ANNUAL REVIEWS
Further
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Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
Copyright 1975. All rights reserved
HYPERGLYCEMIA,POLYOL
.7170
METABOLISM, AND
COMPLICATIONS OF DIABETES MELLITUS
Kenneth H. Gabbay, MD. 1
Department of Pediatrics. Children's Hospital Medical Center and Harvard Medical School, Boston. Massachusetts 02115
INTRODUCTION The discovery of insulin and its therapeutic use in diabetes has changed the natural history of this disease. Today, the longevity afforded the patient by insulin is asso ciated with the indiscriminate and sometimes crippling long term development of retinopathy, neuropathy, nephropathy, cataracts, and generalized atherosclerosis
(1, 2). It is becoming increasingly apparent that these manifestations of diabetes are an intrinsic part of basic and as yet unknown disease processes which affect the whole organism. The processes leading to the chronic damage in diabetes may be related to subtle alterations in intracellular glucose metabolism in diabetic cells, with or without attendant hyperglycemia. The tissues bearing the brunt of diabetic mani festations (lens, nerve, retina, kidney, blood vessels, and islet cells) are freely perme able to glucose and do not require insulin for glucose penetration
as
do muscle and
adipose tissues, and hence are exposed to the ambient blood glucose levels. The relationship of the blood sugar control to the long term development of diabetic manifestations is problematic. There is definite evidence of a beneficial effect of "good" control of blood glucose in reducing the incidence of infections and diabetic ketoacidosis
(3, 4), as well as evidence of a short term beneficial
effect on some other
diabetic manifestations (5). However, a consensus on a convincing long term benefi cial relationship to the prevention of diabetic complications is still lacking, a situa tion which may well be due to our inability to. achieve optimal blood glucose control with current therapeutic regimens (6).
'Supported by U.S. Public Health Service Grant #AM-15019, a grant from the National Foundation-March of Dimes. and an Established Investigatorship of the American Heart Association. 521
522
GABBAY
Recent investigations of accessory pathways of glucose metabolism in tissues indicate a role for some pathways in the formation of some diabetic complications. This chapter will review current knowledge of the sorbitol pathway and its possible significance in diabetes and galactosemia. THE SORBITOL PATHWAY
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
General
In 1924 Orr described the presence of fructose in human fetal blood (7). Hubbard & Russell (8) reported the finding of free fructose in human cerebrospinal fluid. Mann (9) subsequently characterized the main sugar of seminal fluid as fructose and demonstrated in rabbits that fructose is derived from blood glucose and is responsive to fluctuations of the latter in diabetes with and without insulin therapy (10). He further showed (11) that seminal fluid fructose content is directly influenced by hormonal factors, virtually disappearing in castrated and hypophysectomized ani mals. Hers (12) later demonstrated that seminal fructose is formed in the seminal vesicles from blood glucose, primarily through the activity of the "sorbitol path way." This pathway consists of two enzymes that are able to convert glucose to fructose via the intermediate step of sorbitol.
