Lessons from models of pancreatic β cells for engineering glucose-sensing cells

Abstract

Mathematical models of pancreatic β cells suggest design principles that can be applied to engineering cells to sense glucose and secrete insulin. Engineering cells can potentially both contribute to future diabetes therapies and generate new insights into β cell function. The focus is on ion channels, Ca2+ handling, and elements of metabolism that combine to produce the varied oscillatory patterns exhibited by β cells.

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

“…Readers are referred to earlier reviews for an overview of the different mechanisms proposed for islet oscillations ([86, 87],[88],[89],[90–92],[93]).…”

Mathematical models of electrical activity of the pancreatic β-cell: A physiological review

“…For instance, it has been suggested that mathematical models of b-cells could establish the principles of design for engineered cells capable of sensing glucose and secreting insulin. 112,142 Considering the importance of the changes in [Ca 2C ] i in GSIS, it is surprising that the spatial aspects have not been explicitly considered in the models of b-cells. We think that a necessary extension to the models is the inclusion of a more realistic description of the spatiotemporal distribution of [Ca 2C ] i , such as its effects on the different cellular processes (e.g., regulation of ionic channels, metabolism, insulin exocytosis) occurring at different locations of the intracellular space are adequately simulated.…”

“…5B and C), in contrast to models that depend on a single slow process (e.g., [Ca 2C ] i in the CK model or [ADP] in the SK model), which only generated bursting with a periodicity of seconds (fast oscillations). 16,112 The period of the oscillations in models including the ER is determined by the release rate of Ca 2C from the ER. When the release rate is low, [Ca 2C ] ER reaches a high level during the active phase, and because Ca 2C is released from the ER slowly, [Ca 2C ] i stays elevated (thus making the Ca 2C -dependent Ca 2C channels inactive), preventing the initiation of a new burst of action potentials.…”

Modelo matemático de la actividad eléctrica y las oscilaciones de Ca2+ asociadas a la liberación de insulina en células ß humanas

“…Los modelos matemáticos de la célula β han ido creciendo en complejidad conforme ha surgido nueva evidencia experimental. En esta sección, se presenta un breve recuento de la evolución del campo de modelado matemático de la célula β. Una discusión más extensa sobre el tema se puede encontrar en nuestra reciente revisión [21] (Artículo 2), o en otras revisiones sobre el tema [51,[152][153][154].…”

“…En 1990, Smith et al [170] reportaron actividad eléctrica en ráfagas con un período en el orden de minutos (oscilaciones lentas, ver sección 3.2.2), la cual no fue posible reproducir con los primeros modelos matemáticos basados en unúnico mecanismo marcapasos [154,171]. Esto propició el surgimiento de modelos más complejos en términos de las variables marcapasos propuestas como responsables del inicio y término de las ráfagas de potenciales de acción.…”