Background The integrity of the interactions and the 3D architecture amongbeta cell populations in pancreatic islets is critical for proper biosynthesis,storage and release of insulin. The aim of this study was to evaluate the effecton electrophysiological signalling of beta cells that is produced by progressivelymphocytic islet cell infiltration (insulitis), by modelling the disruption of pancreaticislet anatomy as a consequence of insulitis and altered glucose concentrations.Methods On the basis of histopathological images of murine islets from nonobesediabetic mice, we simulated the electrophysiological dynamics of a 3Dcluster of mouse beta cells via a stochastic model. Progressive damage wasmodelled at different glucose concentrations, representing the differentglycaemic states in the autoimmune progression towards type 1 diabetes.Results At 31% of dead beta cells (normoglycaemia) and 69% (hyperglycaemia),the system appeared to be biologically robust to maintain regular Ca2+ion oscillations guaranteeing an effective insulin release. Simulations at 84%,94% and 98% grades (severe hyperglycemia) showed that intracellular calciumoscillations were absent. In such conditions, insulin pulsatility is not expected tooccur.Conclusions Our results suggest that the islet tissue is biophysically robustenough to compensate for high rates of beta cell loss. These predictions canbe experimentally tested in vitro by quantifying space and time electrophysiologicaldynamics of animal islets kept at different glucose gradients. The modelindicates the necessity of maintaining glycaemia within the physiological rangeas soon as possible after diabetes onset to avoid a dramatic interruption of Ca2+pulsatility and the consequent drop of insulin release.

A stochastic mathematical model to study the autoimmune progression towards type 1 diabetes

CHERUBINI C;GIZZI A;POZZILLI P;FILIPPI S
2013-01-01

Abstract

Background The integrity of the interactions and the 3D architecture amongbeta cell populations in pancreatic islets is critical for proper biosynthesis,storage and release of insulin. The aim of this study was to evaluate the effecton electrophysiological signalling of beta cells that is produced by progressivelymphocytic islet cell infiltration (insulitis), by modelling the disruption of pancreaticislet anatomy as a consequence of insulitis and altered glucose concentrations.Methods On the basis of histopathological images of murine islets from nonobesediabetic mice, we simulated the electrophysiological dynamics of a 3Dcluster of mouse beta cells via a stochastic model. Progressive damage wasmodelled at different glucose concentrations, representing the differentglycaemic states in the autoimmune progression towards type 1 diabetes.Results At 31% of dead beta cells (normoglycaemia) and 69% (hyperglycaemia),the system appeared to be biologically robust to maintain regular Ca2+ion oscillations guaranteeing an effective insulin release. Simulations at 84%,94% and 98% grades (severe hyperglycemia) showed that intracellular calciumoscillations were absent. In such conditions, insulin pulsatility is not expected tooccur.Conclusions Our results suggest that the islet tissue is biophysically robustenough to compensate for high rates of beta cell loss. These predictions canbe experimentally tested in vitro by quantifying space and time electrophysiologicaldynamics of animal islets kept at different glucose gradients. The modelindicates the necessity of maintaining glycaemia within the physiological rangeas soon as possible after diabetes onset to avoid a dramatic interruption of Ca2+pulsatility and the consequent drop of insulin release.
type 1 diabetes; islet cells; beta cells; hyperglycaemia; mathematical modelling; calcium oscillations; insulitis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/2898
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