Cerebral Taurine Transport Is Increased During Streptozocin-lnduced Diabetes in Rats HOWARD TRACHTMAN, STEPHEN FUTTERWEIT, AND JOHN A. STURMAN
Taurine is a cerebral osmolyte whose intracellular content changes in parallel with plasma osmolality. We conducted experiments to assess whether cerebral taurine transport is modified during chronic hyperglycemia. Rats with STZ-induced diabetes were studied after 1 wk of sustained hyperglycemia. Cerebral taurine uptake in synaptosomes (metabolically active nerve terminal vesicles) was measured using a rapid filtration technique. The synaptosomes were isolated by homogenization of the brain and purification on discontinuous Ficoll gradients (n = 8 synaptosome preparations). Diabetic rats (n = 13) displayed a 15-25% increase in synaptosomal taurine uptake compared with normoglycemic control animals (n = 12) at all time points assayed between 5 and 120 min. Thus, after a 30-min incubation, cerebral taurine uptake increased from a control level of 3.53 ± 0.23 to 4.10 ± 0.24 ixmol/mg protein (n = 10) in hyperglycemic rats, P < 0.03. The magnitude of the plasma-to-brain cell taurine gradient was unchanged in diabetic animals. The intrasynaptosomal taurine concentration (~2 \JM) and taurine efflux from the synaptosomes were no different in hyperglycemic versus control rats; efflux amounted to 50% in rats with alloxan-induced diabetes (21). Administration of myoinositol or the aldose reductase inhibitor, sorbinil, corTABLE 6 Effect of insulin on synaptosomal taurine uptake
Na + - external medium Na + - external medium + insulin, 500 mU/ml
Normoglycemic control ((imol/mg protein)
STZ-diabetic (n-mol/mg protein)
4.42 ± 0.11
5.46 ±0.12*
4.37 ± 0.14
5.24 ±0.16*
Values are means ± SE. Total taurine uptake was assayed after 15-min incubation with Na+-containing external medium containing no additives or supplemented with insulin, 500 mU/ml. The data represent the results of 8 experiments conducted using synaptosomes from 3 separate preparations. *P < 0.001 vs. normoglycemic control.
1138
rected this derangement in transport. No explanation is apparent for the differences in amino acid transport by peripheral nerves and brain synaptosomes in hyperglycemic rats. Normalization of cerebral taurine transport in STZinduced diabetic rats rendered euglycemic with insulin therapy suggests that the change in uptake is caused by hyperglycemia per se and is not an effect of STZ or insulin. This was confirmed by the failure of insulin to alter synaptosomal taurine uptake when it was added to the in vitro assay system. Insulinopenia may have opposing actions on cerebral osmolyte content. Although insulin deficiency and hyperglycemia stimulate taurine uptake via the p-amino acid carrier system, this condition may interfere with cellular accumulation of electrolytes. When insulin is administered to hyperglycemic rats, the development of cerebral edema correlates with insulin-stimulated uptake of Na+, K+, and CI" (9). Increased cerebral taurine transport during diabetes is consistent with an osmoprotective role for this molecule (4,5,22,23,24). The initial phase in the brain cell volume regulatory response to elevated serum osmolality is characterized by a rapid influx of inorganic ions (25,26). More prolonged hyperosmolal states trigger a delayed, gradual increase in compatible, organic osmolytes (27). The accumulation of nonperturbing, osmoprotective molecules in brain cells is a combined result of increased synthesis and enhanced transmembrane movement of these solutes. Because the cerebral taurine biosynthetic capacity is marginal in mature animals (28), the doubling of brain cell taurine content during hyperosmolal states primarily reflects contributions from increased carriermediated uptake across the cell membrane. The brain cell volume regulatory response during hyperglycemia, hypematremia, and uremia is qualitatively similar (9). However, the timing of the appearance of osmoprotective molecules and the quantitative composition of the osmolyte pool differ in these conditions. Hyperglycemia is characterized by a more brisk appearance and dissipation of