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K. Brunfeldt, T. Deckert and J. Thomsen


Crystalline insulin was prepared from pooled pancreases from deceased maturity onset diabetics and non-diabetics. A comparison was made of the amino acid composition, immunological reactivity and hypoglycaemic activity. No differences could be demonstrated between the two preparations.

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Vagn Bonnevie-Nielsen


Oral administration to mice with soybean trypsin inhibitor (SBTI) (27–30 mg/mouse/day) or aprotinin (5500–6000 KIU/mouse/day) for six weeks increased the total pancreatic insulin (IRI). The pancreatic IRI was also increased after sc injections of synthetic caerulein (0.05 μg/mouse/day divided into 3 daily doses), being 82% above the control levels when expressed per g pancreas. Aprotinin (6000 KIU/mouse/day divided into 3 daily doses) injected sc had no effect on the insulin content. The total glucagon did not change significantly in any of the groups, but the molar ratio of insulin to glucagon was increased in the caerulein- and SBTI-treated mice. Caerulein-treatment led to an increased disappearance rate of glucose with k-values being 7.1 ± 0.3 compared to 6.0 ± 0.1 (mean ± sem) in the controls (P < 0.02). In islets isolated by collagenase-digestion of the pancreas and subjected to an overnight incubation, the content of insulin and glucagon was increased in islets from caerulein-treated animals. This corresponded to the results observed in the whole pancreas. The present study suggests that oral administration of proteolytic enzyme inhibitors or treatment with caerulein has a trophic effect on the endocrine pancreas. A difference in specificity seems to exist as SBTI affected both the pancreatic weight and IRI, and aprotinin orally did not influence the pancreatic weight, but increased the total content of IRI. Caerulein led to an increase in IRI, but did not affect the weight of pancreas.

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Torsten Deckert and Kai R. Jorgensen


The purpose of this study was to investigate whether a difference could be demonstrated between crystalline insulin extracted from normal human pancreas, and crystalline insulin extracted from bovine and porcine pancreas. Using Hales & Randle's (1963) immunoassay no immunological differences could be demonstrated between human and pig insulin. On the other hand, a significant difference was found, between pig and ox insulin.

An attempt was also made to determine whether an immunological difference could be demonstrated between crystalline pig insulin and crystalline human insulin from non diabetic subjects on the one hand and endogenous, circulating insulin from normal subjects, obese subjects and diabetic subjects on the other. No such difference was found. From these experiments it is concluded that endogenous insulin in normal, obese and diabetic human sera is immunologically identical with human, crystalline insulin from non diabetic subjects and crystalline pig insulin.

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V. Grill and L. Herberg


To investigate whether preferential responsiveness of residual B-cells is a feature of a diabetic state we compared insulin-releasing effects of glucose and arginine in perfused pancreases from moderately diabetic BB-Wistar rats. BB-rats were hyperglycaemic and insulin-dependent but possessed some insulin reserves (6 per cent of pancreatic content of control Wistar rats). Glucose (27.7 mm) failed to release insulin from diabetic pancreases while, conversely, arginine (8 mm) evoked a several-fold increase in insulin secretion. Ratios between responses from diabetic and normal pancreases were 0.01 and 0.29, respectively, when glucose or arginine were used as stimuli. This difference was significant (P < 0.05, Wilcoxon test). Glucose furthermore failed to exert a time-dependent (= priming) effect on arginine induced insulin secretion in the diabetic animals. Also A-cell responsiveness to glucose (acute and priming effects) were lost in BB-rats. It is concluded that selective loss of glucose effects on B- and A-cell secretion are associated with the diabetic state of the BB-Wistar rats.

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L. Ø. Dolva, K. F. Hanssen, O. Flaten, L. E. Hanssen and H. von Schenck


Thyrotrophin-releasing hormone (TRH) is present in the pancreas, mainly in the islets of Langerhans.

We studied the effect of iv infused TRH on the plasma levels of pancreatic islet hormones in man, under different experimental conditions:

1) Arginine infusion.

2) Insulin induced hypoglycaemia.

3) Glucose clamp technique (maintainance of normoglycaemia by glucose infusion during insulin infusion).

4) TRH injection.

Except for a minor inhibition of glucagon and pancreatic polypeptide following hypoglycaemic stimulation in one study, TRH had no significant effect on basal, stimulated or inhibited plasma glucagon, on insulin, somatostatin, pancreatic polypeptide or blood glucose.

