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β Cell–specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity
Tatyana Gurlo, … , Alexandra E. Butler, Peter C. Butler
Tatyana Gurlo, … , Alexandra E. Butler, Peter C. Butler
Published November 3, 2016
Citation Information: JCI Insight. 2016;1(18):e89590. https://doi.org/10.1172/jci.insight.89590.
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Research Article Endocrinology

β Cell–specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity

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Abstract

The islet in type 2 diabetes (T2D) shares many features of the brain in protein misfolding diseases. There is a deficit of β cells with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin. Small intracellular membrane-permeant oligomers, the most toxic form of IAPP, are more frequent in β cells of patients with T2D and rodents expressing human IAPP. β Cells in T2D, and affected cells in neurodegenerative diseases, share a comparable pattern of molecular pathology, including endoplasmic reticulum stress, mitochondrial dysfunction, attenuation of autophagy, and calpain hyperactivation. While this adverse functional cascade in response to toxic oligomers is well described, the sequence of events and how best to intervene is unknown. We hypothesized that calpain hyperactivation is a proximal event and tested this in vivo by β cell–specific suppression of calpain hyperactivation with calpastatin overexpression in human IAPP transgenic mice. β Cell–specific calpastatin overexpression was remarkably protective against β cell dysfunction and loss and diabetes onset. The critical autophagy/lysosomal pathway for β cell viability was protected with calpain suppression, consistent with findings in models of neurodegenerative diseases. We conclude that suppression of calpain hyperactivation is a potentially beneficial disease-modifying strategy for protein misfolding diseases, including T2D.

Authors

Tatyana Gurlo, Safia Costes, Jonathan D. Hoang, Jacqueline F. Rivera, Alexandra E. Butler, Peter C. Butler

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Figure 1

Calpastatin levels in islets from mice overexpressing human IAPP.

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Calpastatin levels in islets from mice overexpressing human IAPP.
(A) Re...
(A) Representative Western blot (from 1 of 3 independent experiments performed) reflecting calpastatin protein levels in cytosolic and nuclear enriched fractions of islet lysates obtained from 9-week-old WT (average fasting blood glucose, 76.8 ± 6.5 mg/dl) and human IAPP transgenic mice (hTG; average fasting blood glucose, 79.3 ± 7.6 mg/dl). GAPDH and PARP were used as loading controls for cytosolic and nuclear fractions, respectively. The lanes were run on the same gel but were noncontiguous. The graph shows quantification of calpastatin levels in the cytosolic fraction. (B) mRNA levels of calpastatin in islets from 9-week-old WT mice (average fasting blood glucose, 65.1 ± 4.3 mg/dl) and hTG mice (average fasting blood glucose, 72.0 ± 3.8 mg/dl) were assessed by quantitative RT-PCR. Data are expressed as mean ± SEM; n = 3 (A) and n = 6 (B) for each group; #P < 0.05, ###P < 0.001, 2-tailed Student’s t test.
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