cerebral osmolytes during the development and correction of the hyperosmolal state (9). Sorbitol is a constituent of the brain pool of osmoprotective molecules during hyperglycemia, but not hypematremia or uremia (29,30). Under hyperglycemic conditions, the brain resembles the renal medulla in its use of sorbitol as an osmolyte (31,32). Increased transmembrane taurine flux is part of the cerebral response to hyperosmolality caused by an elevated serum concentration of all three endogenous solutes—Na+, glucose, and urea (7,33). The cerebral dependence on taurine as an osmolyte may be enhanced during hyperglycemia, because cellular accumulation of sorbitol may cause depletion of myo-inositol (34). In addition, taurine may act as a membrane stabilizing agent to limit neuronal excitability (28,35). A common signal-transduction mechanism may mediate increased synaptosomal taurine uptake during hypernatremia and hyperglycemia. Protein kinase C and alterations in intracelluar calcium concentration participate in the control of cell volume and transmembrane taurine flux (36,37,38,39). Protein kinase C activity is
DIABETES, VOL 41, SEPTEMBER 1992
H. TRACHTMAN AND ASSOCIATES
increased in a number of organs removed from rats with STZ-induced diabetes (40). Alternatively, cerebral taurine uptake during hypernatremia and hyperglycemia may be stimulated by cellular acidification induced by increased activity of the Na + -H + antiporter (41,42). We are unable to make any statement about the effect of hyperglycemia on cerebral taurine transport in specific regions of the brain. Microdialysis techniques have been used to assess neuronal uptake and release of taurine during perfusion of discrete areas with hyper- or hypoosmolal solutions (43,44); however, no previous studies have evaluated the effect of in vivo disturbances in plasma osmolality on cerebral taurine transport. To put our findings in perspective as to how the whole brain adapts to hyperglycemia, one can make the following calculations to estimate the contribution of taurine transport to brain accumulation of the amino acid. The synaptosomal membrane protein content accounts for 1% of brain wet weight (45). A lower limit of the increment in taurine transport during hyperglycemia can be set at 0.25 jjimol/mg protein. If these two figures are multiplied, then enhanced taurine uptake yields a 2.5 mmol/kg wet brain weight increase in taurine content during hyperglycemia. This value is comparable with the elevation in cerebral taurine content observed during chronic hypernatremia (6). Taurine efflux was the same from synaptosomes isolated from normoglycemic or STZ-induced diabetic rats and was substantially less than corresponding uptake values. The intrasynaptosmal taurine concentration was ~2 |xM in control and hyperglycemic rats, indicating that nonspecific diffusional leakage of taurine from synaptosomes was minimal. If taurine that accumulates in brain cells fails to exit in parallel with therapeutic correction of hyperglycemia, then this may contribute to the occurrence of cerebral edema when the serum glucose concentration falls rapidly during the treatment of diabetic ketoacidosis (46,47). In summary, we have demonstrated that a 20% stimulation of cerebral taurine transport occurs in hyperglycemic rats. This alteration in amino acid transport, mediated by increased activity of the (3- amino acid transporter, is designed to expand the cytosolic pool of osmolytes, diminish the plasma-to-brain cell osmolal gradient, and limit cerebral cell shrinkage. Treatment of the diabetic rats with insulin to maintain euglycemia prevented the adaptive increase in brain taurine uptake.
ACKNOWLEDGMENTS
This work was supported by Grant 88-023G from the American Heart Association, New York State Affiliate, and a Long Island Jewish Medical Center Faculty Research Award. It was presented in part at the annual meeting of the Society for Pediatric Research, Anaheim, CA, May 1990. The authors thank Jeffrey Messing for measuring plasma, brain, and synaptosome taurine levels and Steve Moran for performing electron micrographs of the synaptosomes.
