Amyloid‐Forming Amylin Secreted by the Pancreas Promotes Hypoxia‐Inducible Factor Activation and Mitochondrial Alterations in Liver and Heart During Type 2 Diabetes Pathogenesis

ABSTRACT In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid‐forming amylin would activate hypoxia‐inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β‐cells, comparing tissues from 14 to 16‐month‐old rats with those from age‐matched wild‐type, hyperglycemic UCD and amylin‐knockout (AKO) rats. We found greater accumulation of HIF‐1α and HIF‐2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF‐1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF‐1α and HIF‐2α accumulation. This was associated with suppression of ETS capacity, and increased p‐AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human‐relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.