Human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely: Evidence supporting specific desensitization rather than β-cell exhaustion

Alberto M. Davalli, Antonio E. Pontiroli, Carlo Socci, Federico Bertuzzi, Bruno Fattor, Simona Braghi, Valerio Di Carlo, Guido Pozza

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Abstract

The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/ L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 μmol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/ L), L-arginine (10 mmol/L), and tolbutamide (100 μmol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (Δ AUC), 11% of control], and a reduced response to acute tolbutamide (Δ AUC, 35% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (Δ AUC, 11% of control) and tolbutamide (Δ AUC, 27% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in tolbutamide did not respond to tolbutamide (Δ AUC, 14% of control) and showed a reduced responses to acute glucose (Δ AUC, 36% of control) and L-arginine (Δ AUC, 24% of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 μmol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.

Original languageEnglish
Pages (from-to)790-794
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume74
Issue number4
Publication statusPublished - Apr 1992

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Tolbutamide
Area Under Curve
Glucose
Arginine
Insulin
Culture Media
In Vitro Techniques
Tissue culture
Islets of Langerhans

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely : Evidence supporting specific desensitization rather than β-cell exhaustion. / Davalli, Alberto M.; Pontiroli, Antonio E.; Socci, Carlo; Bertuzzi, Federico; Fattor, Bruno; Braghi, Simona; Di Carlo, Valerio; Pozza, Guido.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 74, No. 4, 04.1992, p. 790-794.

Research output: Contribution to journalArticle

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abstract = "The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/ L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 μmol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/ L), L-arginine (10 mmol/L), and tolbutamide (100 μmol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (Δ AUC), 11{\%} of control], and a reduced response to acute tolbutamide (Δ AUC, 35{\%} of control), but responded to L-arginine (Δ AUC, 75{\%} of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (Δ AUC, 11{\%} of control) and tolbutamide (Δ AUC, 27{\%} of control), but responded to L-arginine (Δ AUC, 75{\%} of control). Islets cultured in tolbutamide did not respond to tolbutamide (Δ AUC, 14{\%} of control) and showed a reduced responses to acute glucose (Δ AUC, 36{\%} of control) and L-arginine (Δ AUC, 24{\%} of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 μmol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.",
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T2 - Evidence supporting specific desensitization rather than β-cell exhaustion

AU - Davalli, Alberto M.

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AU - Socci, Carlo

AU - Bertuzzi, Federico

AU - Fattor, Bruno

AU - Braghi, Simona

AU - Di Carlo, Valerio

AU - Pozza, Guido

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N2 - The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/ L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 μmol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/ L), L-arginine (10 mmol/L), and tolbutamide (100 μmol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (Δ AUC), 11% of control], and a reduced response to acute tolbutamide (Δ AUC, 35% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (Δ AUC, 11% of control) and tolbutamide (Δ AUC, 27% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in tolbutamide did not respond to tolbutamide (Δ AUC, 14% of control) and showed a reduced responses to acute glucose (Δ AUC, 36% of control) and L-arginine (Δ AUC, 24% of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 μmol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.

AB - The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/ L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 μmol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/ L), L-arginine (10 mmol/L), and tolbutamide (100 μmol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (Δ AUC), 11% of control], and a reduced response to acute tolbutamide (Δ AUC, 35% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (Δ AUC, 11% of control) and tolbutamide (Δ AUC, 27% of control), but responded to L-arginine (Δ AUC, 75% of control). Islets cultured in tolbutamide did not respond to tolbutamide (Δ AUC, 14% of control) and showed a reduced responses to acute glucose (Δ AUC, 36% of control) and L-arginine (Δ AUC, 24% of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 μmol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.

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