Abstract
Type 2 diabetes (T2D) has many cardiovascular complications, including a thrombotic propensity. Many such chronic, inflammatory diseases are accompanied (and may be exacerbated, and possibly even largely caused) by amyloid fibril formation. Recognising that there are few strong genetic associations underpinning T2D, but that amyloidogenesis of amylin is closely involved, we have been seeking to understand what might trigger the disease. Serum levels of bacterial lipopolysaccharide are raised in T2D, and we recently showed that fibrin(ogen) polymerisation during blood clotting can be affected strongly by LPS. The selectivity was indicated by the regularisation of clotting by lipopolysaccharide-binding protein (LBP). Since coagulopathies are a hallmark of T2D, we wondered whether they might too be caused by LPS (and reversed by LBP). We show here, using SEM and confocal microscopy, that platelet-poor-plasma from subjects with T2D had a much greater propensity for hypercoagulability and for amyloidogenesis, and that these could both be reversed by LBP. These data imply that coagulopathies are an important feature of T2D, and may be driven by ‘hidden’ LPS. Given the prevalence of amyloid formation in the sequelae of diabetes, this opens up novel strategies for both the prevention and treatment of T2D.
Highlights
There is an increasing recognition that many chronic, inflammatory diseases are accompanied by amyloid fibril formation[1,2,3,4,5,6]
In this paper, we show that lipopolysaccharide binding protein (LBP) added to naïve Type 2 diabetes (T2D) plasma, followed by the addition of thrombin, led to a fibrin fibre structure similar to that of healthy platelet poor plasma (PPP)
This is entirely consistent with the fact that at least some of the amyloidogenesis must be catalysed by fibrinogen-bound LPS, given too, as we show here, that it could be removed, and the amyloidogenesis largely reversed, by LBP
Summary
There is an increasing recognition that many chronic, inflammatory diseases are accompanied (and may be exacerbated, and possibly even largely caused) by amyloid fibril formation[1,2,3,4,5,6]. As part of an extensive study of anomalous blood clotting (e.g. refs 29, 30, 33, 64–68), we recently found[48, 68,69,70] that the anomalous clotting was amyloid in nature. The fact that it could be caused by tiny amounts of lipopolysaccharide was seen as consistent with a role for dormant bacteria in the aetiology of such diseases[71,72,73,74,75,76,77,78]. The present paper shows that the answers to both these questions are strongly in the affirmative
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