Memoria metabolica

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HYPOTHESIS Open Access
Metabolic memory: a vascular perspective

Thomas W Jax1,2
Abstract
Multiple and complex pathways promote the deleterious effects of hyperglycemia in diabetes, ultimately leading to micro- and macrovascular disease. Some of the known mechanisms in diabetic vascular disease may explain the initiation of the “metabolic memory”, but
fall short if long periods of time areinvolved.
Vascular research has been prolific in the past in finding links between microvascular dysfunction and subsequent macrovascular disease. Thus, this text will extend the current discussion of the “metabolic memory” by including available data from vascular research.
The hypothesis proposes that structural and functional changes in the microcirculation interact within the vascularcontinuum with larger arteries. This interaction may lead to subsequent upstream endothelial dysfunction,
atherosclerosis and vascular complications ("Micro/ Macro Interaction”). The underlying microvascular structural changes may be more long-term and possibly mediate the “metabolic memory”.
This hypothesis, that the “not-so new” interaction
between micro-and macrovasculature may promote “metabolicmemory” effects extends and unifies currently discussed theories.

The vascular perspective of the metabolic
memory
In vascular research it is well established, that microvascular dysfunction eventually leads to subsequent macrovascular disease [1]. A dilation of prearterioles and arterioles results in an increase of shear stress, which triggers flow dependent dilation in conductance arteries[1,2], less shear stress secondary to microvascular dysfunction may lead to less vasodilation and thus endothelial dysfunction in conductance arteries.
In diabetes, hyperglycemia promotes both micro- and macrovascular damage by activating a network of multiple and complex pathways. Many of these may explain the initiation of the “metabolic memory” but fall short if long periods of time areinvolved. Structural changes in
the microcirculation alter microvessels and their function, resulting in microvascular endpoints in the most susceptible organs.
The interaction within the vascular continuum between microvessels and larger arteries may lead to subsequent upstream endothelial dysfunction, atherosclerosis and vascular complications ("Micro/Macro Interaction”).
In addition local intravessel wall microvascular changes can promote localized atherosclerosis. These underlying microvascular structural changes may be more long-term and possibly mediate the “metabolic memory”. The fact, that early intensive treatment of diabetes may be superior to intensification at a later disease stage indicates an early time window one has to make use of for intensive therapy in order to achieve along-lasting therapeutic benefit by signifying the role of a structural fixation up to a “point of no return”, when a regression of vascular disease progression is no longer possible. This extended,
or rather unifying hypothesis will promote new research in this exiting area.

Good metabolic control mediates long-term
benefit
One of the major principles of the clinical long-term management ofpatients with diabetes mellitus is to prevent cardiovascular (CV) complications. Recently it was observed in several large scale clinical trials, that an intensive antihyperglycaemic treatment of diabetic patients, both in type 1 and 2, reduces the incidence of microvascular complications [3-5]. After the end of each study the participants were followed without any further intervention and,despite no further treatment differences, the advantage of intensive antidiabetic treatment persisted and even extended to a reduction of macrovascular events. The underlying cause of this phenomenon remains unclear; it is currently being discussed to be a “metabolic memory” effect: A defined period of good metabolic control conciliates a long term beneficial effect on cardiovascular endpoints....
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