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V. Grill, M. Rundfeldt and S. Efendić

Abstract. The effects of prior exposure to glucose or an inhibitor of glycolysis (iodoacetate) on A-cell sensitivity to glucose in the perfused pancreas of the rat was investigated. Inhibition of glucagon secretion by a high glucose concentration (22 mm) was attenuated and delayed when tested 20 min after a previous infusion with the same glucose concentration. Previously elevated glucose also delayed for 2 min a glucagon response to glucose omission whereas the total response was not significantly affected. During a 20 min perfusion with 1 mm iodoacetate, glucagon secretion increased and rates of secretion were further augmented after withdrawal of iodoacetate. When introduced 10 min after cessation of the iodoacetate pulse, 22 mm glucose failed to affect insulin or somatostatin release but, conversely, induced a profound decrease in glucagon secretion which was more marked than during control conditions.

Conclusions: A-cell sensitivity to glucose is diminished and enhanced by prior fuel abundance and deprivation, respectively. Such effects could be due to persisting changes in A-cell energy availability rather than to pertubations in insulin or somatostatin secretion.

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Kaori Ishida, Akira Mizuno, Toshiaki Sano, Keju Shi and Kenji Shima

Pancreatic A-cell function in the newly developed Otsuka Long Evans Tokushima Fatty (OLETF) strain of non-insulin-dependent diabetes mellitus (NIDDM) rats was examined in relation to the morphological changes in their islets and the plasma glucagon responses to insulin-induced hypoglycemia and an arginine test by chronological studies in seven male OLETF and seven male non-diabetic control Long Evans Tokushima Otsuka (LETO) rats each at 10, 16 and 24 weeks of age and eight male OLETF rats that were placed in a cage with a wheel for exercising from 5 to 24 weeks of age. The hormonal contents and morphological features of the pancreas of these rats were examined. After iv injection of insulin, the plasma glucagon level rose significantly from the basal level in OLETF rats at 10 weeks old, but little if at all in those of 16 and 24 weeks old. The pancreatic A cells of LETO rats of all age groups responded equally well to glucopenia. The areas under the response curves of plasma glucagon (∑ΔIRG) during the 90 min of insulin-induced hypoglycemia were 14496±7860 vs 9588±3930, 2257±3018 vs 9235±5447 (p<0.05) and 826±985 vs 9707±2510 (p<0.01) ng·min−1·l−1 in OLETF rats vs LETO rats of 10, 16 and 24 weeks old, respectively. The plasma glucagon responses during the arginine test were higher in OLETF rats than in LETO rats at 10 and 16 weeks but not at 24 weeks of age. Exercise-trained OLETF rats of 24 weeks old had normal ability to secrete glucagon from the pancreas in response to glycopenia (∑ΔIRG: 8645±2467 ng·min −1·l−1). There were no significant differences in the insulin and glucagon contents of the pancreas of young and old OLETF rats. Morphological studies on the pancreas of sedentary OLETF rats of 24 weeks old revealed enlarged, multilobulate, fibrotic islets in which A cells did not occupy a peripheral position but were widely dispersed, whereas in sections of the islets from exercise-trained rats the microstructure and locations of A and B cells appeared normal. These results demonstrated that the pancreatic A-cell response to glucopenia was impaired in old sedentary OLETF rats, probably due to an abnormal A-cell-B-cell morphofunctional relationship.

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H. J. Gjessing, B. Reinholdt, O. K. Faber and O. Pedersen


The dose-response relationships between prestimulatory blood glucose concentration and the plasma C-peptide responses to stimulation with 1 mg of glucagon iv or a standard mixed meal were studied in 8 C-peptide positive patients with insulin-dependent diabetes mellitus. Hyperglycemia was maintained for 90 min before stimulation using a hyperglycemic clamp technique. Each test was performed at the steady state blood glucose levels ~5, ~12, and ~20 mmol/l. The glucose potentiation of the incremental plasma C-peptide area under the curve at the two levels of hyperglycemia in percent of the area at normoglycemia (median and range) was 343% (53-1053) (p<0.05) and 341% (267-1027) (p<0.05) after glucagon and 140% (76-227) (NS) and 251% (95-1700) (p<0.05) after the meal. The corresponding relative glucose potentiation of plasma C-peptide 6 min after stimulation with glucagon was 124% (100-427) (p<0.02) and 144% (100-209) (p<0.05). There was no significant difference in the degree of glucose potentiation at ~12 or ~20 mmol/l. Furthermore, there was no significant difference in the degree of glucose potentiation of the different estimated values of B-cell function. In conclusion, the plasma C-peptide responses to iv glucagon or to a standard test meal were markedly potentiated by acute hyperglycemia in insulin-dependent diabetes mellitus. No further potentiation was, however, obtained when the prestimulatory blood glucose concentration was raised above 12 mmol/l. These findings contrast those reported in non-insulin-dependent diabetes, where endogenous insulin secretion is potentiated further when the blood glucose concentration is raised to ~20 mmol/l.