It is concluded that iv administration of TRH does not produce significant changes in peripheral plasma levels of pancreatic hormones.

Application of techniques, which allow studies closer to the pancreatic islet, is probably necessary to assess the role of TRH in the regulation of endocrine pancreas.

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Lise D. Wogensen, Thomas Mandrup-Poulsen, Helle Markholst, Jens Mølvig, Åke Lernmark, Jens J. Holst, Charles A. Dinarello and Jørn Nerup

Abstract. The acute effects of recombinant human interleukin-1 beta (rIL-1) on basal and glucose-stimulated insulin release were investigated in the isolated perfused pancreas. At a concentration of 20 μg/l rIL-1 had no effect on basal insulin release, but increased the total amount of insulin released during first and second phase insulin release in response to 20 mmol/l D-glucose in the rat pancreas (P < 0.05). In addition, 26 μg/l of rIL-1 potentiated insulin release in response to square wave infusions of stimulatory concentrations of glucose (11 mmol/l) in the porcine pancreas. We hypothesize that IL-1 in the systemic circulation may affect B cell function in vivo.

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Jens Høiriis Nielsen

Diabetes mellitus is characterized by insufficient supply of insulin from the pancreas to maintain normoglycemia. In insulin-dependent (type I) diabetes a profound destruction of the insulin-producing β cells takes place while in non-insulindependent (type II) diabetes the secretion of insulin is hampered often in association with reduced insulin responsiveness. Although glucose is the major stimulus for insulin secretion, the function of the β cells is influenced by a large number of agents including metabolites, hormones, neurotransmitters, immunological factors, infectious agents or toxic chemicals. It is, however, difficult in vivo to assess whether changes in the levels of glucose and insulin are due to direct effects on the release of insulin from the β cells or mediated by effects on other tissues. Isolated pancreatic islets therefore offer a valuable tool to test whether a factor which alters levels of glucose and insulin are able directly to affect the β cell function.

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Annette Svenningsen, Thomas Dyrberg, Helle Markholst, Christian Binder and Åke Lernmark

Abstract. The pancreases of approximately 50 days old diabetes-prone BB/Hagedorn (BB/H) and of the genetically closely related, but non-diabetic BB w-subline (control BB) rats were perfused to determine the capacity of D-glucose to release insulin before the expected development of diabetes. The BB/H rats were from a colony with 82–84% incidence of insulin-dependent diabetes mellitus (IDDM) by 140 days of age. The total amount of insulin released from the BB/H rat pancreas during stimulation with 20 mmol/l D-glucose was reduced by nearly 50% (P <0.01). The initial peak of insulin release was similar between the two groups of animals, whereas the amount of insulin released during the second peak accounted for the diminished release (P < 0.01). The extractable pancreatic insulin was 30% (P < 0.05) less in the BB/H rats. Total insulin release expressed relative to the pancreatic insulin content, was therefore not different between the two groups. It is concluded that about 20–40 days before the mean age of clinical onset of IDDM in BB/H rats, the capacity to release insulin in response to D-glucose is reduced along with a diminished pancreatic insulin content. This abnormality seems to be preceded only by islet cell surface antibodies but not by insulitis.

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Filip K Knop

Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues – most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common ‘pancreacentric’ and ‘glucocentric’ understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver–alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.

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Suad Efendić, Franz Enzmann, Mark Gutniak, Anita Nylén and Manfred Zoltobrocki


HB 699 (100 μg/ml), almost identical with the left residue of the sulphonylurea glibenclamide, enhanced basal insulin and somatostatin release from the perfused rat pancreas. The compound also augmented both the early and the late insulin release stimulated by 6.7 mm glucose, while with 16.7 and 33.3 mm glucose only late insulin release was increased. Furthermore, HB699 enhanced both phases of glucose induced somatostatin release irrespective of whether 6.7, 16.7 or 33.3 mM glucose were used. As for glucagon release, HB 699 suppressed basal and arginine stimulated glucagon secretion.

The present findings imply that the sulphonylurea moiety of glibenclamide is not a prerequisite for its stimulatory action on insulin and somatostatin release. It is suggested that the enhanced somatostatin release mediates the inhibitory effect of the compound on glucagon release.