D-Glucose + NADPH + H+
Aldose . ' Sorbitol + NADP+ Reductase
OehSorbitol D-Fructose + NADH + H+ ydrogenase
. Sorbitol + NAD+
•
Later work by Hers (13) showed that the pathway is responsible for the formation of sorbitol in sheep placenta, and further conversion to fructose by the fetal liver. Fructose is the main fetal blood sugar in sheep, disappearing within hours after the separation of the fetus from the placenta (14). Aldose reductase catalyzes the conversion of free glucose to its sugar alcohol sorbitol. It possesses broad substrate specificity for many aldoses, and is characterized by low affinity for glucose and galactose (15-21). The low affinity for hexoses, and the availability of excess amounts of free hexoses in diabetes and galactosemia cause increased formation of the sugar alcohols sorbitol and galactitol respectively. Aldose reductase requires NADPH for its activity, and since NADPH is provided in the cell primarily by the action of the hexose monophos phate shunt (HMP shunt), a relationship between the HMP shunt and the sorbitol pathway has been described in lens and peripheral nerve (22, 23). In vitro, aldose reductase activity is enhanced in the presence of mercaptoethanol and stimulated by lithium sulfate. The enzyme displays allosteric properties and exists in an equilib rium between an active form and two inactive subunits (24). The coenzyme product of its reaction, NADP+, inhibits the enzyme at physiological concentrations by altering the equilibrium in favor of the inactive subunits. The reaction catalyzed by
ALDOSE REDUCTASE
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
SORBITAL PATHWAY IN DIABETES
523
aldose reductase is virtually unidirectional, the equilibrium favoring the forward reaction. An enzyme of the glucuronic acid-xylulose shunt, NADP-L-hexonate dehydroge nase, which has many similarities to aldose reductase, is also present in many tissues. Hexonate dehydrogenase (16-19, 25, 26) has a poor ability to convert hexoses to their respective sugar alcohols (Km 0.5-2 M), and is most active in the reduction of uronic acids. Since this enzyme is present in many tissues, care must be taken to differentiate between it and aldose reductase. The two enzymes may be differen tiated by different mobilities on DEAE-cellulose column chromatography, reac tivity with glucuronate and glyceraldehyde as substrates (a ratio 3.5 gs/24 hr) which occurs randomly without correlation to the amount of glycosuria. However, the urine of uncontrolled streptozotocin diabetic rats contained only sorbitol. Because of the close relationship between fructose, sorbitol, and mannitol,. and dietary differences between rats and humans, fructose was administered orally to human volunteers and rats with resultant urinary excre tion of mannitol in both species. Further studies of the aldose reductase enzyme from both human and rat tissues demonstrated a previously unsuspected capacity (Km 25 mM) to reduce fructose to a mixture of sorbitol and mannitol with both NADH and NADPH as coenzymes. Treatment of normal rats with AY-22, 284 resulted in a significant reduction in mannitol excretion following an oral fructose dose. Presently, it is thought that a portion of the orally ingested fructose is con verted to a mixture of mannitol and sorbitol, with recycling of.the sorbitol back to fructose via the sorbitol dehydrogenase enzyme (Km for sorbitol is 0.5 mM and for mannitol 50-100 mM), followed by excretion of the mannitol into the urine. It is postulated that the major site of mannitol formation may be the liver. SUMMARY
This brief review of the sorbitol pathway has attempted to present our current knowledge of the possible role of this accessory pathway of glucose metabolism in the development of some diabetic complications. Clearly hyperglycemia in the diabetic patient is an important factor controlling the activity of the sorbitol path way. Hyperglycemia in both diabetic patients and experimental animals results in significant accumulations of the products of this pathway in some tissues, and these accumulations have been demonstrated to play an important role in some of these diabetic manifestations. The development of inhibitors of the aldose reductase en zyme affords new means for preventing and treating some of these complications. Nevertheless, we are still hampered by the lack of knowledge of the normal role of this pathway in tissue metabolism. Many technical problems still exist concerning sensitive and specinc assays for the products of the sorbitol pathway in tissue studies, as well as with valid techniques for the measurement of the activity of this pathway in clinical sjtuations. It is hoped that clinical studies with aldose reductase inhibo tors in the future will further clarify the importance of this accessory pathway of glucose metabolism in diabetes.
SORBITAL PATHWAY IN DIABETES
535
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
Literature Cited
I. United States Department of Health, Education, and Welfare, Public Health Service, Division of Chronic Diseases. 1964. Diabetes Source Book. Washing ton, DC: Public Health Service (Pub!. No. 1168) 2. Pirart, J. 1965. Diabetes 14:1-9 3. Knowles, H. C., Guest, G. M., Lampe, J., Kissler, M., Skillman, T. G. 1965. Diabetes 14:239-73 4. Marble, A. 1967. Diabetes 16:825 5. Gregersen, G. 1968. Diabetologia 4: 273-77 6. Albisser, A. M. et al 1974. Diabetes 23:397 7. Orr, A. P. 1924. Biochem. J. 18:171-72 8. Hubbard, R. S., Russell, N. M. 1937. J. Biol Chem. 119:647-61 9. Mann, T. 1946. Biochem. J. 40:481-91 10. Mann, T., Parsons, U. 1950. Biochem. J. 46:440-50 II. Mann, T. 1964. Biochemistry of Semen and of the Male Reproductive Tract.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
New York: Wiley Hers, H. G. 1956. Biochim. Biophys. Acta 22:202-3 Hers, H. G. 1960. Biochim. Biophys. Acta 37:137 Hugget, A. St. G., Warren, F. L., War ren, N. V. 1951. J. Physiol 113:258 Hayman, S., Kinoshita, J. H. 1965. J. Bioi. Chem. 240:877 Moonsammy, G. I., Stewart, M. A. 1967. J. Neurochem. 14:118-93 Gabbay, K. H., Tze, W. J. 1972. Proc. Nat. Acad. Sci. USA 69:1435-39 Gabbay, K. H. 1972. Isr. J. Med. Sci. 8:1626-29 . Gabbay, K. H., Cathcart, E. S. 1974. Diabetes 23:460-68 Clements, R. S. Jr., Weaver, J. P., Winegrad, A. I. 1969. Biochem. Bio phys. Res. Commun. 37:347 Clements, R. S., Winegrad, A. I. 1972. Biochem.