DIABETES, VOL. 41, SEPTEMBER 1992
REFERENCES 1. Chesney RW: Taurine: its biological role and clinical implications. AdvPediatr 32:1-42, 1985 2. Jacobsen JG, Smith LH Jr: Biochemistry and physiology of taurine and taurine derivatives. Physiol Rev 48:424-511, 1968 3. Thurston JH, Hauhart RE, Dirgo JA: Taurine: a role in osmotic regulation of mammalian brain and possible clinical significance. LifeSci 26:1561 -68, 1980 4. Trachtman H, Barbour R, Sturman JA, Finberg L: Taurine and osmoregulation: taurine is a cerebral osmoprotective molecule in chronic hypernatremic dehydration. Pediatr Res 23:35-39, 1988 5. Trachtman H, Del Pizzo R, Sturman JA: Taurine and osmoregulation: III. Taurine deficiency protects against cerebral edema during acute hypontremia. Pediatr Res 27:85-88, 1990 6. Lien YHH, Shapiro Jl, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 85:1427-35, 1990 7. Trachtman H, Futterweit S, Del Pizzo R: Taurine transport is increased in synaptosomes isolated from brains of rats with hypernatremic dehydration (Abstract). Pediatr Res 25:343A, 1989 8. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med 88:681-95, 1978 9. Pollack AS, Arieff Al: Abnormalities of cell volume regulation and their functional consequences. Am J Phys/o/239:F195-205, 1980 10. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 13:22-33, 1990 11. Fraser CL, Sarnacki P, Arieff Al: Abnormal sodium transport in synaptosomes from brain of uremic rats. J Clin Invest 75:2014-23, 1985 12. Omura T, Takesue S. A new method for simultaneous purification of cytochrome b5 and NADPH-cytochrome c reductase from rat liver microsomes. J Biochem 67:249-57, 1970 13. Kontro P, Oja SS: Taurine uptake by rat brain synaptosomes. J Neurochem 30:1297-1304, 1978 14. Kontro P, Oja SS: Sodium dependence of taurine uptake in rat brain synatosomes. Neuroscience 3:761-65, 1978 15. Trachtman H, DelPizzo R, Rao P, Rujikarn N, Sturman JA: Taurine lowers blood pressure in the spontaneously hypertensive rat by a catecholamine independent mechanism. Am J Hypertens 2:90912, 1989 16. Snedecor GW, Cochran WG: Statistical Methods. 7th ed. Ames, Iowa State Univ. Press, 1980, p. 166 17. Goldstein L, Brill SR, Freund EV: Activation of taurine efflux in hypotonically stressed elasmobranch cells: inhibition by stilbene disulfonates. J Exp Zoo/254:114-18, 1990 18. Pardridge WM, Triguero D, Farrell CR: Downregulation of bloodbrain barrier glucose transporter in experimental diabetes. Diabetes 39:1040-44, 1990 19. Satoh O, Koyama SY, Yamada K, Kawasaki T: Changes in amino acid and glucose transport in brush-border membrane vesicles of hyperglycemic guinea-pig small intestine. Biochim Biophys Acta 1063:155-161, 1991 20. Uchida S, Kwon HM, Preston AS, Handler JS: Expression of MadinDarby canine kidney cell Na+- and Cr-dependent taurine transporter in Xenopus laevis oocytes. J Biol Chem 266:9605-609,1991 21. Greene DA, Lattimer SA, Carroll PB, Fernstrom JD, Finegold DN: A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve: correction with an aldose reductase inhibitor or myo-inositol administration. J Clin Invest 85:1657-65, 1990 22. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA: Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10:1583-91, 1990 23. Pasantes Morales H, Schousboe A: Volume regulation in astrocytes: a role for taurine as an osmoeffector. J Neurosci Res 20:505-509, 1988 24. Olson JE, Goldfinger MD: Amino acid content of rat cerebral astrocytes adapted to hyperosmotic medium in vitro. J Neurosci Res 27:241-46, 1990 25. Pierce SK: Invertebrate cell volume control mechanisms: a coordinated use of intracellular amino acids and inorganic ions as osmotic solute. Biol Bull 163:405-19, 1982 26. Eveloff JL, Warnock DG: Activation of ion transport systems