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Kjeld Hermansen

Abstract.

We studied the actions of tolbutamide on the release of somatostatin, insulin, and glucagon from the isolated, perfused dog pancreas. Tolbutamide (180 μm) elicited a biphasic response of all three islet hormones in the absence of glucose. In the presence of normal glucose (5.5 mm), 180 μm tolbutamide was again stimulatory, however, now the D cell response appeared uniphasic and the relative increase of somatostatin was lower than in the absence of glucose. At the highest perfusate glucose of 11 mm, no augmentation of the somatostatin output was seen to 180 μm tolbutamide, whereas the B and A cell secretion was still stimulated. In dose-response studies with tolbutamide (1.8–1800 μm) it was found that the D cell threshold to tolbutamide was 18 μm, Furthermore, that maximal D cell secretion was attained in the presence of 180 μm tolbutamide at low glucose (1.4 mm) and of 18 μm tolbutamide at normal glucose (5.5 mm), respectively. The insulin and glucagon responses showed clearcut dose-dependency over the range of tolbutamide doses applied. The B and A cell threshold to tolbutamide was 1.8 μm when the prevailing glucose level was stimulatory for the B and A cell, respectively. The finding that D and B cell responses to tolbutamide were eliminated during calcium deprivation indicates a key role of calcium in the events that proceeds to tolbutamide-mediated somatostatin and insulin release. In conclusion, the primary effect of tolbutamide on the islet cells is to stimulate hormone secretion, however, pertubations in terms of appearance and magnitude of D, B, and A cell responses depend on the balance between the concentrations of tolbutamide and glucose.

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E. Martino, S. Grasso, G. Bambini, G. Pardo, P. Vitti, F. Aghini-Lombardi and A. Pinchera

Abstract. The ontogeny of thyrotropin-releasing hormone (TRH) in pancreata of human foetuses from 15–36 weeks of gestation and of infants has been studied. TRH was detectable in the pancreas of a 15 week old foetus; a progressive increase of pancreatic TRH content was observed until the 34th week of gestation, whereas a progressive decrease was found in the late period of pregnancy and in 1 year old infants. In contrast, the pancreatic insulin content showed a progressive increase during the entire pregnancy and in the first year after birth. These data indicate that TRH and insulin have different ontogenetic patterns in the human pancreas.

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Ambjörn Ågren, Bernard Portha and Birger Petersson

Injection of streptozotocin has been shown to induce an acute diabetic state in the neonatal rat. A spontaneous, if not quite complete recovery is characteristic for streptozotocin diabetes in the neonate compared with that in the adult. The aim of the present investigation was to study the recovery of diabetes by morphological techniques.

Neonatal rats were given a single intravenous dose of streptozotocin (100 μg/g body weight) to produce a diabetic state. The rats were then killed on the 4th, 7th and 14th days and the pancreas was carefully removed, weighed and samples were taken for estimation of hormone content and histological examination.

The insulin content of the streptozotocin treated rat was only about 10 % of that of the controls on day 4, whereas on day 14 it was about 50 %. Calculations by point sampling technique of the percentage volume of the total pancreas occupied by islet cells were consistent

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Yoshiyuki Tanaka, Yoshiki Seino, Makoto Ishida, Kanji Yamaoka, Hyakuji Yabuuchi, Hitoshi Ishida, Susumu Seino, Yutaka Seino and Hiroo Imura

Abstract. To clarify the role of vitamin D in the regulation of the endocrine pancreas, we have studied insulin and somatostatin secretion in vitamin D deficient rats (reared on a vitamin D dificient diet), D-replete rats (reared on a vitamin D deficient diet and given 160 IU of vitamin D3 sc twice a week) and control rats (reared on laboratory chow), using the isolated perfused rat pancreas.