22. 23. 24. 25. 26.
Biophys.
Res.
Commun.
47:1473-80 Kinoshita, J. H., Futterman, S., Satoh, K., Merola, L. O. 1963. Biochim. Bio phys. Acta 74:340-50 Gabby, K. H. 1969. Diabetes (Suppl.l) 18:336-37 Jedziniak, J. A., Kinoshita, J. H. 1971. Invest. Ophthalmol. 10:357-66 Mano, Y., Suzuki, K., Yamata, K., Schimazono, N. 1961. J. Biochem. 49:618 Beutler, E., Guinto, E. 1974. J. Clin. Invest. 53: 1258-64
27. Blakely, R. L. 1951. Biochem. J. 49:257-71 28. McCorkindale, J., Edson, N. L. 1954. Biochem. J. 57:518 29. Smith, M. G. 1962. Biochem. J. 83:135-44 30. Jedziniak, J. A., Yates, E. M., Kino shita, J. H. 1973. Exp. Eye Res. 99-104 31. Gabbay, K. H. Unpublislied 32. Mills, N. C., Means, A. R. 1972. Endo crinology 91:147-56 33. Gabbay, K. H. 1974. Clin. Res. 22: 468A 34. Kinoshita, J. H. 1965. Invest. Ophthal mol 4:786-99 35. Gabbay, K. H., O'Sullivan, J. B. 1968. Diabetes 17:239-43 36. Gabbay, K. H., O'Sullivan, J. B. 1968. Diabetes 17:300 37. Kinoshita, J. H., Dvomik, D., Kram1, M., Gabbay, K. H. 1968. Biochim. Bio phys. Acta 158:472-75 38. Dvornik, D. et al 1973. Science 182: 1146-48 39. LeFevre, P. G., Davies, R. I. 1951. J. Gen. Physiol. 34:515 40. Wick, A. N., Drury, D. R. 1951. Am. J. Physiol 166:421-23 41. DaCosta, J. M. 1890. Medical Diagno sis. Philadelphia: Lippincott. 7th ed. 42. Duke-Elder, W. S. 1925. Brit. J. Oph thalmol 9:167-87 43. Van Heyningen, R. 1959. Nature (Lon don) 184:194-95 44. Kinoshita, J. H., Merola, L. 0., Satoh, K., Dikmak, E. 1962. Nature (London) 194:1085 45. Kinoshita, J. H., Merola, L. 0., Dik mak, E. 1962. Exp. Eye Res. 1:405 46. Kinoshita, J. H., Merola, L. O. and Dikmak, .E. 1962. Biochim. Biophys. Acta 62:176 47. Hayman, S., Lou, M. F., Merola, L. 0., Kinoshita, J. H. 1966. Biochim. Bio phys. Acta 128:474 48. Lou, M. F., Kinoshita, J. H. 1967. Bio chim. Biophys. Acta 141:547 49. Chylack, L. T. Jr., Kinoshita, J. H. 1969. Invest. Ophthalmol 8:401-12 50. Gabbay, K. H., Kinoshita, J. H. 1972. Isr. J. Med. Sci. 8:1557-61 51. Stewart, M. A., Passoneau, J. V. 1964. Biochem.