during cell volume regulation. Am J Physiol 252:F1-10, 1987 27. Somero GN: Protons, osmolytes, and fitness of internal milieu for protein function. Am J Physiol 251 :R197-213, 1986 28. Huxtable RJ: Taurine in the central nervous system and mammalian actions of taurine. Prog Neurobiol (NY) 32:471-533, 1989 29. Clements RS, Prockop LD, Winegrad Al: Acute cerebral edema during treatment of hyperglycemia: an experimental model. Lancet 2:384-86, 1968 30. Star RA: Hyperosmolar states. Am J Med Sci 300:402-12, 1990 31. Garcia-Perez A, Burg MB: Renal medullary organic osmolytes. Physiol Rev7^•.^081 -115,1991 32. Grunewald RW, Kinne RKH: Sorbitol metabolism in inner medullary
1139
CEREBRAL TAURINE TRANSPORT IN HYPERGLYCEMIA
33. 34. 35. 36. 37. 38. 39.
40.
collecting duct cells of diabetic rats. Pfluegers Arch 414:346-50, 1989 Trachtman H, Rizzo J, Futterweit S: Taurine transport is increased in synaptosomes isolated from the brain of rats with acute renal failure (Abstract). J Am Soc Nephrol 1:605, 1990 Burg MB, Kador PF: Sorbitoi, osmoregulation, and the complications of diabetes. J Clin Invest 81:635-40, 1988 Wright CE, Talln HH, Lin YY: Taurine: biological update. Annu Rev Biochem 55:427-53, 1986 Leite MV, Goldstein L: Ca + + ionophore and phorbol ester stimulate taurine efflux from skate erythrocytes. J ExpZool 242:95-97, 1987 Philibert RA, Dutton GR: Phorbol ester and dibutyryl cyclic AMP reduce content and efflux of taurine in primary cerebellar astrocytes in culture. Neurosci Let(95:323-28, 1988 McConnell FM, Goldstein L: Intracellular signals and volume regulatory response in skate erythrocytes. Am J Physiol 255:R982-87, 1988 Kulanthaivel P, Cool DR, Ramamoorthy S, Mahesh VB, Leibach FH, Ganapathy V: Transport of taurine and its regulation by protein kinase C in the JAR human placental choriocarcinoma cell line. Biochem J 277:53-58, 1991 Craven PA, DeRubertis FR: Protein kinase C is activated in glomeruli
1140
41. 42.
43. 44. 45. 46. 47.
from streptozotocin diabetic rats: possible mediation by glucose. J Clin Invest 83:1667-75, 1989 Van Der Meulen JA, Klip A, Grinstein S: Possible mechanism for cerebral oedema in diabetic ketoacidosis. Lancet 2:306-308,1987 Grinstein S, Goetz-Smith JD, Stewart D, Beresford BJ, Mellors A: Protein phosphorylation during activation of Na + -H + exchange by phorbol esters and by osmotic shrinking: possible relation to cell pH and volume regulation. J Biol Chem 261:8009-16, 1986 Lehmann A: Effects of microdialysis-perfusion with anisosmotic media on extracellular amino acids in the rat hippocampus and skeletal muscle. J Neurochem 53:525-35, 1989 Wade JV, Olson JP, Samson FE, Nelson SR, Pazdernik TL: A possible role for taurine in osmoregulation within the brain. J Neurochem 51:740-45, 1988 Kontro P, Marnela KM, Oja SS: Free amino acids in the synaptosome and synaptic vesicle fraction of different bovine brain areas. Brain Res 184:129-41, 1980 Duck SC, Wyatt DT: Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr 113:10-14, 1988 Krane EJ, Rockoff MAS, Wallman JK, Wolfsdorf Jl: Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N EnglJMed 312:1147-51, 1985
DIABETES, VOL. 41, SEPTEMBER 1992
Taurine is a cerebral osmolyte whose intracellular content changes in parallel with plasma osmolality. We conducted experiments to assess whether cerebral taurine transport is modified during chronic hyperglycemia. Rats with STZ-induced diabetes were studied after 1 wk of sustained hyperglycemia. Cerebral taurine uptake in synaptosomes (metabolically active nerve terminal vesicles) was measured using a rapid filtration technique. The synaptosomes were isolated by homogenization of the brain and purification on discontinuous Ficoll gradients (n = 8 synaptosome preparations). Diabetic rats (n = 13) displayed a 15-25% increase in synaptosomal taurine uptake compared with normoglycemic control animals (n = 12) at all time points assayed between 5 and 120 min. Thus, after a 30-min incubation, cerebral taurine uptake increased from a control level of 3.53 ± 0.23 to 4.10 ± 0.24 ixmol/mg protein (n = 10) in hyperglycemic rats, P < 0.03. The magnitude of the plasma-to-brain cell taurine gradient was unchanged in diabetic animals. The intrasynaptosomal taurine concentration (~2 \JM) and taurine efflux from the synaptosomes were no different in hyperglycemic versus control rats; efflux amounted to 50% in rats with alloxan-induced diabetes (21). Administration of myoinositol or the aldose reductase inhibitor, sorbinil, corTABLE 6 Effect of insulin on synaptosomal taurine uptake
Na + - external medium Na + - external medium + insulin, 500 mU/ml
Normoglycemic control ((imol/mg protein)
STZ-diabetic (n-mol/mg protein)
4.42 ± 0.11
5.46 ±0.12*
4.37 ± 0.14
5.24 ±0.16*
Values are means ± SE. Total taurine uptake was assayed after 15-min incubation with Na+-containing external medium containing no additives or supplemented with insulin, 500 mU/ml. The data represent the results of 8 experiments conducted using synaptosomes from 3 separate preparations. *P < 0.001 vs. normoglycemic control.
1138
rected this derangement in transport. No explanation is apparent for the differences in amino acid transport by peripheral nerves and brain synaptosomes in hyperglycemic rats. Normalization of cerebral taurine transport in STZinduced diabetic rats rendered euglycemic with insulin therapy suggests that the change in uptake is caused by hyperglycemia per se and is not an effect of STZ or insulin. This was confirmed by the failure of insulin to alter synaptosomal taurine uptake when it was added to the in vitro assay system. Insulinopenia may have opposing actions on cerebral osmolyte content. Although insulin deficiency and hyperglycemia stimulate taurine uptake via the p-amino acid carrier system, this condition may interfere with cellular accumulation of electrolytes. When insulin is administered to hyperglycemic rats, the development of cerebral edema correlates with insulin-stimulated uptake of Na+, K+, and CI" (9). Increased cerebral taurine transport during diabetes is consistent with an osmoprotective role for this molecule (4,5,22,23,24). The initial phase in the brain cell volume regulatory response to elevated serum osmolality is characterized by a rapid influx of inorganic ions (25,26). More prolonged hyperosmolal states trigger a delayed, gradual increase in compatible, organic osmolytes (27). The accumulation of nonperturbing, osmoprotective molecules in brain cells is a combined result of increased synthesis and enhanced transmembrane movement of these solutes. Because the cerebral taurine biosynthetic capacity is marginal in mature animals (28), the doubling of brain cell taurine content during hyperosmolal states primarily reflects contributions from increased carriermediated uptake across the cell membrane. The brain cell volume regulatory response during hyperglycemia, hypematremia, and uremia is qualitatively similar (9). However, the timing of the appearance of osmoprotective molecules and the quantitative composition of the osmolyte pool differ in these conditions. Hyperglycemia is characterized by a more brisk appearance and dissipation of cerebral osmolytes during the development and correction of the hyperosmolal state (9). Sorbitol is a constituent of the brain pool of osmoprotective molecules during hyperglycemia, but not hypematremia or uremia (29,30). Under hyperglycemic conditions, the brain resembles the renal medulla in its use of sorbitol as an osmolyte (31,32). Increased transmembrane taurine