Hypothesis

Chronic IAPP misfolding in pancreatic beta cells releases oligomeric species via exosomes that seed ER stress in liver, adipose, and skeletal muscle, converting adaptive UPR into a maladaptive, CHOP‑driven state that accelerates systemic metabolic decline.

Mechanistic Basis

• IAPP oligomers activate all three UPR branches (PERK, IRE1, ATF6) in beta cells, shifting from PERK‑eIF2α‑ATF4 adaptation to CHOP‑mediated apoptosis when exposure is prolonged [IAPP aggregation activates UPR].
• Aged beta cells show upregulated HSPA5/BiP and ATF4/6 alongside loss of PDX1, NKX6.1, and MAFA, indicating eroded identity and impaired autophagy [Age‑related proteostasis decline].
• Extracellular vesicles from stressed beta cells can transfer misfolded proteins to recipient cells, a mechanism documented for amyloid‑β and tau [Cross‑seeding potential].
• PERK‑eIF2α‑ATF4 signaling can coordinate mitochondrial UPR (UPRmt) and ER‑UPR under hyperglycemia, suggesting a conduit for spreading stress [UPR coordination].
• AGEs accelerate amyloid deposition in adipocyte lipid droplets, implying that extracellular IAPP may encounter a receptive environment in adipose tissue [AGEs and adipocyte amyloid].

Testable Predictions

1. Plasma exosomes from aged, IAPP‑overexpressing mice will contain detectable IAPP oligomers and induce CHOP upregulation in naïve hepatocytes, adipocytes, and myotubes in vitro.
2. Beta‑cell‑specific knockout of IAPP in aged mice will reduce hepatic, adipose, and muscle UPR markers (phospho‑PERK, spliced XBP1, nuclear ATF6, CHOP) compared with wild‑type controls.
3. Administering an exosome release inhibitor (e.g., GW4869) to aged IAPP‑transgenic mice will ameliorate systemic insulin resistance without altering beta‑cell mass.
4. Overexpressing a dominant‑negative PERK isoform in liver will block the propagation of IAPP‑induced CHOP expression, rescuing glucose tolerance despite persistent beta‑cell stress.

Experimental Approach

• Animal models: Use RIP‑Cre;IAPP‑overexpressing and RIP‑Cre;IAPP‑flox mice aged to 24 months. Harvest plasma, isolate exosomes via ultracentrifugation, and quantify IAPP oligomers by immunoblot and ELISA.
• In vitro exposure: Treat primary hepatocytes, adipocytes, and myotubes with purified beta‑cell exosomes; measure UPR activation (phospho‑PERK, ATF4, CHOP) and downstream apoptosis (caspase‑3 cleavage).
• In vivo intervention: Treat cohorts with GW4869 or a PERK inhibitor (GSK2606414) for 8 weeks; assess glucose tolerance tests, insulin tolerance tests, and tissue‑specific UPR markers.
• Readouts: RNA‑seq for stress pathways, histology for lipid accumulation and fibrosis, and serum metabolomics to link UPR activation to metabolic dysfunction.

Potential Implications

If validated, this hypothesis would reposition IAPP not as a pancreas‑restricted toxin but as a systemic proteostatic propagator. Therapeutic strategies targeting exosome release or peripheral PERK signaling could break the vicious cycle of beta‑cell stress and organ‑wide insulin resistance, offering a unified approach to combat age‑related metabolic disease.