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S. Efendić, P. E. Lins, R. Luft, H. Sievertsson and G. Westin-Sjödal

ABSTRACT

Eighteen analogues of somatostatin have been used in order to elucidate the structure-activity relationship of the peptide on the release of insulin and glucagon from the isolated perfused rat pancreas. Neither the amino terminal nor a free carboxyl terminal seemed to be essential for the activity of the cyclic peptide. Addition of amino acids to the amino terminal did not decrease the activity. On the other hand, minor changes in the structure of linear somatostatin, which lead to the loss of ability to form a cyclic peptide, impaired the activity. Deletion of Asn5 was accompanied by decreased action on glucagon but not on insulin release.

It seems that the major actions of somatostatin on the pancreas are bound to the amino acid sequence 4–13 in the molecule and to the ability of the molecule to cyclize.

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Chun L Shi, Pål Rooth and Inge-Bert Täljedal

Treatment of NMRI mice with cyclosporin A (25 mg/kg body wt) for 11 days caused a marked fall in pancreas insulin content, although plasma glucose and plasma insulin were unchanged. When islets from untreated mice were exposed to cyclosporin A (2 mg/l) in vitro, no effect was seen in the first hour. After 24 h, cyclosporin A had significantly decreased the islet content of insulin. Post-culture microperifusion showed that cyclosporin A for 24 or 72 h inhibited the insulin secretory responsiveness. Verapamil in vivo (0.4 mg/kg body wt per day) or in vitro (37.5 μg/l) did not modify these effects. Verapamil at 25 mg/l suppressed the release of insulin but afforded no obvious protection against cyclosporin A during culture. The beneficial action of verapamil on islets transplanted to the kidney may reflect renal events rather than a primary interaction of drugs in the islets.

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Janice E. Maitland, Ian D. Caterson, Rebecca E. Gauci, Jennifer A. Spaliviero and John R. Turtle

Abstract. Human foetal pancreas has been maintained in organ culture with net synthesis and release of insulin for up to 60 days. The age of the donor foetus affected the basal insulin release rate. A plateau of secretion was reached with foetuses of ≥ 16 weeks of gestation. Explants cultured within 2 h of expulsion following prostaglandin induced termination secreted 3.0 times more insulin after 20 days of culture than those cultured within 2–4 h and 8.1 times more than those cultured more than 4 h post-termination. A high oxygen environment was toxic to the explants during culture.

Fresh tissue responded to a high concentration of glucose (19.3 mm) with a small but significant increase in insulin secretion. The addition of 10 mm theophylline caused a major increase in insulin release. Cultured tissue did not respond to glucose alone but did show increased insulin release following stimulation with glucose (22 mm) together with theophylline (10 mm) in static incubation.

The culture of human foetal pancreatic tissue may be useful in maintaining responsive beta cells and may help to ensure an adequate amount of donor tissue for future transplantation into diabetic patients.

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J. Szecówka, V. Grill, E. Sandberg and S. Efendić

Abstract.

The effects of gastric inhibitory polypeptide (GIP) on insulin secretion as well as on the intra-islet accumulation of [3H]cyclic AMP were investigated in isolated pancreatic islets of the rat. In the presence of 6.7 mmol/l of glucose, 3.0 and 30 nmol/l of GIP induced both insulin and [3H]cyclic AMP responses, while lower and higher concentrations of the peptide were ineffective. A coupling of the two parameters was also found with regard to interaction between glucose and GIP. Thus while 30 nmol/l of GIP was stimulatory together with 6.7, 16.7 or 33.3 mmol/l of glucose, the peptide stimulated neither insulin release, nor the accumulation of [3H]cyclic AMP in the presence of a low concentration of glucose (3.3 mmol/l).

