Hyperamylinemia Increases IL-1β Synthesis in the Heart via Peroxidative Sarcolemmal Injury

Abstract

Hypersecretion of amylin is common in individuals with prediabetes, causes amylin deposition and proteotoxicity in pancreatic islets, and contributes to the development of type 2 diabetes. Recent studies also identified amylin deposits in failing hearts from patients with obesity or type 2 diabetes and demonstrated that hyperamylinemia accelerates the development of heart dysfunction in rats expressing human amylin in pancreatic β-cells (HIP rats). To further determine the impact of hyperamylinemia on cardiac myocytes, we investigated human myocardium, compared diabetic HIP rats with diabetic rats expressing endogenous (nonamyloidogenic) rat amylin, studied normal mice injected with aggregated human amylin, and developed in vitro cell models. We found that amylin deposition negatively affects cardiac myocytes by inducing sarcolemmal injury, generating reactive aldehydes, forming amylin-based adducts with reactive aldehydes, and increasing synthesis of the proinflammatory cytokine interleukin-1β (IL-1β) independently of hyperglycemia. These results are consistent with the pathological role of amylin deposition in the pancreas, uncover a novel contributing mechanism to cardiac myocyte injury in type 2 diabetes, and suggest a potentially treatable link of type 2 diabetes with diabetic heart disease. Although further studies are necessary, these data also suggest that IL-1β might function as a sensor of myocyte amylin uptake and a potential mediator of myocyte injury.

Brain microvascular injury and white matter disease provoked by diabetes‐associated hyperamylinemia

“…Western blot analysis of amylin in plasma samples (Fig 1A) showed multiple molecular weight bands (higher amylin immunoreactive signal is seen in HIP rats compared to WT rats). The higher molecular weight bands could correspond to circulating amylin aggregates, as suggested by previously published data 18,28,49 , or amylin binding to plasma components (including plasma APOE; see below).…”

“…Plasma and whole blood were processed as described previously. 6,18 Capillaries were isolated as described above and then lysed in buffer containing 1% NP-40, 150mM NaCl, 10mM Tris-HCl, 2mM EGTA, 50mM NaF, 1% phosphatase, and 1% protease inhibitors. The lysate was centrifuged at 17,000 3 g for 30 minutes.…”

“…13,14 In patients with type 2 diabetes, amylin forms amyloid in the pancreatic islets that triggers b-cell apoptosis. 9,15,16 Deposits of aggregated amylin are also identified in failing hearts 17,18 and kidneys 19 of individuals with type 2 diabetes or obesity. Of note, apolipoprotein E4 (APOE4), which is strongly associated with b amyloid (Ab) pathology, 20,21 modulates amylin aggregation 22 and amylin amyloid formation.…”

“…[32][33][34][35][36][37] The pathophysiology underlying slowly progressive functional and structural brain changes in the setting of type 2 diabetes is largely unknown. [32][33][34][35][36][37] Given the toxicity of aggregated amylin, 9,[15][16][17][18][19] we hypothesized that the complex pathophysiology [32][33][34][35][36][37] underlying slowly progressive functional and structural brain changes in patients with type 2 diabetes involves accumulation of aggregated amylin in the brain blood vessels. Here, we tested the hypothesis that aggregated amylin circulates through the blood, deposits in brain blood vessels (possibly via the interaction with plasma apolipoproteins), and provokes brain microvascular injury by degrading endothelial cell coverage and tight junctions.…”

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

“…Our finding that toxic h-IAPP LP intermediates bound RAGE and upregulated β cell RAGE expression led us to predict that LP intermediates would modulate inflammatory gene expression and cytotoxicity in cultured β cells and muscle cells, as h-IAPP-induced islet cell and cardiomyocyte inflammation have been reported (40,42,44,45,51). We also expected that sRAGE would compete with cellsurface RAGE for h-IAPP binding, as it targets toxic LP intermediates and is a competitive inhibitor of ligand binding to cell membrane-bound RAGE.…”