Induction of Diabetic Ulcers through Collagen Glycosylation

Introduction: Diabetic ulcers are a significant complication of diabetes mellitus, commonly attributed to peripheral neuropathy and associated vascular insufficiencies.  However, this review aims to elucidate the overlooked role of high blood glucose and glycosylation in the pathogenesis of diabetic ulcers.Methods:Through an extensive review of existing literature, this abstract explores the intricate mechanisms by which elevated blood glucose levels and glycosylation disrupt normal wound healing processes. Special attention is given to the impact of glycosylation on lysine residues and its consequences on collagen maturation, as well as the implications for peripheral nerve cells and arterial blood supply.Results:The findings reveal a complex interplay between high blood glucose levels, glycosylation of lysine residues, and impaired wound healing.Discussion: Lysyl oxidase specifically acts on lysine or hydroxylysine residues in the telopeptide region of the collagen molecule, resulting in the formation of immature divalent crosslinks with opposing amino acids in the triple-helical region [1-4]. These immature crosslinks later spontaneously convert into more stable trivalent crosslinks, increasing collagen interconnectivity, fibril stability, and mechanical integrity of the entire tendon [5].  The excessive amount of glucose in diabetic conditions glycosylates the same lysine residues that serve as substrates for lysyl oxidase [6-8] (shown on the right side of Fig. 4), which, in turn, inhibits the normal maturation of collagen. This biochemical phenomenon, called glycosylation, hinders the normal enzymatic maturation mediated by lysyl oxidase, leading to non-healing ulcers [9]. Furthermore, this glucose also affects the extracellular matrix that supports the nerves and their endings, resulting in significant matrix structural alterations that render it unfit to support synapses [10]. By shedding light on the role of glycosylation in disrupting crucial wound healing pathways, this review calls for a holistic approach in diabetic ulcer management, emphasizing the need for interventions targeting both vascular and molecular aspects of the condition.References:1. Gacheru, S.N., Trackman, P.C., Shah, M.A., O'Gara, C.Y., Spacciapoli, P., Greenaway, F.T. and Kagan, H.M., 1990. Structural and catalytic properties of copper in lysyl oxidase. Journal of Biological Chemistry, 265(31), pp.19022-19027. 2. Chirinos, J.A. ed., 2022. Textbook of Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease. Academic Press. 3. Vallet, S.D., Guéroult, M., Belloy, N., Dauchez, M. and Ricard-Blum, S., 2019. A three-dimensional model of human lysyl oxidase, a cross-linking enzyme. ACS omega, 4(5), pp.8495-8505. 4. Schilter, H., Findlay, A.D., Perryman, L., Yow, T.T., Moses, J., Zahoor, A., Turner, C.I., Deodhar, M., Foot, J.S., Zhou, W. and Greco, A., 2019. The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis. Journal of cellular and molecular medicine, 23(3), pp.1759-1770. 5. Snedeker, J.G. Gautieri, A., 2014. The role of collagen crosslinks in ageing and diabetes-the good, the bad, and the ugly. Muscles, ligaments and tendons journal, 4(3), p.303. 6. Li, W., Shen, S., Robertson, G.A., Khatami, M. and Rockey, J.H., 1984. Increased solubility of newly synthesized collagen in retinal capillary pericyte cultures by nonenzymatic glycosylation. Ophthalmic research, 16(6), pp.315-321. 7. Buckingham, B. and Reiser, K.M., 1990. Relationship between the content of lysyl oxidase-dependent cross-links in skin collagen, nonenzymatic glycosylation, and long-term complications in type I diabetes mellitus. The Journal of clinical investigation, 86(4), pp.1046-1054. 8. Shin, A., Vazmitsel, Y., Connolly, S. and Kabytaev, K., 2022. Comprehensive profiling and kinetic studies of glycated lysine residues in human serum albumin. Analytical and Bioanalytical Chemistry, 414(17), pp.4861-4875. 9. Burgess, J.L., Wyant, W.A., Abdo Abujamra, B., Kirsner, R.S. and Jozic, I., 2021. Diabetic wound- healing science. Medicina, 57(10), p.1072. 10. Huang, Y. and Kyriakides, T.R., 2020. The role of extracellular matrix in the pathophysiology of diabetic wounds. Matrix biology plus, 6, p.100037.