IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

• DOI: 10.1038/s41467-019-10444-1
• Publication Date: 2019-06-18T10:02:40Z
• Authors: 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; Leslie S. Satin; Peter C. Butler; Slavica Tudzarova
• Keywords: Amyloid (mycology); Aggresome

Abstract The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from polypeptide (IAPP), a protein co-expressed with insulin β-cells. In common amyloidogenic proteins implicated neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers misfolded stress. Here, we establish that hIAPP stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged oxidative phosphorylation mitochondrial fragmentation and perinuclear clustering, considered protective posture against increased cytosolic Ca 2+ characteristic of oligomer contrast to tissues the capacity regenerate, β-cells adult humans are minimally replicative, therefore fail execute second pro-regenerative phase injury pathway. Instead, T2D remain trapped pro-survival first HIF1α repair response metabolism network adapted slow rate cell attrition at expense β-cell function.