flux is part of the cerebral response to hyperosmolality caused by an elevated serum concentration of all three endogenous solutes—Na+, glucose, and urea (7,33). The cerebral dependence on taurine as an osmolyte may be enhanced during hyperglycemia, because cellular accumulation of sorbitol may cause depletion of myo-inositol (34). In addition, taurine may act as a membrane stabilizing agent to limit neuronal excitability (28,35). A common signal-transduction mechanism may mediate increased synaptosomal taurine uptake during hypernatremia and hyperglycemia. Protein kinase C and alterations in intracelluar calcium concentration participate in the control of cell volume and transmembrane taurine flux (36,37,38,39). Protein kinase C activity is
DIABETES, VOL 41, SEPTEMBER 1992
H. TRACHTMAN AND ASSOCIATES
increased in a number of organs removed from rats with STZ-induced diabetes (40). Alternatively, cerebral taurine uptake during hypernatremia and hyperglycemia may be stimulated by cellular acidification induced by increased activity of the Na + -H + antiporter (41,42). We are unable to make any statement about the effect of hyperglycemia on cerebral taurine transport in specific regions of the brain. Microdialysis techniques have been used to assess neuronal uptake and release of taurine during perfusion of discrete areas with hyper- or hypoosmolal solutions (43,44); however, no previous studies have evaluated the effect of in vivo disturbances in plasma osmolality on cerebral taurine transport. To put our findings in perspective as to how the whole brain adapts to hyperglycemia, one can make the following calculations to estimate the contribution of taurine transport to brain accumulation of the amino acid. The synaptosomal membrane protein content accounts for 1% of brain wet weight (45). A lower limit of the increment in taurine transport during hyperglycemia can be set at 0.25 jjimol/mg protein. If these two figures are multiplied, then enhanced taurine uptake yields a 2.5 mmol/kg wet brain weight increase in taurine content during hyperglycemia. This value is comparable with the elevation in cerebral taurine content observed during chronic hypernatremia (6). Taurine efflux was the same from synaptosomes isolated from normoglycemic or STZ-induced diabetic rats and was substantially less than corresponding uptake values. The intrasynaptosmal taurine concentration was ~2 |xM in control and hyperglycemic rats, indicating that nonspecific diffusional leakage of taurine from synaptosomes was minimal. If taurine that accumulates in brain cells fails to exit in parallel with therapeutic correction of hyperglycemia, then this may contribute to the occurrence of cerebral edema when the serum glucose concentration falls rapidly during the treatment of diabetic ketoacidosis (46,47). In summary, we have demonstrated that a 20% stimulation of cerebral taurine transport occurs in hyperglycemic rats. This alteration in amino acid transport, mediated by increased activity of the (3- amino acid transporter, is designed to expand the cytosolic pool of osmolytes, diminish the plasma-to-brain cell osmolal gradient, and limit cerebral cell shrinkage. Treatment of the diabetic rats with insulin to maintain euglycemia prevented the adaptive increase in brain taurine uptake.
ACKNOWLEDGMENTS
This work was supported by Grant 88-023G from the American Heart Association, New York State Affiliate, and a Long Island Jewish Medical Center Faculty Research Award. It was presented in part at the annual meeting of the Society for Pediatric Research, Anaheim, CA, May 1990. The authors thank Jeffrey Messing for measuring plasma, brain, and synaptosome taurine levels and Steve Moran for performing electron micrographs of the synaptosomes.