Biophys.
Res.
Commun.
17:536 52. Gabbay, H. K., Merola, L. 0., Field, R. A. 1966. Science 151:209-10 53. Stewart, M. A., Sherman, W. R., An thony, S. 1966. Biochem. Biophys. Res. Commun. 22:488
536
1967. J. Neuro chem. 14:1057-66 55. Ward, J. D. 1972. Diabetes 21:1173-78 56. Stewart, M. A., Passonneau, J. V., Lowry, O. H. +965. 1. Neurochem. 12:719-27 57. Abercrombie, M., Johnson, M. L. 1946. J. Anat. 80:42 58. Thomas, P. K., Lascelles, R. G. 1965. Lancet 1:1355-57 59. Ward, J. D., Barnes, e. G., Fisher, D. J., Jessop, J. D., Baker, R. W. R. 1971. Lancet 1:428 60. Gabbay, K. H. 1972. Vascular and Neurological Changes in Early Diabetes. 54.
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
GABBAY
61.
Stewart, M. A. et al
ed. R. A. Camerini-Davalos, H. S. Cole, 417-24. New York: Academic Gabbay, K. H., Snider, 1. J. 1972. Dia betes 21:295-300
62.
63.
Gabbay, K. H. 1974. Sugars in Nutri tion (monograph), ed. H. L. Sipple, K. W. McNutt, 470--80. New York: Aca demic Greene, D. A., deJesus, P. V., Wine grad, A. I. 1974. Diabetes (Suppl.l)
70. 71. 72. 73.
75.
78.
79.
66.
Wray, H. L., Winegrad, A. I.
68. 69.
Pitkanen,' E., Servo, C. Chim. Acta 44:437-44
1973.
Clin.
Spinowitz, B. S., Altszu1er, N. A. 1973. Diabetes 22:820--24
Clements, R. S. Jr., Prockop, L. D., Winegrad, A. I. 1968. Lancet 2:384-86
Arieff, A. I., Carroll, H. J. 1974.
Dia
Assai, J. P., Aoki, T. T., Manzano, F. M., Kozak, G. P. 1974. Diabetes Schofield, P. J., Hutton, J. C., Williams, J. F. 1974. IRCS 2:1465 Morrison, A. D., Winegrad, A. I., Fink, e. J., Lacy, P. E. 1970. Biochem. Bio Corkey, B., Mayhew, D. Unpublished Malaisse, W. J., Sener, A. 1974. Dia betes (Suppl.l) 23:378 Morrison, A. D., Clements, R. S. Jr., Travis, S. B., Oski, F., Winegrad, A. I. 1970. Biochem. Biophys. Res. Commun. 40:1,199
81.
67.
Arch. Neurol.
phys. Res. Commun. 38:3, 491
76. 77.
65.
Diabetologia 2:82-85
1971.
23:405-11 74.
80.
1966.
Prockop, L. D. betes 23:525-31
23:357
Sci. 21:237
1971. Lancet
25:126-40
Clements, R. S. Jr., deJesus, P. V. Jr., Winegrad, A. 1. 1973. Lancet 1:1137-41 deJesus, P. V. Jr. et al 1974. 1. Neurol.
64.
Clements, R. S. Jr. et al 2:671-75
Travis, S. F., Morrison, A. D., Clem ents, R. S. Jr., Winegrad, A. I., Oski, F. A. 1971. J. Clin. Invest. 50:2104--12 Clements, R. S. Jr., Morrison, A. D., Winegrad, A. I. 1969. Science 166:1007 Morrison, A. D., Clements, R. S., Winegrad, A. I. 1972. J Clin. Invest. 51:3114-23
82.
Kuck, J. F. R. Jr., Crosswell, H. H. Ir.