The concomittant release of insulin and somatostatin was studied in the perfused pancreas in order to assess a possible influence by somatostatin on the dose-response pattern for GIP-induced insulin release. In this preparation 1.0 to 10 nmol/l of GIP stimulated insulin and somatostatin secretion; however while these concentrations were equipotent on insulin release, 10 nmol/l of GIP stimulated somatostatin release more than 1 nmol/l, indicating differences in dose-reponse curves for the GIP-induced stimulation of the two hormones.

It is concluded that 1) modulation of GIP-induced insulin release is coupled to changes in cyclic AMP response in the islet, 2) GIP-induced somatostatin secretion may influence the concomittant insulin response.

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N. J. Christensen and B. Neubauer

ABSTRACT

The present study describes the results of examinations of the noradrenaline and adrenaline concentrations in the human pancreas as well as in a number of other organs. Tissue specimens were obtained at postmortem examination.

Adrenaline was present in small amounts in the cardiovascular system, the liver and the spleen in comparison with the noradrenaline concentration. The pancreas, especially the body of the pancreas, contained, however, considerable amounts of adrenaline. The average adrenaline concentration was approximately 20 times higher in the pancreas than in the other organs examined. The greatest concentration of adrenaline was found in the posterior and superior parts of the body of the pancreas. There was no relationship between the cause of death in the human subjects and the adrenaline concentration in the pancreas and large amounts of adrenaline were also found in tissue specimens of pancreas obtained from long-term diabetic patients.

Adrenaline was present in the pancreas of the rat, dog and rabbit but in small amounts in comparison with the noradrenaline concentration.

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Anja I Franssila-Kallunki, Johan G Eriksson and Leif C Groop

The present study was undertaken to compare the effect of hyperglycemia and euglycemia during identical hyperinsulinemic conditions on glucose metabolism in NIDDM subjects. Eight NIDDM subjects participated in a 4 h hyperglycemic (12.1±0.7 mmol/l), hyperinsulinemic (475±43 pmol/l) and in a 4 h euglycemic (5.5±0.5 mmol/l), hyperinsulinemic (468±36 pmol/l) insulin clamp in combination with indirect calorimetry and [3H]-3-glucose. Six non-diabetic subjects were studied during euglycemia (5.1±0.2 mmol/l) and hyperinsulinemia (474±35 pmol/l) and served as controls. In NIDDM patients the rate of insulin-stimulated glucose disposal was 57% greater during hyperglycemia compared with euglycemia throughout the 4 h clamp (p<0.01). The major part of the increase in glucose metabolism during hyperglycemia was due to an increase in the non-oxidative glucose metabolism (89%). Whereas glucose metabolism could not be normalized during the prolonged euglycemic hyperinsulinemic clamp in NIDDM patients (49.9±6.8 vs 57.5±5.4 μmol·(kgLBM)−1·min−1 in controls) the addition of hyperglycemia resulted in complete normalization of the glucose disposal rates (78.3±5.8 μmol·(kgLBM)−1·min−1). The effect of hyperglycemia was apparent already at 60 min of the clamp. The data thus suggest that glucose metabolism in NIDDM is insulin resistant, but that the defect in insulin-stimulated glucose uptake can be overcome by increasing the glucose concentration.

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Timo Otonkoski, Mikael Knip, Pertti Panula, Sture Andersson, Inés Wong, Hy Goldman and Olli Simell

Abstract. Morphology, yield and function were studied in cultured islet-like cell clusters (ICC) from 140 human fetal pancreata obtained after abortions of different types performed at 11–23 weeks of gestation (12 by hysterotomy, 75 by mechanical dilation and extraction, and 53 induced with prostaglandin). After collagenase digestion and culture in medium supplemented with 10% human serum, up to 2000 free-floating ICC were formed from a single pancreas. Randomly scattered insulin- and glucagon-immunoreactive cells were found in the medullary part of the ICC. More than 100 ICC developed in 100% of the hysterotomies and 87% of the mechanical abortions, but in only 53% of the prostaglandin-induced abortions. Insulin and glucagon levels in the culture medium decreased rapidly during the first 7 days of culture, but then remained stable for at least 31 days. The hysterotomy-derived ICC responded to 10 mmol/l theophylline plus 20 mmol/l glucose by a 12.2 ± 3.1 (sem, N = 7) fold increase in insulin release, as compared with a 5.4 ± 0.9 fold response of the prostaglandin ICC (N = 16; P < 0.02). Despite the low proportion of B-cells, (pro)insulin biosynthesis accounted for 10% of the total protein biosynthesis in low (2 mmol/l) glucose. In conclusion, the yield and viability of the ICC were clearly better, if prostaglandin had not been used for the induction of the abortion.

