Author
Listed:
- Chiara Montemurro
(University of California, Los Angeles)
- Hiroshi Nomoto
(University of California, Los Angeles)
- Lina Pei
(University of California, Los Angeles)
- Vishal S. Parekh
(University of Michigan)
- Kenny E. Vongbunyong
(University of California, Los Angeles)
- Suryakiran Vadrevu
(University of Michigan)
- Tatyana Gurlo
(University of California, Los Angeles)
- Alexandra E. Butler
(University of California, Los Angeles)
- Rohan Subramaniam
(University of California, Los Angeles)
- Eleni Ritou
(University of California, Los Angeles)
- Orian S. Shirihai
(University of California, Los Angeles)
- Leslie S. Satin
(University of Michigan)
- Peter C. Butler
(University of California, Los Angeles)
- Slavica Tudzarova
(University of California, Los Angeles
University of California, Los Angeles)
Abstract
The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by β-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, β-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, β-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of β-cell function.
Suggested Citation
Chiara Montemurro & Hiroshi Nomoto & Lina Pei & Vishal S. Parekh & Kenny E. Vongbunyong & Suryakiran Vadrevu & Tatyana Gurlo & Alexandra E. Butler & Rohan Subramaniam & Eleni Ritou & Orian S. Shirihai, 2019.
"IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function,"
Nature Communications, Nature, vol. 10(1), pages 1-17, December.
Handle:
RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10444-1
DOI: 10.1038/s41467-019-10444-1
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