Abstract
Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.
Highlights
Islet amyloid polypeptide (IAPP, known as amylin) is co-secreted with insulin (Lukinius et al, 1989) from the beta cells of the pancreatic islets, and together with insulin it regulates the glucose metabolism (Lutz, 2010, 2012; Hay et al, 2015)
While T2DM is initially characterized by a reduced insulin response, the loss of beta cells decreases the production of insulin and IAPP and further reduces the regulation of the glucose metabolism (Höppener et al, 2000)
A series of simulations of membranes with DOPC, DOPS, and CHOL was performed to investigate the interactions between IAPP and the lipid components of the membrane and to study the membrane bound structure of IAPP and how it depends on the bilayer composition
Summary
Islet amyloid polypeptide (IAPP, known as amylin) is co-secreted with insulin (Lukinius et al, 1989) from the beta cells of the pancreatic islets, and together with insulin it regulates the glucose metabolism (Lutz, 2010, 2012; Hay et al, 2015). IAPP aggregation is cytotoxic and contributes to the loss of beta cell associated with progressed T2DM (Abedini and Schmidt, 2013; Cao et al, 2013). While T2DM is initially characterized by a reduced insulin response, the loss of beta cells decreases the production of insulin and IAPP and further reduces the regulation of the glucose metabolism (Höppener et al, 2000). The cytotoxic mechanism of IAPP toward beta cells is unclear, but it has been hypothesized to be related to both membrane damage, inflammation, receptor interactions, oxidative stress, mitochondrial dysfunction, and inducing defects in autophagy (Abedini and Schmidt, 2013; Milardi et al, 2021).
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