Carbohydrate Metabolism

Levin, Booker, Smith and Grodsky, Journal of Clinical Endocrinology and Metabolism (1970),1269 studied the effect of PHT on insulin secretion by the isolated perfused rat pancreas. PHT (300 µg/M) completely inhibited immunoreactive insulin release in response to a glucose stimulus.

1269. Levin, S. R., Booker, J., Smith, D. F., and Grodsky, G. M., Inhibition of insulin secretion by diphenylhydantoin in the isolated perfused pancreas, J. Clin. Endocr., 300: 400-401, 1970.

Kizer, Vargas-Cordon, Brendel and Bressler, Journal of Clinical Investigation (1970),1220 studied the effect of PHT on the secretion of insulin in vitro by isolated islets of Langerhans and 5-mg pieces of pancreatic tissue. PHT (30-160 µM) reduced the release of insulin in a dose-dependent manner. The effect was reversed by potassium and ouabain.

1220. Kizer, J. S., Vargas-Cordon, M., Brendel, K., and Bressler, R., The in vitro inhibition of insulin secretion by diphenylhydantoin, J. Clin. Invest., 49: 1942-1948, 1970.

Bihler and Sawh, Biochimica et Biophysica Acta (1971),1750 in a study of rat hemidiaphragm in vitro, demonstrated that PHT (100-500 µM) has a regulatory effect on sugar transport. The transport of the non-metabolized glucose analog 3-0-methyl-D-(14C)-glucose was inhibited by PHT when internal potassium was increased and sodium decreased. Conversely, sugar transport was stimulated by PHT following the opposite ionic changes.

1750. Bihler, 1. and Sawh, P. C., Effects of Diphenylhydantoin on the transport of Na+ and K+ and the regulation of sugar transport in muscle in vitro, Biochim. Biophys. Acta, 249: 240-51, 1971.

Gossel and Mennear, Pharmacologist (1971),1092 studied the effect of pretreatment with PHT on the development of alloxan-induced diabetes in mice. PHT (20-45 mg/ kg), administered one hour prior to alloxan, was found to prevent the development of alloxan-induced diabetes. The authors note that the work of others indicates that PHT has a regulatory effect on insulin secretion by the isolated pancreas and suggest that PHT binds to, and exerts a selective action on, these pancreatic cells. The authors conclude that PHT protects the pancreatic beta-cell binding sites from alloxan.

1092. Gossel, T. A. and Mennear, J. H., Inhibition of alloxan-induced diabetes by diphenylhydantoin sodium, Pharmacologist, 13: 238,1971.

Levin, Grodsky, Hagura, Smith, Licko and Forsham, Clinical Research (1972),1272 and Diabetes (1972),1273 studied the kinetics of PHT's regulation of insulin secretion in isolated perfused pancreas. The authors conclude that PHT exerts its regulatory effect both on the labile compartment of insulin and on the supply of insulin to this compartment prior to secretion.

1272. Levin, S. R., Grodsky, G., Hagura, R., Smith, D., Licko, V., and Forsham, P., Comparison of effects of diphenylhydantoin and diazoxide on insulin secretion in the isolated perfused rat pancreas, using computerized correlation of experimental data, Clin. Res., 19: 375, 1971.
1273. Levin, S. R., Grodsky, G. M., Hagura, R., and Smith, D., Comparison of the inhibitory effects of diphenylhydantoin and diazoxide upon insulin secretion from the isolated perfused pancreas, Diabetes, 21: 856-862, 1972. (cf. Goldberg, Diabetes, 18: 101, 1969.) 

Gerich, Charles, Levin, Forsham and Grodsky, Journal of Clinical Endocrinology (1972),1062 studied the effect of PHT on glucagon secretion in the isolated perfused rat pancreas. At 25 µg/ml, PHT markedly diminished glucagon release and had no effect on insulin release. The authors note that this selective action of PHT in controlling glucagon release presumably reflects the special sensitivity to PHT of the alpha cells of the pancreas as compared with the beta cells. Since glucagon and insulin act in an opposite manner in the control of blood sugar, PHT's influence on the release of both hormones means that it has at least two potential regulatory actions on blood sugar.

