Risk assessment of the development of diabetic complications

Mattias Gäreskog and Jeanette Nikus

Mercodia AB, Sylveniusgatan 8A, SE-754 50 Uppsala, Sweden

Mercodia AB June 2007

Diabetes has become an epidemic that affects 246 million people worldwide and is expected to af-fect 380 million by 2025. Together with the in-creasing outbreaks of diabetes more people suffer from diabetic complications. These complications are the major cause of morbidity and mortality in persons with diabetes. Intervention studies have focused predominantly on glucose and blood pres-sure control and since the introduction of insulin the situation has dramatically improved for per-sons with diabetes. However, there are still mas-sive problems left to solve. The chronic complica-tions of diabetes are predominantly vascular and have impact throughout the body. Several sugges-tions have emerged trying to explain the origin of diabetic complications in order to find a treatment. In a publication in Nature Dr. Brownlee suggested a unifying mechanism based on an overproduc-tion of superoxide from the mitochondria leading to disturbance in several pathways and in the pro-longing, complications. This oxidative stress may be one of the reasons for increased amounts of oxi-dized LDL in diabetic patients.Oxidation of LDL is central to current theories of atherosclerosis, and is implicated in renal damage and diabetic retinopathy. Mercodia Oxidized LDL ELISA assays have been used in several studies as a prognostic marker of developing atherosclerosis and could be a useful tool in the risk assessment of the development of diabetic complications.

Diabetic patients seem to have prevalence for small, dense LDL particles. Small, dense LDL par-ticles are considered more atherogenic than larger LDL particles since they pass more easily into the intima and have a greater capacity to bind to pro-teoglycans in the vessel walls were the oxidative modifications of the LDL particles take place.Mercodia Oxidized LDL ELISA assays, based on the mouse monoclonal 4E6 developed by the pro-fessors Holvoet and Collen at the University of Leuven, Belgium, have in several studies shown to be a predictive marker for developing atherosclero-sis and subsequent events. By the use of Mercodia oxidized LDL assay Scheffer et al. (2003) studied the relationship of LDL size with circulating levels of oxidized LDL in type 2 diabetic patients. They found that the prevalence of small, dense LDL par-ticles in diabetic patients is associated with high circulating levels of oxidized LDL. These findings provide additional evidence for the role of small, dense LDL particles in the development of athero-sclerosis in diabetic patients. Kopprasch and colleagues (2002) studied circula-ting levels of oxidized LDL in subjects with im-paired glucose tolerance compared to control sub-jects with normal glucose tolerance. They found oxidized LDL levels to be significantly increased in subjects with impaired glucose tolerance compa-red to controls. Furthermore, in vitro oxidizability of LDL relative to healthy controls has been re-ported to be greater in diabetic subjects with poor glycaemic control (Tsai et al. 1994) and oxidation of LDL has been shown to be implicated in athe-rosclerosis followed by renal damage and diabetic retinopathy (Jenkins et al. 2004).

Diabetes and its complications are of multifactorial origin and treatment should be directed to meet this fact. Traditionally, great efforts have been made to control glucose and blood pressure with good effect. However, it has been proven not to be suf-ficient. Lately, clinical studies have shown that C-peptide administration in type 1 diabetic patients, who lack the peptide, results in amelioration of di-abetes-induced renal and nerve dysfunction (Wah-ren et al. 2007).Monitoring of oxidized LDL and further research on the biological activity of C-peptide would contri-bute to the understanding and treatment of diabetic complications.

Background Diabetes and lipoproteins Risk assessment of diabetic complications

The chronic complications of diabetes are predominantly vascular and are often divided into macro- and microvascular complications. Microvascular complications often affect the eye, kidney and peripheral sensitivity leading to blindness, end-stage renal disease and leg wounds. Macrovascular complications affect the heart and great arteries leading to stroke and heart failure. The cause of these complications are not fully understood although it seems that they are closely associated with the high blood glucose levels of diabetic patients. High blood glucose may enhance the development of vascular complications by contributing to elevated blood pressure, al-ternation of proteins by glucosylation or by stimulating the production of reactive oxygen species. In addition, diabetic patients seem to have predominance for small, dense LDL particles. Small, dense LDL particles pass more easily into the vessel walls where they may be subjected to oxidative modifications. High blood pressure and the LDL particle size may be an explanation for the elevated levels of oxidized LDL found in diabetic patients compared to healthy controls. Oxidized LDL has in contrast to native LDL been found to be atherogenic and directly involved in the initiation and progression of atherosclerosis.

References

Brownlee M (2001) Biochemistry and Molecular Cell Bio-logy of Diabetic Complications. Nature 414:813-820Holvoet P, Vanhaecke J, Janssens S, Van de Werf F and Collen D (1998) Oxidized LDL and Malondialdehyde-Mo-dified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease. Circulation 98: 1487-1494Jenkins AJ, Rowley KG, Lyons TJ, Best JD, Hill MA and Klein RL (2004) Lipoproteins and Diabetic Microvacular Complications. Curr Pharm Des 10:3395-3418Kopprasch S, Pietzsch J, Kuhlisch E, Fuecker K, Temel-kova-Kurktschiev T, Hanefeld M, Kuhne H, Julius U and Graessler J (2002) In Vivo Evidence for Increased Oxida-tion of Circulating LDL in Impaired Glucose Tolerance. Diabetes 51:3102-3106Scheffer PG, Bos G, Volwater HG, Dekker JM, Heine RJ and Teerlink T (2003) Association of LDL Size with In Vi-tro Oxidizability and Plasma Levels of In Vivo Oxidized LDL in Type 2 Diabetic Patients. Diabetic Med 20:563-567Tsai EC, Hirsch IB, Brunzell JD and Chait A (1994) Re-duced Plasma Peroxyl Radical Trapping Capacity and In-creased Susceptibility of LDL to Oxidation in Poorly Con-trolled IDDM. Diabetes 43:1010-1014Wahren J, Ekberg K and Jornvall H (2007) C-peptide is a Bioactive Peptide. Diabetologia 50:503-509

DIAB ETES

With diabetes come complications like nephropathy, retinopathy and neuropathy.