TY - JOUR
T1 - IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function
AU - Montemurro, Chiara
AU - Nomoto, Hiroshi
AU - Pei, Lina
AU - Parekh, Vishal S.
AU - Vongbunyong, Kenny E.
AU - Vadrevu, Suryakiran
AU - Gurlo, Tatyana
AU - Butler, Alexandra E.
AU - Subramaniam, Rohan
AU - Ritou, Eleni
AU - Shirihai, Orian S.
AU - Satin, Leslie S.
AU - Butler, Peter C.
AU - Tudzarova, Slavica
N1 - Funding Information:
This work was supported by funding from the National Institutes of Health (NIH/ NIDDK Grant #DK077967) and the Larry Hillblom Foundation (Grant #2014-D-001-NET and Start-up Grant #2017-D-002-SUP). The work in Dr. Satin’s lab was supported by NIH/NIDDK Grant #DK46409. V.S.P. was supported by an Upjohn Postdoctoral Fellowship. L.P. was supported by Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China. This research was performed with the support of the nPOD, a collaborative T1D research project sponsored by the Juvenile Diabetes Research Foundation International. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. The authors thank Dr. Arthur Sherman for discussions of cellular Ca2+ dynamics and statistics, Benjamin Thompson for his help with the experiments involving Ca2+ measurements, and UCLA Metabolomics Center for generation of metabolomics data.
Funding Information:
Human islets. Human pancreatic islets were from the Islet Cell Resource Consortium. Using of human islets was determined as not human subjects research by the UCLA Office of Human Research Protection Program (IRB Exception, 01.06.2016). They were derived from brain-dead (cadaveric) organ donors, for whom consent has been provided by the relatives, through the Integrated Islet Distribution Program (IIDP) in a collaborative manner. IIDP is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and provides a network for pancreatic islet availability for fundamental research. Dithizone staining was performed to assess the islet purity that was 90–95%. The donors, aged 25–60 years, were heart-beating cadaveric organ donors. Islets were cultured in RPMI 1640 medium (5.5 mM glucose) containing 100 units/ml penicillin, 100 g/ml streptomycin, and 10% fetal bovine serum (Invitrogen, Carlsbad, CA, USA) for 1 day and then processed for western blotting analysis.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067623439&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10444-1
DO - 10.1038/s41467-019-10444-1
M3 - Article
C2 - 31213603
AN - SCOPUS:85067623439
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2679
ER -