Collagen Molecules In Diabetes

A significant issue caused by the raised blood glucose concentration in diabetic individuals is premature aging of collagen. The normal structure of collagen-1 is a triple helix, a shape which lends itself well to being tightly packed into fibrils. Advanced glycation end products (AGEs) naturally accumulate in the body over time and their accumulation is one of the principal signs of, and indeed one of the reasons for aging. They are formed when a sugar reacts with free amino groups in proteins to form a Schiff base, which spontaneously becomes an Amidori product. This reaction is reversible and the direction favoured by the reaction is dependent on sugar levels with high glucose concentration favouring the production of Amidori products (Peppa et al 2003). A series of further reactions produces the AGE. The protein's tertiary structure is now altered, as an AGE will be attached to the protein in the place of the initial free amino group. In the case of collagen, the addition of AGEs renders the protein less streamlined. In diabetics, the concentration of glucose in the bloodstream and therefore the extracellular space surrounding the fibroblasts is higher than a healthy individual, thus meaning that the amount of glucose available to bind with proteins is increased, resulting in a greater number of opportunities for AGEs to form on the procollagen and collagen molecules once released from the fibroblasts. This, combined with the fact that high glucose environments favour production of the AGE precursor Amidori complex means that in diabetics, more AGEs are found on collagen molecules, some of which are earmarked for tendon production (Peppa et al 2003). Indeed, it has been shown that collagen glucosylation is markedly increased in individuals who have suffered from diabetes since childhood, when compared to healthy individuals of the same age (Schnider and Kohn 1980). While this is a process that occurs naturally with age, it is believed that suffering from diabetes accelerates the process, leading to premature aging (Monnier et al 1984). The problem caused by the addition of AGEs is twofold; firstly, the addition of the AGEs alters the shape of the molecule and thus alters how collagen molecules pack together in a collagen fibril, while secondly, the addition of AGEs increases the occurrence of cross linking in the collagen molecules, again altering how the molecules bind together to produce the fibril (Jozsa and Kannus 1997). It is apparent therefore, that the glucose-rich environment present in diabetes, alters the chemical composition of collagen molecules, which in turn alters how these molecules interact with each other in order to form collagen fibrils. A further complication of this is that collagen turnover rates have shown to be lower in diabetics (Jozsa and Kannus 1997), so not only is the collagen produced more readily damaged, the rate at which damaged collagen could be replaced is also slower, limiting the efficiency of collagen regeneration. A further complication is that it is believed that procollagen is degraded intracellularly in diabetics. During collagen synthesis, procollagen is initially produced by the cell, which is subsequently converted into collagen. In diabetics, it has been shown that procollagen is more readily degraded before its conversion to collagen (Leung et al 1986), thus reducing the efficiency of collagen production. This reduces the availability of collagen, and given that much of the collagen produced is of poor quality, the overall pool of available good-quality collagen in diabetics is much reduced compared to healthy individuals. Further differences observed in collagen in diabetics is a decreased ratio of alpha to beta subunits in collagen molecules in addition to a decreased solubility. It is also believed that 'diabetic collagen' is more prone to polymerisation when compared to the collagen of a healthy individual (Golub et al 1978). Quite clearly, collagen molecules are altered in diabetes in a number of ways, with each change likely to alter the way in which the molecules behave. It is also apparent that the efficiency of collagen production, repair and regeneration is also compromised in diabetic individuals.