Simvastatin Rapidly and Reversibly Inhibits Insulin Secretion in Intact Single-Islet Cultures.
BACKGROUND
Epidemiological studies suggest that statins may promote the development or exacerbation of diabetes, but whether this occurs through inhibition of insulin secretion is unclear. This lack of understanding is partly due to the cellular models used to explore this phenomenon (cell lines or pooled islets), which are non-physiologic and have limited clinical transferability.


METHODS
Here, we study the effect of simvastatin on insulin secretion using single-islet cultures, an optimal compromise between biological observability and physiologic fidelity. We develop and validate a microfluidic device to study single-islet function ex vivo, which allows for switching between media of different compositions with a resolution of seconds. In parallel, fluorescence imaging provides real-time analysis of the membrane voltage potential, cytosolic Ca2+dynamics, and insulin release during perfusion under 3 or 11 mM glucose.


RESULTS
We found that simvastatin reversibly inhibits insulin secretion, even in high-glucose. This phenomenon is very rapid (<60 s), occurs without affecting Ca2+concentrations, and is likely unrelated to cholesterol biosynthesis and protein isoprenylation, which occur on a time span of hours.


CONCLUSIONS
Our data provide the first real-time live demonstration that a statin inhibits insulin secretion in intact islets and that single islets respond differently from cell lines on a short time scale.


BACKGROUND
University of Padova, EASD Foundation.
Department of Medicine, University of Padova, Via Giustiniani 2, 35129, Padua, Italy.|Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy.
Valentina
V
Scattolini
Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy.|Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 99 Haike Road, Shanghai, 201210, China.|Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
Camilla
C
Luni
Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy.|Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
Alessandro
A
Zambon
Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy.|Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
Silvia
S
Galvanin
Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy.|Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
Onelia
O
Gagliano
CNR Institute of Cell Biology and Neurobiology, 00015, Monterotondo, Italy.
Catalin Dacian
CD
Ciubotaru
Department of Medicine, University of Padova, Via Giustiniani 2, 35129, Padua, Italy.
Angelo
A
Avogaro
CNR Institute of Cell Biology and Neurobiology, 00015, Monterotondo, Italy.|Department of Physics, University of Padova, Via Marzolo 8, 35131, Padua, Italy.
Fabio
F
Mammano
Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy. nicola.elvassore@unipd.it.|Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy. nicola.elvassore@unipd.it.
Nicola
N
Elvassore
Department of Medicine, University of Padova, Via Giustiniani 2, 35129, Padua, Italy. gianpaolo.fadini@unipd.it.|Venetian Institute of Molecular Medicine, Via Orus 2, 35128, Padua, Italy. gianpaolo.fadini@unipd.it.
Gian Paolo
GP
Fadini
Insulin; Islet; Microfluidic; Simvastatin; Statin