Biosynthesis of proinsulin and insulin in newborn rat pancreas. Interaction of glucose, cyclic AMP, somatostatin, and sulfonylureas on the (3H) leucine incorporation into immunoreactive insulin.

García, S. Ovejero; Jarrousse, C.; Rosselin, G

doi:10.1172/jci108264

Cited by 28 publications

(9 citation statements)

References 64 publications

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“…It has been attributed to a protein kinase C activation following glibenclamide stimulation of diacylglycerol synthesis (21,26). During these in vitro studies up to 2-h incubation periods, the sulfonylurea stimulation of insulin release was not associated with an increase in insulin synthesis (27)(28)(29)(30). When administered to normal rodents, the drugs induce elevated basal insulin levels and result in degranulation of ␤-cells (31).…”

Section: Discussionmentioning

confidence: 99%

Glibenclamide Treatment Recruits β-Cell Subpopulation Into Elevated and Sustained Basal Insulin Synthetic Activity

et al. 2006

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Use of sulfonylureas in diabetes treatment is based on their insulin-releasing effect on pancreatic ␤-cells. Prolonged action is known to degranulate ␤-cells, but functional consequences have not been examined at the cellular level. This study investigates influences of in vivo (48-h) and in vitro (24-h) glibenclamide treatment on the functional state of the ␤-cell population. Both conditions decreased cellular insulin content by >50% and caused an elevated basal insulin biosynthetic activity that was maintained for at least 24 h after drug removal. Glibenclamide stimulation of basal insulin synthesis was not achieved after a 2-h exposure; it required a calcium-dependent translational activity and involved an increase in the percent activated ␤-cells (50% after glibenclamide pretreatment vs. 8% in control cells). The glibenclamide-activated ␤-cell subpopulation corresponded to the degranulated ␤-cell subpopulation that was isolated by fluorescenceactivated cell sorter on the basis of lower cellular sideward scatter. Glibenclamide pretreatment did not alter cellular rates of glucose oxidation but sensitized ␤-cells to glucoseinduced changes in metabolic redox and insulin synthesis and release. In conclusion, chronic exposure to glibenclamide results in degranulation of a subpopulation of ␤-cells, which maintain an elevated protein and insulin synthetic activity irrespective of the presence of the drug and of glucose. Our study demonstrates that the in situ ␤-cell population also exhibits a functional heterogeneity that can vary with drug treatment. Glibenclamide induces degranulated ␤-cells with a sustained elevated basal activity that might increase the risk for hypoglycemic episodes. Diabetes 55:78 -85, 2006 P revious studies (1-9) led us to propose that the normal pancreatic ␤-cell population exhibits intercellular differences that are functionally relevant, in particular for generating the normal dose-response curves to glucose. Chronic exposure to high glucose was found to reduce intercellular differences in glucose sensitivity and thus decrease the net effect of an acute glucose stimulation (7,10,11). Since this view is mainly based on in vitro studies, its potential relevance for the in situ endocrine pancreas needs to be addressed in in vivo models. There are a few reports in which differences among ␤-cells have been described in the intact pancreas, mostly in terms of the intensity of cellular staining for insulin (12,13). After treatment of rats with the insulin secretagogue glibenclamide, the degranulation of ␤-cells was not homogenous (12,13). This observation might thus disclose in situ differences in cellular responsiveness to the drug and in subsequent functional activity. The present work examines this possibility by investigating the ␤-cells that are isolated from glibenclamide-treated rats and comparing them with ␤-cells isolated from normal control rats either without or with a preincubation with glibenclamide. The data indicate that glibenclamide treatment causes a degranulation in a subpopula...

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Section: Discussionmentioning

confidence: 99%

Glibenclamide Treatment Recruits β-Cell Subpopulation Into Elevated and Sustained Basal Insulin Synthetic Activity

et al. 2006

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“…[ 15]), this appears not to be the case for (pro-)insulin biosynthesis (unpublished, [16-181, but cf. [19]). In [S ,201 an increase in insulin release with antisomatostatin serum was also observed but only at a sub-stimulatory or intermediate but not at high glucose concentration.…”

Section: Discussionmentioning

confidence: 99%

Studies on the local (paracrine) actions of glucagon, somatostatin and insulin in isolated islets of rat pancreas

Schatz

Kullek

1980

FEBS Letters

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“…Augmented glucose-mediated insulin release is seen in mature islets following methylxanthine exposure in vitro [2,[4][5][6] and biosynthesis is enhanced in islets from both adult [7][8][9] and infant animals [10]. Discrepancies exist between the concentrations of methylxanthines used in these investigations in vitro and the low dose exposure which may be expected in the fetus or neonate following maternal consumption [11,121. Caffeine (1,3,7-trimethylxanthine) is the most consistent source of methylxanthine exposure of the human fetus.…”

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confidence: 99%

The effect of maternal caffeine ingestion on pancreatic function in the neonatal rat

1982

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Summary. Pancreatic function was investigated in neonatal suckling offspring of caffeine-ingesting dams, with or without maternal sucrose supplementation, throughout pregnancy and lactation. In offspring of rats ingesting caffeine without sucrose supplementation, there was initial hyperinsulinaemia, followed by a progressive fall of plasma insulin to subnormal levels. This fall in plasma insulin coincided with depletion of pancreatic insulin stores. Both the fall in plasma insulin and depletion of pancreatic insulin stores were prevented by sucrose supplementation of caffeine-ingesting dams. Offspring of dams fed sucrose alone and control offspring also maintained pancreatic insulin stores and circulating insulin levels over the first 14 days of postnatal life. Pancreases from offspring of caffeine-exposed animals tested in vitro showed enhanced sensitivity of the insulin release process to glucose. This was reflected in the glucose concentration required to elicit half-maximal insulin release (2.4 ___ 0.2 mmol/1 for caffeine offspring, 2.3 + 0.2 mmol/1 for caffeine with sucrose, 3.8 _+ 0.3 mmol/1 for sucrose and 4.1 + 0.3 mmol/1 for control offspring, mean +_ SEM). In contrast, offspring of sucrose-supplemented (with or without caffeine) dams showed increased sensitivity of the proinsulin biosynthetic process to glucose, whereas offspring of dams ingesting caffeine alone showed no significant enhancement of the biosynthetic process compared with control offspring. Thus enhanced sensitivity of the insulin secretory process to glucose without a change in the sensitivity of the biosynthetic process in the offspring of the caffeine ingesting (nonsucrose supplemented) dams could explain the progressive depletion of pancreatic insulin stores and eventual hypoinsulinaemia seen in this group.

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Biosynthesis of proinsulin and insulin in newborn rat pancreas. Interaction of glucose, cyclic AMP, somatostatin, and sulfonylureas on the (3H) leucine incorporation into immunoreactive insulin.

Cited by 28 publications

References 64 publications

Glibenclamide Treatment Recruits β-Cell Subpopulation Into Elevated and Sustained Basal Insulin Synthetic Activity

Glibenclamide Treatment Recruits β-Cell Subpopulation Into Elevated and Sustained Basal Insulin Synthetic Activity

Studies on the local (paracrine) actions of glucagon, somatostatin and insulin in isolated islets of rat pancreas

The effect of maternal caffeine ingestion on pancreatic function in the neonatal rat

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