In the vitamin D deficient rats, the perfusate insulin induced by 16.7 mm glucose was only 35% of the secretion in the control rats. In the D-replete rats, the insulin release was restored to that of the controls. Similarly, the plasma insulin level in the vitamin D deficient rats was very low and the level in the D-replete rats was also restored to the level of the controls. The perfusate somatostatin response to glucose was not significantly different in any of the three groups. In addition, since the plasma calcium level in the vitamin D deficient rats was very low and in the D-replete rats was still lower, compared to normal rats, we suggest that vitamin D acts not only via the plasma calcium level but possibly also directly on the B cell.

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O. Schmitz, J. Arnfred, O. Hother Nielsen, H. Beck-Nielsen and H. Ørskov

Abstract. To test the hypothesis that insulin has a greater effect on glucose metabolism when given as pulsatile than as continuous infusion, a 354-min euglycaemic clamp study was carried out in 8 healthy subjects. At random order soluble insulin was given intravenously either at a constant rate of 0.45 mU/kg · min or in identical amounts in pulses of 1½ to 2¼ min followed by intervals of 10½ to 9¾ min. Average serum insulin levels were similar during the two infusion protocols, but pulsatile administration induced oscillations ranging between 15 and 62 μU/ml. Glucose uptake expressed as metabolic clearance rate (MCR) for glucose was significantly increased during pulsatile insulin delivery as compared with continuous administration (270–294 min: 8.7 ± 0.7 vs 6.8 ± 0.9 ml/kg · min, P < 0.01, and 330–354 min: 8.9 ± 0.5 vs 7.4 ± 0.9 ml/kg · min, P <0.05). The superior efficacy of pulsatile insulin delivery on glucose uptake was not consistently found until after 210 min of insulin administration. In both infusion protocols, endogenous glucose production as estimated by the [3-3H]glucose infusion technique was suppressed to insignificant values. Finally, the effect of insulin on endogenous insulin secretion and lipolysis as assessed by changes in serum C-peptide and serum FFA was uninfluenced by the infusion mode. In conclusion, insulin infusion resulting in physiological serum insulin levels enhances glucose uptake in peripheral tissues in healthy subjects to a higher degree when given in a pulsed pattern mimicking that of the normal endocrine pancreas than when given as a continuous infusion.

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Ulf Adamson and Erol Cerasi

ABSTRACT

The acute effects of human growth hormone (GH) on the basal levels of glucose and insulin in blood were investigated in 11 healthy men. GH doses of 5, 10, 20, and 40 μg/kg body weight were given iv as a constantrate infusion over 30 min, and resulted in peak hormone levels (30 min) of 20.5 ± 1.0, 48.5 ± 2.2, 108.2 ± 4.5, and 229.2 ± 14.6 ng/ml, respectively. There was a small (max 9.8 ± 2.6 %) but significant decrease in the blood glucose level, observed already at 15 min after the beginning of the GH infusion and persisting up to 90 min. The highest dose of GH induced the most marked changes, but there was otherwise no clear correlation between dose and effect. The basal plasma insulin levels showed a more marked (max 16.0 ± 4.7 %) decrease which was not correlated, in time or in magnitude, with the changes in blood glucose. In some subjects, in whom no significant decrease in blood glucose was observed, plasma insulin still demonstrated a similar fall (max 20.2 ± 7.6 %). Neither were these changes in plasma insulin correlated to the dose of GH within the range used in this study. The findings suggest that the early, insulin-like effect of GH on blood glucose is distinct from its effect on the pancreas. The latter is a suppressive one, consistent with earlier findings on glucose-induced insulin release.

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Kenji Shima, Meisei Hirota, Chizuko Ohboshi, Mitsuyo Sato and Tomoyoshi Nishino

Abstract. A reliable radioimmunoassay for glucagon-like peptide 1 (GLP-1) was developed with a detection limit of 12 pmol/l, which enabled us to detect the subtle change in concentrations of this peptide in the perfusate from the perfused rat pancreas. With this RIA, GLP-1 immunoreactivity (GLP-1 IR) was found to be secreted synchronously with glucagon immunoreactivity upon arginine stimulation from the perfused rat pancreas. Gel chromatographic analysis showed the presence of GLP-1 IR in the pancreatic extract which is eluted at the same position as synthetic GLP-1 (1-37). Moreover HPLC analysis confirmed the presence of GLP-1 IR, which eluted at exactly the same position as synthetic GLP-1, in the perfusate from pancreas perfusion upon stimulation of arginine. These results suggest that the pancreas stores and secretes GLP-1 IR concomitantly with glucagon as one of the cleavage products of their common precursor.

