The etiology of diabetic complications has been a major focus of diabetes research. Hyperglycemia is considered the primary cause of the development of diabetic complications. Research in the last 10 years has focused on two theories, non-enzymatic glycation and sorbitol accumulation /myoinositol depletion as the main abnormalities responsible for the pathology of diabetes. However, it is likely that other conditions also exist in the diabetic milieu that may contribute to the pathology. An overlooked condition that exists in the diabetic milieu which may have a major influence on the development of diabetic complications is the accumulation of L-fucose. L-Fucose is a monosaccharide that is produced from glucose and accumulates in both a protein bound form and free in serum of diabetic patients. The goal of this project is to determine the influence L-fucose has on the development of diabetic complications. L-Fucose is the only levorotatory monosaccharide synthesized and utilized by mammalian tissues. Our studies have shown that L-fucose is a potent inhibitor of myo-inositol transport and a glycating agent. Both activities could induce or enhance the development of diabetic complications. The studies presented in this proposal will evaluate the contribution L-fucose makes to diabetic pathology. In the first specific aim the uptake and utilization of L-fucose by neural and endothelial cells will be examined. These studies will include analysis of properties influencing glycation and synthesis of glycolipids and glycoproteins containing L-fucose. In addition, the serum levels of protein-bound and free L-fucose in diabetic patients and animal models will be determined. In the second specific aim the influence of L-fucose on the development of diabetic complications will be addressed. For these studies animal models and cell culture systems will be used. Analysis of the effect of L-fucose on myo-inositol metabolism and phosphatidylinositol signal transduction pathways will be conducted. In addition, the influence of L-fucose on endothelial cell proliferation, basement membrane synthesis and cellular properties will be determined. Laboratory rats will be fed a diet supplemented with L-fucose to determine if rats develop neurological or connective tissue defects similar to diabetic rats. We will also test whether the effects of L-fucose on cultured cells and animal models are reversible or blocked by myo-inositol supplementation or aminoguanidine treatment. The studies outlined in this proposal will answer two important questions. First, myo-inositol depletion in rats induced by an L-fucose diet will provide valuable evidence about whether altered myo-inositol metabolism is responsible for pathological conditions in diabetes. Second, these studies will show whether L-fucose accumulation itself contributes to diabetic pathology.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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University of Iowa
Schools of Medicine
Iowa City
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Yorek, M A; Dunlap, J A; Lowe Jr, W L (2000) Wortmannin and LY294002 inhibit myo-inositol accumulation by cultured bovine aorta endothelial cells and murine 3T3-L1 adipocytes. Biochim Biophys Acta 1497:328-40
Yorek, M A; Dunlap, J A; Liu, W et al. (2000) Normalization of hyperosmotic-induced inositol uptake by renal and endothelial cells is regulated by NF-kappaB. Am J Physiol Cell Physiol 278:C1011-8
Yorek, M A; Dunlap, J A; Lowe Jr, W L (1999) Osmotic regulation of the Na+/myo-inositol cotransporter and postinduction normalization. Kidney Int 55:215-24
Yorek, M A; Dunlap, J A; Thomas, M J et al. (1998) Effect of TNF-alpha on SMIT mRNA levels and myo-inositol accumulation in cultured endothelial cells. Am J Physiol 274:C58-71
Yorek, M A; Wiese, T J; Davidson, E P et al. (1996) Reduced Na+/K+ adenosine triphosphatase activity and motor nerve conduction velocity in L-fucose-fed rats is reversible after dietary normalization. Metabolism 45:229-34
Wiese, T J; Dunlap, J A; Conner, C E et al. (1996) Osmotic regulation of Na-myo-inositol cotransporter mRNA level and activity in endothelial and neural cells. Am J Physiol 270:C990-7
Wiese, T J; Matsushita, K; Lowe Jr, W L et al. (1996) Localization and regulation of renal Na+/myo-inositol cotransporter in diabetic rats. Kidney Int 50:1202-11
Yorek, M A; Conner, C E; Spanheimer, R G (1995) L-fucose reduces collagen and noncollagen protein production in cultured cerebral microvessel endothelial cells. J Cell Physiol 165:658-66
Wachtel, R E; Kraske, S A; Yorek, M A (1995) Sodium channels in cultured neuroblastoma cells grown in high glucose or L-fucose. J Membr Biol 145:187-92
Yorek, M A; Dunlap, J A; Stefani, M R et al. (1994) Reduced Na+/K+ ATPase transport activity, resting membrane potential, and bradykinin-stimulated phosphatidylinositol synthesis by polyol accumulation in cultured neuroblastoma cells. Neurochem Res 19:321-30

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