1062. Gerich, J. E., Charles, M. A., Levin, S. R., Forsham, P. H., and Grodsky, G. M., In vitro inhibition of pancreatic glucagon secretion by diphenylhydantoin, J. Clin. Endocr., 35: 823-824,1972.

Karp, Lerman, Doron and Laron, Helvetica Paediatrie Acta (1973),2646 investigated glucose and insulin response in eight epileptic children treated for three to eight years with PHT (200-300 mg/day). Glucose tolerance was normal in all, but insulin responses were slightly altered: three patients had lowered, and three had delayed insulin peaks.

2646. Karp, M., Lerman, P., Doron, M., Laron, Z., Effect of diphenylhydantoin on insulin response in the oral glucose tolerance test in children and adolescents, Helv. Paediatr. Acta, 28: 617-20,1973.

Mennear and Gossel, Toxicology and Applied Pharmacology (1973),1355 studied the effect of PHT (5 mg/kg), administered intraperitoneally, on blood glucose levels in normally fed mice. PHT did not alter resting blood glucose levels, but did reduce glucose tolerance. PHT did not interfere with the hypoglycemic effect of injected insulin, but reversed the hypoglycemic effect of tolbutamide.

1355. Mennear, J. H., and Gossel, T. A., Interactions between diphenylhydantoin and tolbutamide in mice, Toxic. Appl. Pharmacol., 24: 309-316,1973.

Esposito-Avella and Mennear, Proceedings of the Society of Experimental Biology and Medicine (1973),1015 studied the protective effect of PHT against alloxan-induced diabetes in mice. The authors found that both PHT (10-45 mg/kg), administered intraperitoneally, and D-glucose administered intravenously afforded complete protection against alloxan. The authors conclude that both D-glucose and PHT exert their protective effects by binding to the pancreatic beta-cell.

1015. Esposito-Avelia, M. and Mennear, J. H., Studies on the protective effect of diphenylhydantoin against alloxan diabetes in mice, Proc. Soc. Exp. Biol. Med., 142: 82-85, 1973.

Schimmel and Graham, Hormone and Metabolic Research (1974),1509 studied the protective effect of PHT against streptozotocin-induced diabetes in rats. Intravenous injection of PHT, 20 mg/kg, nineteen minutes prior to or within sixty minutes after administration of streptozotocin, was found to prevent the development of diabetes.

1509. Schimmel, R. J., and Graham, D., Inhibition by diphenylhydantoin of the diabetogenic action of streptozotocin, Horm. Metab. Res., 6: 475-477, 1974.

Stambaugh and Tucker, Diabetes (1974),1583 describe the successful treatment, with PHT, of five patients with functional hypoglycemia previously unresponsive to dietary management. Clinical reversal of hypoglycemia was observed in all five cases. In addition, laboratory tests confirmed this observation in both six-hour glucose tolerance and insulin level tests, performed before and after PHT therapy. (See p. 11.)

1583. Stambaugh, J. E. and Tucker, D., Effect of diphenylhydantoin on glucose tolerance in patients with hypoglycemia, Diabetes, 23: 679-683, 1974.

Cudworth and Cunningham, Clinical Science and Molecular Medicine (1974),924 studied glucose tolerance tests, serum insulin, and growth hormone levels in healthy volunteers before and after receiving PHT, 100 mg every eight hours, for fourteen days. Although the response of insulin to oral glucose was reduced in some individuals, glucose tolerance remained normal. No changes in growth hormone levels were observed.

924. Cudworth, A. G. and Cunningham, J. L., The effect of diphenylhydantoin on insulin response, Clin. Sci. Molec. Med., 46: 131-136, 1974.

Madsen, Hansen and Deckert, Acta Neurologica Scandanavica (1974),1327 investigated intravenous glucose tolerance in eight patients before and during treatment with PHT. They found that neither glucose tolerance nor insulin secretion was affected after a glucose load. In eight additional patients, who had for several years been treated with PHT, the results were comparable.

