Diabetic complications from hyperglycemia affect the health of both type 1 and type 2 diabetics. There are several theories to explain the development of complications. The fact that inhibitors of aldose reductase prevent complications in experimental diabetes suggests a central role for this enzyme. The central hypothesis of this study is that aldose reductase is involved in the development of all diabetic complications and that the level of expression of aldose reductase is the determining factor in the development of complications. A second hypothesis is that human aldose reductase differs significantly from other aldose reductases and that animal aldose reductases are not good models for human aldose reductase. The objectives of this proposal are: 1) to develop an integrative model of diabetic complications that has a central role for aldose reductase and that accommodates the experimental evidence that supports current theories of complications; and 2) to conduct a detailed kinetic and chemical study of human aldose reductase with emphasis on the inhibitor binding site.
The Specific Aims of this proposal focus on human aldose reductase and include enzyme, chemical, cellular and tissue studies. These studies are designed to test the idea that the complication of diabetes result both from reactions involving glucose and from reactions involving acetol and methylglyoxal, which are derived from glucose. Glucose, methylglyoxal and acetol are substrates for aldose reductase. In addition, all of these compounds react nonenzymatically with proteins. The longterm goals are: 1) to establish an enzymological foundation to our understanding of human aldose reductase that will contribute to the development of new aldose reductase inhibitors; and 2) to develop a paradigm for predicting which diabetics will develop complications and will benefit from therapy with aldose reductase inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043238-02
Application #
3244585
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1992-09-30
Project End
1995-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Vander Jagt, D L; Torres, J E; Hunsaker, L A et al. (1997) Physiological substrates of human aldose and aldehyde reductases. Adv Exp Med Biol 414:491-7
Vander Jagt, D L; Hunsaker, L A; Vander Jagt, T J et al. (1997) Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes. Biochem Pharmacol 53:1133-40
Ratliff, D M; Vander Jagt, D J; Eaton, R P et al. (1996) Increased levels of methylglyoxal-metabolizing enzymes in mononuclear and polymorphonuclear cells from insulin-dependent diabetic patients with diabetic complications: aldose reductase, glyoxalase I, and glyoxalase II--a clinical research center study. J Clin Endocrinol Metab 81:488-92
Vander Jagt, D L; Kolb, N S; Vander Jagt, T J et al. (1995) Substrate specificity of human aldose reductase: identification of 4-hydroxynonenal as an endogenous substrate. Biochim Biophys Acta 1249:117-26
Kolb, N S; Hunsaker, L A; Vander Jagt, D L (1994) Aldose reductase-catalyzed reduction of acrolein: implications in cyclophosphamide toxicity. Mol Pharmacol 45:797-801
Griffey, R H; Sibbitt Jr, W L; Sibbitt, R R et al. (1994) Polyol and water accumulation in muscle of galactose-fed rats. Biochem Pharmacol 48:1839-41
Robinson, B; Hunsaker, L A; Stangebye, L A et al. (1993) Aldose and aldehyde reductases from human kidney cortex and medulla. Biochim Biophys Acta 1203:260-6
Vander Jagt, D L (1993) Glyoxalase II: molecular characteristics, kinetics and mechanism. Biochem Soc Trans 21:522-7
Vander Jagt, D L; Hunsaker, L A (1993) Substrate specificity of reduced and oxidized forms of human aldose reductase. Adv Exp Med Biol 328:279-88