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G. Ribes, R. Gross, D. Chenon and M. M. Loubatières-Mariani

Abstract. The effect of insulin on basal pancreaticoduodenal output of SRIH was investigated in vivo and compared in normal and alloxan diabetic dogs. The experiments were performed on anesthetized dogs having a T-shaped catheter inserted into the pancreaticoduodenal vein just at the exit of the pancreas for blood sampling. In normal dogs, an insulin infusion (1 IU/kg for 20 min) or an iv insulin injection (0.2 IU/kg over 30 sec) produced, before any change in glycemia, an immediate reduction of the venous pancreaticoduodenal output of SRIH. Then pancreaticoduodenal output of SRIH rose close to starting values and decreased again when blood glucose level became very low. In alloxandiabetic dogs, insulin infusion (1 IU/kg for 20 min) also induced an immediate inhibitory effect on pancreaticoduodenal SRIH output; the effect was more transient and from 20 min, unlike in normal dogs, an increase in pancreaticoduodenal output of SRIH was observed. In conclusion, exogenous insulin induces an immediate reduction in pancreaticoduodenal SRIH secretion both in normal and diabetic dogs, independently of basal blood glucose level and before any change in glycemia. In contrast, the delayed effect is different: SRIH secretion is reduced in normal dogs, whereas it is enhanced in diabetic dogs.

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Tsutomu Kazumi, Masafumi Utsumi, Yoshikazu Hirose, Kazuhide Ishihara, Hiroyuki Makimura, Kazushige Ejiri, Hiroshi Taniguchi and Shigeaki Baba

Abstract.

The concentration of thyrotrophin-releasing hormone (TRH) immunoreactivity was determined in pancreatic islets and acini in the rat. In addition, timecourse changes in TRH in response to an iv injection of streptozotocin (65 mg/kg body weight) with or without nicotinamide (500 mg/kg body weight) were examined in the whole pancreas. Furthermore, pancreatic TRH was measured in diabetic rats treated with insulin for 3 weeks. The TRH concentration in rat islets was 42-fold higher than in exocrine glands, indicating that the majority of pancreatic TRH is of islet origin. The mean concentration of pancreatic TRH decreased to 60 and 65% of the respective control values at 4 and 7 h after administration of streptozotocin, respectively. At 24 h, it fell to 10% of control values without significant changes in TRH levels in the hypothalamus and gastrointestinal tract. In contrast, no significant change in pancreatic TRH was noted in rats given combined treatment with streptozotocin and nicotinamide. The injection of streptozotocin alone resulted in severe hypoglycaemia at 7 h and hyperglycaemia at 24 h, whereas neither resulted from the combined treatment. Insulin therapy had no influence on the decreased TRH concentrations in the diabetic pancreas. These results suggest that TRH may be localized to the B cells of pancreatic islets, and that the marked reduction in TRH in diabetic pancreases is not a metabolic consequence of insulin deficiency.

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A Battezzati, A Mari, L Zazzeron, G Alicandro, L Claut, P M Battezzati and C Colombo

Background

Cystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance.

Aim

To evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population.

Methods

A total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration.

Results

Fifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m2 per mM, P<0.001) and decreased significantly with age by −2.7 pmol/min per m2 per mM per year (confidence interval (CI) −4.5 to −0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity.

Conclusion

The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.