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  • Author: A. E. PONTIROLI x
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A M Davalli, E Biancardi, A Pollo, C Socci, A E Pontiroli, G Pozza, F Clementi, E Sher and E Carbone

Abstract

Calcium ion entry through voltage-operated calcium channels is a crucial step in the coupling of β cell depolarization with insulin secretion. Various calcium channel subtypes have been shown to be coexpressed in single neurons and endocrine cells. Using the patch-clamp technique, we investigated the biophysical and pharmacological properties of calcium channels in freshly dispersed human pancreatic β cells.

Both low and high voltage activated currents were expressed, the two current types being easily distinguishable on the basis of biophysical criteria. The high voltage activated currents were not homogeneous: one component was affected by the dihydropyridine antagonist nitrendipine and the agonist Bay-K-8644; the other was insensitive to both dihydropyridines and ω-conotoxin GVIA. In line with this pharmacology, nitrendipine reduced and Bay-K-8644 increased glucose-induced insulin secretion from perifused human islets, whereas ω-conotoxin GVIA had no effect. However, about 20% of the glucose-induced insulin release was found to be resistant to high nitrendipine concentrations.

These data show that human pancreatic β cells express heterogeneous voltage-operated calcium channels, only one of which is dihydropyridine-sensitive (L type). The L type channels are clearly involved in the control of insulin secretion, but our data suggest that dihydropyridine- and ω-conotoxin GVIA-insensitive channels may also play a role in the stimulus-secretion coupling of human β cells.

Journal of Endocrinology (1996) 150, 195–203

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F Bertuzzi, C Berra, C Socci, A M Davalli, G Pozza and A E Pontiroli

Abstract

Hyperglucagonemia is commonly found in insulin-dependent as well as in non-insulin-dependent diabetes mellitus, and is likely to be caused by absolute or relative insulin deficiency. The aim of the present study was to evaluate whether a chronic glucagon exposure (1·0 μm for 4 h) modifies the insulin response to acute stimuli with glucagon (1·0 μm), arginine (10·0 mm) and glucose (16·7 mm), or the glucagon response to arginine and glucose, in human islets. Chronic exposure to glucagon did not affect the insulin response to glucose and arginine, but inhibited its response to glucagon (44·6 ± 9·3 vs 168·6 ± 52·3 pg/islet per 20 min, P<0·05); the latter effect was not observed when exposure to glucagon was discontinuous (2·0 μm glucagon alternated with control medium for 30 min periods). The chronic exposure to glucagon also reduced the glucagon response to arginine (−4·9 ± 5·7 vs 19·9 ± 7·9 pg/islet per 20 min, P<0·05) without affecting the inhibition of glucagon release exerted by glucose. These data indicate that chronic exposure to glucagon desensitizes pancreatic α and β cells in response to selected stimuli.

Journal of Endocrinology (1997) 152, 239–243

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F. CAVAGNINI, M. PERACCHI, G. SCOTTI, U. RAGGI, A. E. PONTIROLI and R. BANA

SUMMARY

The effect of both oral and intravenous administration of l-DOPA on growth hormone (GH) secretion was studied in a group of normal volunteers: a significant rise of serum GH levels was observed in both cases.

Growth hormone release in response to insulin hypoglycaemia and to arginine infusion was evaluated in a group of Parkinsonian patients before and after 25 days' treatment with l-DOPA plus a DOPA-decarboxylase inhibitor. In addition, GH response to the above stimuli was studied in a group of patients who had been under treatment for more than 6 months with l-DOPA alone. In untreated Parkinsonian patients, GH response to insulin hypoglycaemia was at the lower limit of normal range while arginine-induced GH release was significantly reduced. Treatment with l-DOPA did not increase GH responses. Some possible interpretations of the results are discussed.

The findings support the possibility that dopamine plays a role in the physiological regulation of GH secretion, as in the case of luteinizing hormone, follicle-stimulating hormone and prolactin release.

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F Bertuzzi, C Berra, C Socci, A M Davalli, G Calori, M Freschi, L Piemonti, P De Nittis, G Pozza and A E Pontiroli

Abstract

It has been shown that peripheral glucagon secreting cells (A-cells) are lost during most of the isolation procedures employed for pig islets. Loss of A-cells decreases intra-islet glucagon levels and cAMP levels in B-cells and might reduce glucose-induced insulin release. This study was designed to test this hypothesis, by evaluating the effects of culture of porcine islets with exogenous glucagon on insulin secretion and on insulin and cAMP content in islets. Islets were isolated from adult 2-year old Large White pigs using an automated method. The number of A-cells was calculated by immunostaining for glucagon in islets before and after isolation and a significant decrease in A-cells was observed. After an overnight culture, islets were cultured for 48 h in a standard medium (CMRL 1066, 10% foetal calf serum, 1% antibiotics, 1% glutamine) alone or in the presence of glucagon at two different concentrations (1·0 and 10·0 μm); exposure to glucagon was either continuous or alternated with periods of incubation in CMRL 1066 alone. After the 48-h culture in standard medium, the islet glucagon response to arginine was almost negligible and significantly lower than that observed in human islets. After culture, islet insulin response to glucose, and islet insulin and cAMP content were evaluated; continuous exposure to glucagon did not produce any significant effect on either insulin secretion or insulin and cAMP content; in contrast, discontinuous exposure to glucagon induced a significant improvement in insulin release, proportional to glucagon concentrations (integrated insulin release: −13·8 ±20·12 pg/islet/20 min in control islets, 111·0±50·73 and 144·7± 47·54 pg/islet/20 min in islets exposed to 1·0 and 10·0 μg glucagon respectively; n=10, P=0·01). Intracellular insulin and cAMP content of islets cultured in different culture media were not different. In conclusion, discontinuous exposure of isolated pig islets to exogenous glucagon induced a significant increase in glucose-induced insulin release which was not associated with an increase in cAMP content. The fact that even in the presence of glucagon the secretory activity of pig islets was lower than the reported activity of human or rat islets suggests that glucagon is only one of the factors involved in the poor insulin responsiveness of pig islets.

Journal of Endocrinology (1995) 147, 87–93