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Ove Berglund


The dynamics of insulin release were studied in the perfused pancreas of rats and mice. Perfusion of the rat pancreas with 20 mm D-glucose resulted in the classical biphasic release of insulin with a rising second phase. However, in normal C57BL/KsJ-mice and noninbred mice, whether fed or starved, the second phase was nearly constant. The secretory dymanics of KsJ-mice were essentially the same, whether the glucose concentration was 30 or 20 mm, whether the medium contained 2.56 or 8 mm Ca2+, and whether or not the medium was supplemented with 5 mm pyruvate, 5 mm glutamate, and 5 mm fumarate. Insulin secretion in these mice was almost totally inhibited by omission of Ca2+, and was markedly enhanced by 3-isobutyl-1-methylxanthine. Insulin release during the constant phase was reversed by lowering the glucose concentration. A second rise of glucose from 3 to 20 mm produced a secretory pattern very similar to the first response. These studies indicate that the dynamics of insulin secretion are somewhat different in rats and mice. Since similar results were obtained with C57BL/KsJ-mice and non-inbred mice, the liability of KsJ-mice to develop β-cell failure when stressed by the mutated db gene is not related to the constancy of the second insulin secretory phase.

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A. Widström and E. Cerasi


The initial as well as the late plasma insulin responses to low and high dose glucose infusions were enhanced by iv administration of tolbutamide in eight normal subjects. When expressed as change of the dose-response relationship between blood glucose level and plasma insulin response, the effect of tolbutamide consisted of a shift to the left of the dose-response curve, without increasing the maximum insulin response. This indicates that the drug acts as a sensitizer of the pancreas to the insulinogenic effect of glucose. In this respect, the effect of tolbutamide was of a similar nature both with regard to the initial and late insulin responses. The administration of tolbutamide at the beginning or towards the end of the one hour glucose infusion resulted in comparable enhancements of the late insulin response. Therefore, the effect of tolbutamide on the pancreas seems to be instantaneous, and does not change with prolonged exposure to the drug. Adrenaline, in a moderate dose, inhibited the synergism between glucose and tolbutamide. Since adrenaline in this dose probably does not interfere with glucose metabolism in the β-cell, it is concluded that tolbutamide does not act by modifying the metabolism of glucose, but rather by enhancing its direct insulinogenic signal in the β-cell.

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Chizuko Yokota, Koichi Kawai, Shinichi Ohashi, Yasuko Watanabe, Seiji Suzuki and Kamejiro Yamashita

Rat pancreas perfusion was performed to study the effects of pituitary adenylate cyclase activating polypeptide (PACAP) on pancreatic hormone release. Under the perfusate glucose concentration of 5.5 mmol/l, 0.1 nmol/l PACAP27 significantly stimulated both insulin and glucagon release. The degree of stimulation was in a dose dependent manner. The stimulation of insulin release was clearly dependent on the perfusate glucose concentration, when compared with 2.8, 5.5 and 8.3 mmol/l. The potency of PACAP38 on the stimulation of insulin release was greater than that of PACAP27 at 5.5 mmol/l of perfusate glucose concentration, but not at 8.3 mmol/l. No differences for glucagon and cAMP release were found between the two peptides. PACAP's stimulatory effects on insulin and glucagon release were completely abolished by an equimolar and ten times lower concentration of somatostatin, respectively. The physiologic significance of these potent effects of PACAP's islet hormones release must be clarified by further studies.

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Chin-Hsiao Tseng


A retrospective cohort study, using a population-based reimbursement database, was conducted for investigating the relationship between diabetes and colon cancer and assessing whether metformin had a protective effect.


Overall, 493 704 men and 502 139 women, covered by the National Health Insurance, without colon cancer were followed from 2003 to 2005. Cox regression evaluated the adjusted relative risk (RR), considering confounders and detection examinations.


