Altered autonomic inputs as a cause of pancreatic β-cell amyloid

Abstract

A partial loss of β-cell mass and β-cell dysfunction in Type 2 Diabetes Mellitus (T2DM) is associated with amyloid deposition but whether it is causal or consequential is debated. Although the in vitro polymerization of amylin has been studied in detail, the exact trigger for the mechanism in vivo has not been identified. One suggestion is that an increased load on β-cells results in inefficient handling of proteins leading to misfolding and aggregation, but this hypothesis is faced with certain paradoxes. We suggest an alternative mechanism based on the assumption that polymerization is a spontaneous process. The concentration of the polypeptide in β-cell granules is shown to be sufficient to allow polymerization. However if the rate of turnover in normal cells is greater than the rate of polymerization, amyloid deposition will not be observed. If this is true, it follows that amyloid deposition could be a result of increased retention time of amylin in the β-cell granules. In T2D, the sympathetic inputs are known to increase which could result in suppression of the secretion process. The increase in the retention time due to this suppression can allow polymerization. In addition to this in a prediabetic state parasympathetic stimulation increases β-cell proliferation. This reduces the insulin demand per cell thereby increasing the mean retention time. Thus a combination of contrasting actions of sympathetic and parasympathetic systems could lead to increase in the amyloid deposition. We suggest testable predictions of the alternative hypotheses and the lines of research needed to test them.