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Mark Gutniak, Valdemar Grill, Arved Roovete and Suad Efendic

Abstract.

We have investigated the effects of hyperglycemia in Type II diabetic patients on the somatostatin response to oral glucose. In these patients hyperglycemia prevailed (11.8 ± 1.4 mmol/l) and was markedly increased to a maximum of 18.9 ±1.0 mmol/l following the ingestion of 75 g of glucose. The rise in blood glucose following glucose ingestion failed to induce a rise in plasma levels of somatostatin-like immunoreactivity. Biostator-regulated insulin infusion normalized fasting levels of blood glucose and reduced the hyperglycemia following glucose ingestion, i.e. blood glucose now rose from 4.6 ± 0.1 to a maximum of 7.3 ±0.8 mmol/l. This moderate rise in blood glucose was accompanied by a significant (p <0.05) rise in somatostatin-like immunoreactivity. Somatostatin-28 and somatostatin-14 were separated using a Sephadex G-50 fine column. Biostator treatment suppressed plasma levels of both peptides during fasting conditions. Treatment was also accompanied by a rise in both peptides during the first hour following glucose ingestion; this rise did not occur in the untreated state. In conclusion: lack of somatostatin response to glucose in non-insulin-dependent diabetes mellitus is associated with deranged metabolic control. Unresponsiveness to glucose entails the secretion of both somatostatin-28 and -14.

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A. Stewart Peden

Bornstein (1950) described a technique for the preparation of alloxan diabetic, hypophysectomized, adrenalectomized (A. D. H. A.) rats. These animals had a very sensitively balanced carbohydrate metabolism and were capable of detecting extremely small quantities of injected insulin as noted by variation in their blood sugar. This preparation has been extensively used for assaying insulin in plasma, e.g. Bornstein & Trewhella (1950), Bornstein & Lawrence (1951).

In the present work, the preparation of A. D. H. A. rats was undertaken initially with a view to (a) assaying very small quantities of glucagon and (b) with the possibility in mind of subsequently using the A. D. H. A. rats to repeat and enlarge upon work done by Bornstein, Reid & Young (1951).

Considerable evidence has been adduced that a hyperglycaemic, glycogenolytic factor (H. G. F.) can be extracted from the pancreas and that it probably is derived from the A-cells of

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Donald L. Curry and Leslie L. Bennett

Abstract. Rat pancreas perfusions were performed using a perfusate with a fixed calcium concentration of 5 mEq/l and magnesium varying from 0 to 0.6 mEq/dl. Insulin secretion was stimulated by a constant glucose infusion of 300 mg/dl. This glucose concentration produces the typical biphasic insulin secretory response. We observed that in the absence of magnesium, somatostatin concentrations of 0.5 and 2.0 ng/ml were without effect on first phase insulin secretion. However, these same somatostatin levels produced 50% or more inhibition of insulin secretion in the presence of magnesium at 0.3 or 0.6 mEq/l. Similarly, in the absence of magnesium, somatostatin at 50 ng/ml failed to inhibit second phase insulin secretion, whereas this same somatostatin level produced about 50% inhibition of insulin secretion in the presence of magnesium at 0.3 mEq/l. Thus, altering perfusate magnesium concentrations without changing calcium is an important determinant of the degree of inhibition of secretion produced by somatostatin. In particular, in the absence of magnesium ion, somatostatin concentrations which would 'normally' produce 50% inhibition of secretion (ID50) are without effect. Therefore, magnesium ion is necessary for the full inhibitory effect of somatostatin to occur. These results suggest that inhibitors, as well as potentiators, of the insulin secretory process may act by altering intracellular/membrane calcium-magnesium ratios, but in opposite directions.