insulin-like growth factor I did not affect medium insulin accumulation, DNA or insulin content or short-term glucose-induced insulin release of human islets. However, in rat islets the peptide induced a significant decrease in the insulin increase ratio in response to 16.7 mmol/l glucose. In conclusion, the present data suggest that IGF-I does not directly affect the function of human pancreatic β-cells If this in vitro data can be extrapolated to the in vivo situation, it suggests that the observed inhibitory effects of IGF-I on serum insulin levels may be secondary to peripheral effects of the peptide.

Décio L Eizirik, Department of Medical Cell Biology, Biomedicum, PO Box 571, S-751 23 Uppsala, Sweden