Even though diabetes patients had a significantly higher probability of receiving examinations that could lead to the detection of colon cancer, they had a significantly higher risk (24%) of this cancer after adjustment. Metformin users had a significantly lower risk (27%) of colon cancer. While comparing patients with diabetes for <1, 1–3, and ≥3 years to nondiabetes individuals, the adjusted RR (95% confidence interval) was 1.308 (1.020–1.679), 1.087 (0.900–1.313), and 1.185 (1.055–1.330) respectively. The higher risk among those with diabetes for <1 year suggested a possible reverse causality or a link with prediabetes. However, diabetes still might play some role in the development of colon cancer in those with diabetes for ≥3 years. The duration of metformin use showed an inverse trend, with a significant RR of 0.643 (0.490–0.845) in users for ≥3 years, when compared with nonusers. In addition, metformin may reduce colon cancer risk associated with chronic obstructive pulmonary disease (a surrogate for smoking).


Following adjustment for potential detection bias and other covariates, diabetes remains a significant risk factor for colon cancer. Metformin may protect against colon cancer.

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M. R. Rajarama Rao and N. N. De

Soon after the discovery of insulin it was observed that most insulin preparations contained a fraction (Gibbs et al., 1923) which had blood-sugar raising property. Later studies (Sutherland & de Duve, 1948) revealed that this substance (HGF) was present in the pancreas as well as in the gastric and duodenal mucosa of many species of animals. As HGF could be demonstrated in the extracts of pancreas which was fibrosed after ligature of the duct, and also in the extracts of pancreas in which the beta cells of the islets of Langerhans were selectively destroyed by alloxan, it was postulated that the alpha cells of the islet tissue might be the site of its formation. In support of this hypothesis Vuylsteke et al. (1952) reported a 60% fall in HGF content of pancreas of guinea pigs in which the alpha cells were selectively destroyed by the administration of cobalt chloride. Volk

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M Zaiko, A Estreicher, B Ritz-Laser, P Herrera, J Favor, P Meda and J Philippe

Pax2 is a paired box transcription factor expressed in a spatially and temporally restricted manner and its absence results in major developmental defects of the central nervous system, eyes, ears and urogenital system. We recently reported that Pax2 is expressed in pancreatic endocrine cell lines and adult islets of Langerhans and activates glucagon gene expression. We have shown here that the Pax2 gene is expressed during pancreas development as early as embryonic day 10.5. Its absence, as assessed in Pax2(1Neu) mutant mice, results in a two- to threefold increase in the average pancreas volume occupied by the islets in both heterozygous and homozygous mutant mice with a gene-dependent dosage effect. This increase, which is due to a change in the number of islets per unit pancreas volume and in the size of individual islets, is not accompanied by significant modification in the insulin or glucagon content of the pancreas, indicating that the content of these hormones per cell is decreased. We have concluded that Pax2 may be implicated in the prenatal determination of the relative proportion of the endocrine and exocrine tissues of the pancreas.

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Kjeld Hermansen, Noboru Yanaihara and Bo Ahrén


Galanin, a 29 amino acid peptide, inhibits insulin and somatostatin secretion from the isolated, perfused dog pancreas. To assess the nature of the influences of galanin on the endocrine pancreas, we examined the effects of porcine galanin and six different galanin analogues at the equimolar concentration of 1 nmol/l on the hormone release from the isolated, perfused dog pancreas. It was found that galanin2–29 (by 75 ± 4%), like the native galanin1–29 (by 90 ± 3%) potently inhibited insulin secretion (p < 0.001). In contrast, galanin3–29 did not significantly affect insulin secretion. This indicates that removal of the two N-terminal amino acids markedly reduces the potency of galanin. Also, the replacement of the amino acid number 2 (Trp) by Tyr or Phe was followed by a loss of the insulin lowering effect of galanin at this dose level. Likewise, galanin 10–29 had no significant effect on insulin secretion. In contrast, the C-terminally deleted galanin1–15 significantly inhibited insulin secretion (by 24 ± 5%; p < 0.01), though with a lower potency than did native galanin (p < 0.05). Consequently, the C-terminal end of galanin is also of importance for the effect. Somatostatin secretion was inhibited by galanin (p < 0.001), but not by any of the other investigated peptides. Glucagon secretion was not affected by galanin. It is concluded that the two N-terminal amino acids of galanin are essential for the inhibitory action on the insulin secretion. The removal of the N-terminal Gly residue decreases the action of galanin on insulin secretion to a much smaller extent than does the removal of, in addition, the Trp residue. However, the remainder of the molecule seems necessary for full potency. It is also concluded that the inhibition by galanin of somatostatin secretion seems to require the entire molecule.