DIABETES, VOL. 41, SEPTEMBER 1992
REFERENCES 1. Chesney RW: Taurine: its biological role and clinical implications. AdvPediatr 32:1-42, 1985 2. Jacobsen JG, Smith LH Jr: Biochemistry and physiology of taurine and taurine derivatives. Physiol Rev 48:424-511, 1968 3. Thurston JH, Hauhart RE, Dirgo JA: Taurine: a role in osmotic regulation of mammalian brain and possible clinical significance. LifeSci 26:1561 -68, 1980 4. Trachtman H, Barbour R, Sturman JA, Finberg L: Taurine and osmoregulation: taurine is a cerebral osmoprotective molecule in chronic hypernatremic dehydration. Pediatr Res 23:35-39, 1988 5. Trachtman H, Del Pizzo R, Sturman JA: Taurine and osmoregulation: III. Taurine deficiency protects against cerebral edema during acute hypontremia. Pediatr Res 27:85-88, 1990 6. Lien YHH, Shapiro Jl, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 85:1427-35, 1990 7. Trachtman H, Futterweit S, Del Pizzo R: Taurine transport is increased in synaptosomes isolated from brains of rats with hypernatremic dehydration (Abstract). Pediatr Res 25:343A, 1989 8. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med 88:681-95, 1978 9. Pollack AS, Arieff Al: Abnormalities of cell volume regulation and their functional consequences. Am J Phys/o/239:F195-205, 1980 10. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 13:22-33, 1990 11. Fraser CL, Sarnacki P, Arieff Al: Abnormal sodium transport in synaptosomes from brain of uremic rats. J Clin Invest 75:2014-23, 1985 12. Omura T, Takesue S. A new method for simultaneous purification of cytochrome b5 and NADPH-cytochrome c reductase from rat liver microsomes. J Biochem 67:249-57, 1970 13. Kontro P, Oja SS: Taurine uptake by rat brain synaptosomes. J Neurochem 30:1297-1304, 1978 14. Kontro P, Oja SS: Sodium dependence of taurine uptake in rat brain synatosomes. Neuroscience 3:761-65, 1978 15. Trachtman H, DelPizzo R, Rao P, Rujikarn N, Sturman JA: Taurine lowers blood pressure in the spontaneously hypertensive rat by a catecholamine independent mechanism. Am J Hypertens 2:90912, 1989 16. Snedecor GW, Cochran WG: Statistical Methods. 7th ed. Ames, Iowa State Univ. Press, 1980, p. 166 17. Goldstein L, Brill SR, Freund EV: Activation of taurine efflux in hypotonically stressed elasmobranch cells: inhibition by stilbene disulfonates. J Exp Zoo/254:114-18, 1990 18. Pardridge WM, Triguero D, Farrell CR: Downregulation of bloodbrain barrier glucose transporter in experimental diabetes. Diabetes 39:1040-44, 1990 19. Satoh O, Koyama SY, Yamada K, Kawasaki T: Changes in amino acid and glucose transport in brush-border membrane vesicles of hyperglycemic guinea-pig small intestine. Biochim Biophys Acta 1063:155-161, 1991 20. Uchida S, Kwon HM, Preston AS, Handler JS: Expression of MadinDarby canine kidney cell Na+- and Cr-dependent taurine transporter in Xenopus laevis oocytes. J Biol Chem 266:9605-609,1991 21. Greene DA, Lattimer SA, Carroll PB, Fernstrom JD, Finegold DN: A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve: correction with an aldose reductase inhibitor or myo-inositol administration. J Clin Invest 85:1657-65, 1990 22. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA: Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10:1583-91, 1990 23. Pasantes Morales H, Schousboe A: Volume regulation in astrocytes: a role for taurine as an osmoeffector. J Neurosci Res 20:505-509, 1988 24. Olson JE, Goldfinger MD: Amino acid content of rat cerebral astrocytes adapted to hyperosmotic medium in vitro. J Neurosci Res 27:241-46, 1990 25. Pierce SK: Invertebrate cell volume control mechanisms: a coordinated use of intracellular amino acids and inorganic ions as osmotic solute. Biol Bull 163:405-19, 1982 26. Eveloff JL, Warnock DG: Activation of ion transport systems during cell volume regulation. Am J Physiol 252:F1-10, 1987 27. Somero GN: Protons, osmolytes, and fitness of internal milieu for protein function. Am J Physiol 251 :R197-213, 1986 28. Huxtable RJ: Taurine in the central nervous system and mammalian actions of taurine. Prog Neurobiol (NY) 32:471-533, 1989 29. Clements RS, Prockop LD, Winegrad Al: Acute cerebral edema during treatment of hyperglycemia: an experimental model. Lancet 2:384-86, 1968 30. Star RA: Hyperosmolar states. Am J Med Sci 300:402-12, 1990 31. Garcia-Perez A, Burg MB: Renal medullary organic osmolytes. Physiol Rev7^•.^081 -115,1991 32. Grunewald RW, Kinne RKH: Sorbitol metabolism in inner medullary
1139
CEREBRAL TAURINE TRANSPORT IN HYPERGLYCEMIA
33. 34. 35. 36. 37. 38. 39.