1974. Ophthalmol. Res. 6:189-96 83. Aloia, J. F. 1973. J Lab. Clin. Med. 82:5 84. Pitkanen, E. 1972. Clin. Chim. Acta 38:221-30 85. Blau, K. 1972. Clin. Chim. Acta 38:441-47
Further
Quick links to online content
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
Copyright 1975. All rights reserved
HYPERGLYCEMIA,POLYOL
.7170
METABOLISM, AND
COMPLICATIONS OF DIABETES MELLITUS
Kenneth H. Gabbay, MD. 1
Department of Pediatrics. Children's Hospital Medical Center and Harvard Medical School, Boston. Massachusetts 02115
INTRODUCTION The discovery of insulin and its therapeutic use in diabetes has changed the natural history of this disease. Today, the longevity afforded the patient by insulin is asso ciated with the indiscriminate and sometimes crippling long term development of retinopathy, neuropathy, nephropathy, cataracts, and generalized atherosclerosis
(1, 2). It is becoming increasingly apparent that these manifestations of diabetes are an intrinsic part of basic and as yet unknown disease processes which affect the whole organism. The processes leading to the chronic damage in diabetes may be related to subtle alterations in intracellular glucose metabolism in diabetic cells, with or without attendant hyperglycemia. The tissues bearing the brunt of diabetic mani festations (lens, nerve, retina, kidney, blood vessels, and islet cells) are freely perme able to glucose and do not require insulin for glucose penetration
as
do muscle and
adipose tissues, and hence are exposed to the ambient blood glucose levels. The relationship of the blood sugar control to the long term development of diabetic manifestations is problematic. There is definite evidence of a beneficial effect of "good" control of blood glucose in reducing the incidence of infections and diabetic ketoacidosis
(3, 4), as well as evidence of a short term beneficial
effect on some other
diabetic manifestations (5). However, a consensus on a convincing long term benefi cial relationship to the prevention of diabetic complications is still lacking, a situa tion which may well be due to our inability to. achieve optimal blood glucose control with current therapeutic regimens (6).
'Supported by U.S. Public Health Service Grant #AM-15019, a grant from the National Foundation-March of Dimes. and an Established Investigatorship of the American Heart Association. 521
522
GABBAY
Recent investigations of accessory pathways of glucose metabolism in tissues indicate a role for some pathways in the formation of some diabetic complications. This chapter will review current knowledge of the sorbitol pathway and its possible significance in diabetes and galactosemia. THE SORBITOL PATHWAY
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
General
In 1924 Orr described the presence of fructose in human fetal blood (7). Hubbard & Russell (8) reported the finding of free fructose in human cerebrospinal fluid. Mann (9) subsequently characterized the main sugar of seminal fluid as fructose and demonstrated in rabbits that fructose is derived from blood glucose and is responsive to fluctuations of the latter in diabetes with and without insulin therapy (10). He further showed (11) that seminal fluid fructose content is directly influenced by hormonal factors, virtually disappearing in castrated and hypophysectomized ani mals. Hers (12) later demonstrated that seminal fructose is formed in the seminal vesicles from blood glucose, primarily through the activity of the "sorbitol path way." This pathway consists of two enzymes that are able to convert glucose to fructose via the intermediate step of sorbitol.
D-Glucose + NADPH + H+
Aldose . ' Sorbitol + NADP+ Reductase
OehSorbitol D-Fructose + NADH + H+ ydrogenase
. Sorbitol + NAD+
•
Later work by Hers (13) showed that the pathway is responsible for the formation of sorbitol in sheep placenta, and further conversion to fructose by the fetal liver. Fructose is the main fetal blood sugar in sheep, disappearing within hours after the separation of the fetus from the placenta (14). Aldose reductase catalyzes the conversion of free glucose to its sugar alcohol sorbitol. It possesses broad substrate specificity for many aldoses, and is characterized by low affinity for glucose and galactose (15-21). The low affinity for hexoses, and the availability of excess amounts of free hexoses in diabetes and galactosemia cause increased formation of the sugar alcohols sorbitol and galactitol respectively. Aldose reductase requires NADPH for its activity, and since NADPH is provided in the cell primarily by the action of the hexose monophos phate shunt (HMP shunt), a relationship between the HMP shunt and the sorbitol pathway has been described in lens and peripheral nerve (22, 23). In vitro, aldose reductase activity is enhanced in the presence of mercaptoethanol and stimulated by lithium sulfate. The enzyme displays allosteric properties and exists in an equilib rium between an active form and two inactive subunits (24). The coenzyme product of its reaction, NADP+, inhibits the enzyme at physiological concentrations by altering the equilibrium in favor of the inactive subunits. The reaction catalyzed by