40.
collecting duct cells of diabetic rats. Pfluegers Arch 414:346-50, 1989 Trachtman H, Rizzo J, Futterweit S: Taurine transport is increased in synaptosomes isolated from the brain of rats with acute renal failure (Abstract). J Am Soc Nephrol 1:605, 1990 Burg MB, Kador PF: Sorbitoi, osmoregulation, and the complications of diabetes. J Clin Invest 81:635-40, 1988 Wright CE, Talln HH, Lin YY: Taurine: biological update. Annu Rev Biochem 55:427-53, 1986 Leite MV, Goldstein L: Ca + + ionophore and phorbol ester stimulate taurine efflux from skate erythrocytes. J ExpZool 242:95-97, 1987 Philibert RA, Dutton GR: Phorbol ester and dibutyryl cyclic AMP reduce content and efflux of taurine in primary cerebellar astrocytes in culture. Neurosci Let(95:323-28, 1988 McConnell FM, Goldstein L: Intracellular signals and volume regulatory response in skate erythrocytes. Am J Physiol 255:R982-87, 1988 Kulanthaivel P, Cool DR, Ramamoorthy S, Mahesh VB, Leibach FH, Ganapathy V: Transport of taurine and its regulation by protein kinase C in the JAR human placental choriocarcinoma cell line. Biochem J 277:53-58, 1991 Craven PA, DeRubertis FR: Protein kinase C is activated in glomeruli
1140
41. 42.
43. 44. 45. 46. 47.
from streptozotocin diabetic rats: possible mediation by glucose. J Clin Invest 83:1667-75, 1989 Van Der Meulen JA, Klip A, Grinstein S: Possible mechanism for cerebral oedema in diabetic ketoacidosis. Lancet 2:306-308,1987 Grinstein S, Goetz-Smith JD, Stewart D, Beresford BJ, Mellors A: Protein phosphorylation during activation of Na + -H + exchange by phorbol esters and by osmotic shrinking: possible relation to cell pH and volume regulation. J Biol Chem 261:8009-16, 1986 Lehmann A: Effects of microdialysis-perfusion with anisosmotic media on extracellular amino acids in the rat hippocampus and skeletal muscle. J Neurochem 53:525-35, 1989 Wade JV, Olson JP, Samson FE, Nelson SR, Pazdernik TL: A possible role for taurine in osmoregulation within the brain. J Neurochem 51:740-45, 1988 Kontro P, Marnela KM, Oja SS: Free amino acids in the synaptosome and synaptic vesicle fraction of different bovine brain areas. Brain Res 184:129-41, 1980 Duck SC, Wyatt DT: Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr 113:10-14, 1988 Krane EJ, Rockoff MAS, Wallman JK, Wolfsdorf Jl: Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N EnglJMed 312:1147-51, 1985
DIABETES, VOL. 41, SEPTEMBER 1992