ALDOSE REDUCTASE
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
SORBITAL PATHWAY IN DIABETES
523
aldose reductase is virtually unidirectional, the equilibrium favoring the forward reaction. An enzyme of the glucuronic acid-xylulose shunt, NADP-L-hexonate dehydroge nase, which has many similarities to aldose reductase, is also present in many tissues. Hexonate dehydrogenase (16-19, 25, 26) has a poor ability to convert hexoses to their respective sugar alcohols (Km 0.5-2 M), and is most active in the reduction of uronic acids. Since this enzyme is present in many tissues, care must be taken to differentiate between it and aldose reductase. The two enzymes may be differen tiated by different mobilities on DEAE-cellulose column chromatography, reac tivity with glucuronate and glyceraldehyde as substrates (a ratio 3.5 gs/24 hr) which occurs randomly without correlation to the amount of glycosuria. However, the urine of uncontrolled streptozotocin diabetic rats contained only sorbitol. Because of the close relationship between fructose, sorbitol, and mannitol,. and dietary differences between rats and humans, fructose was administered orally to human volunteers and rats with resultant urinary excre tion of mannitol in both species. Further studies of the aldose reductase enzyme from both human and rat tissues demonstrated a previously unsuspected capacity (Km 25 mM) to reduce fructose to a mixture of sorbitol and mannitol with both NADH and NADPH as coenzymes. Treatment of normal rats with AY-22, 284 resulted in a significant reduction in mannitol excretion following an oral fructose dose. Presently, it is thought that a portion of the orally ingested fructose is con verted to a mixture of mannitol and sorbitol, with recycling of.the sorbitol back to fructose via the sorbitol dehydrogenase enzyme (Km for sorbitol is 0.5 mM and for mannitol 50-100 mM), followed by excretion of the mannitol into the urine. It is postulated that the major site of mannitol formation may be the liver. SUMMARY
This brief review of the sorbitol pathway has attempted to present our current knowledge of the possible role of this accessory pathway of glucose metabolism in the development of some diabetic complications. Clearly hyperglycemia in the diabetic patient is an important factor controlling the activity of the sorbitol path way. Hyperglycemia in both diabetic patients and experimental animals results in significant accumulations of the products of this pathway in some tissues, and these accumulations have been demonstrated to play an important role in some of these diabetic manifestations. The development of inhibitors of the aldose reductase en zyme affords new means for preventing and treating some of these complications. Nevertheless, we are still hampered by the lack of knowledge of the normal role of this pathway in tissue metabolism. Many technical problems still exist concerning sensitive and specinc assays for the products of the sorbitol pathway in tissue studies, as well as with valid techniques for the measurement of the activity of this pathway in clinical sjtuations. It is hoped that clinical studies with aldose reductase inhibo tors in the future will further clarify the importance of this accessory pathway of glucose metabolism in diabetes.
SORBITAL PATHWAY IN DIABETES
535
Annu. Rev. Med. 1975.26:521-536. Downloaded from www.annualreviews.org by NORTH CAROLINA STATE UNIVERSITY on 10/04/12. For personal use only.
Literature Cited
I. United States Department of Health, Education, and Welfare, Public Health Service, Division of Chronic Diseases. 1964. Diabetes Source Book. Washing ton, DC: Public Health Service (Pub!. No. 1168) 2. Pirart, J. 1965. Diabetes 14:1-9 3. Knowles, H. C., Guest, G. M., Lampe, J., Kissler, M., Skillman, T. G. 1965. Diabetes 14:239-73 4. Marble, A. 1967. Diabetes 16:825 5. Gregersen, G. 1968. Diabetologia 4: 273-77 6. Albisser, A. M. et al 1974. Diabetes 23:397 7. Orr, A. P. 1924. Biochem. J. 18:171-72 8. Hubbard, R. S., Russell, N. M. 1937. J. Biol Chem. 119:647-61 9. Mann, T. 1946. Biochem. J. 40:481-91 10. Mann, T., Parsons, U. 1950. Biochem. J. 46:440-50 II. Mann, T. 1964. Biochemistry of Semen and of the Male Reproductive Tract.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
New York: Wiley Hers, H. G. 1956. Biochim. Biophys. Acta 22:202-3 Hers, H. G. 1960. Biochim. Biophys. Acta 37:137 Hugget, A. St. G., Warren, F. L., War ren, N. V. 1951. J. Physiol 113:258 Hayman, S., Kinoshita, J. H. 1965. J. Bioi. Chem. 240:877 Moonsammy, G. I., Stewart, M. A. 1967. J. Neurochem. 14:118-93 Gabbay, K. H., Tze, W. J. 1972. Proc. Nat. Acad. Sci. USA 69:1435-39 Gabbay, K. H. 1972. Isr. J. Med. Sci. 8:1626-29 . Gabbay, K. H., Cathcart, E. S. 1974. Diabetes 23:460-68 Clements, R. S. Jr., Weaver, J. P., Winegrad, A. I. 1969. Biochem. Bio phys. Res. Commun. 37:347 Clements, R. S., Winegrad, A. I. 1972. Biochem.
22. 23. 24. 25. 26.
Biophys.
Res.
Commun.
47:1473-80 Kinoshita, J. H., Futterman, S., Satoh, K., Merola, L. O. 1963. Biochim. Bio phys. Acta 74:340-50 Gabby, K. H. 1969. Diabetes (Suppl.l) 18:336-37 Jedziniak, J. A., Kinoshita, J. H. 1971. Invest. Ophthalmol. 10:357-66 Mano, Y., Suzuki, K., Yamata, K., Schimazono, N. 1961. J. Biochem. 49:618 Beutler, E., Guinto, E. 1974. J. Clin. Invest. 53: 1258-64
27. Blakely, R. L. 1951. Biochem. J. 49:257-71 28. McCorkindale, J., Edson, N. L. 1954. Biochem. J. 57:518 29. Smith, M. G. 1962. Biochem. J. 83:135-44 30. Jedziniak, J. A., Yates, E. M., Kino shita, J. H. 1973. Exp. Eye Res. 99-104 31. Gabbay, K. H. Unpublislied 32. Mills, N. C., Means, A. R. 1972. Endo crinology 91:147-56 33. Gabbay, K. H. 1974. Clin. Res. 22: 468A 34. Kinoshita, J. H. 1965. Invest. Ophthal mol 4:786-99 35. Gabbay, K. H., O'Sullivan, J. B. 1968. Diabetes 17:239-43 36. Gabbay, K. H., O'Sullivan, J. B. 1968. Diabetes 17:300 37. Kinoshita, J. H., Dvomik, D., Kram1, M., Gabbay, K. H. 1968. Biochim. Bio phys. Acta 158:472-75 38. Dvornik, D. et al 1973. Science 182: 1146-48 39. LeFevre, P. G., Davies, R. I. 1951. J. Gen. Physiol. 34:515 40. Wick, A. N., Drury, D. R. 1951. Am. J. Physiol 166:421-23 41. DaCosta, J. M. 1890. Medical Diagno sis. Philadelphia: Lippincott. 7th ed. 42. Duke-Elder, W. S. 1925. Brit. J. Oph thalmol 9:167-87 43. Van Heyningen, R. 1959. Nature (Lon don) 184:194-95 44. Kinoshita, J. H., Merola, L. 0., Satoh, K., Dikmak, E. 1962. Nature (London) 194:1085 45. Kinoshita, J. H., Merola, L. 0., Dik mak, E. 1962. Exp. Eye Res. 1:405 46. Kinoshita, J. H., Merola, L. O. and Dikmak, .E. 1962. Biochim. Biophys. Acta 62:176 47. Hayman, S., Lou, M. F., Merola, L. 0., Kinoshita, J. H. 1966. Biochim. Bio phys. Acta 128:474 48. Lou, M. F., Kinoshita, J. H. 1967. Bio chim. Biophys. Acta 141:547 49. Chylack, L. T. Jr., Kinoshita, J. H. 1969. Invest. Ophthalmol 8:401-12 50. Gabbay, K. H., Kinoshita, J. H. 1972. Isr. J. Med. Sci. 8:1557-61 51. Stewart, M. A., Passoneau, J. V. 1964. Biochem.
Biophys.
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