1327. Madsen, S. N., Hansen, J. M. and Deckert, T., Intravenous glucose tolerance during treatment with phenytoin, Acta Neurol. Scand., 50: 257-260, 1974.

Petrack, Czernik, Itterly, Ansell and Chertock, Diabetes (1976),2022 demonstrated that PHT (2.7 µg/ml) suppressed the second-phase release of both insulin and glucagon from isolated perfused rat pancreas. The authors suggest that PHT might therefore suppress glucagon secretion in insulin-dependent juvenile diabetics.

2022. Petrack, B., Czernik, A. J., Itterly, W., Ansell, J. and Chertock, H., On the suppression of insulin and glucagon released by diphenylhydantoin, Diabetes, 25, Suppl. 1: 380, 1976.

Callaghan, Feely, O’Callaghan, Duggan, McGarry, Cramer, Wheelan and Seldrup, Acta Neurologica Scandinavica (1977),1762 demonstrated that non-toxic levels of PHT do not disturb carbohydrate tolerance or insulin levels in epileptic patients.

1762. Callaghan, N., Feely, M., O’Callaghan, M., Duggan, B., McGarry, J., Cramer, B., Wheelan, J. and Seldrup, J., The effects of toxic and non-toxic serum phenytoin levels on carbohydrate tolerance and insulin levels, Acta Neurol. Scand., 56: 563-71, 1977.

Draznin, Ayalon, Hoerer, Oberman, Harell, Ravid and Laurian, Acta Diabetologica Latina (1977),1809 demonstrated that PHT (300 mg/day, for three days) significantly decreased insulin release after glucose ingestion, but did not alter the basal insulin level in obese patients. Because a secondary hyperinsulinemia has been suggested to play an important role in the pathogenesis of obesity, PHT is proposed as a possible treatment for this condition.

1809. Drazin, B., Ayalon, D., Hoerer, E., Oberman, Z., Harell, A., Ravid, R. and Laurian, L., Effect of diphenylhydantoin on patterns of insulin secretion in obese subjects, Acta Diabetol. Lat., 14: 51-61, Jan/Apr 1977.

Pace and Livingston, Diabetes (1979),2011 studied the effects of PHT on insulin release and metabolism of isolated rat islets of Langerhans. Glucose and veratridine were used to stimulate insulin release by activating the calcium and sodium channels. PHT (100 µM) inhibited glucose-stimulated insulin release (77%) and glycolysis (74%). PHT also inhibited veratridine-stimulated insulin release (60%) and glycolysis (100%). When extracellular calcium was raised from 2.5 to 5.0 mM, PHT's effects were less. Noting that PHT has been reported to hyperpolarize the beta-cell membrane and to inhibit glucose-induced spike activity, the authors conclude that the inhibitory action of PHT on the pancreatic beta-cell is due to its regulatory effect on sodium and calcium channels.

2011. Pace, C. S. and Livingston, E., Ionic basis of phenytoin sodium inhibition of insulin secretion in pancreatic islets, Diabetes, 28: 1077-82, 1979.

Herchuelz, Lebrun, Sener and Malaisse, European Journal of Pharmacology (1981),2589 investigated the mechanism by which PHT inhibits glucose-stimulated insulin release by studying its effects on calcium and rubidium fluxes in isolated pancreatic islets. PHT inhibited both basal and glucose-stimulated calcium uptake by islet cells and markedly reduced the secondary rise in calcium efflux normally provoked by glucose. PHT also decreased the calcium exchange evoked by an increase in extracellular calcium concentration. Rubidium up-take was not affected, indicating that PHT's effects on insulin release were not attributable to activation of sodium-potassium-ATPase. The authors conclude that PHT inhibits glucose-induced insulin release by limiting calcium entry into islet cells.

2589. Herchuelz, A., Lebrun, P., Sener, A., Malaisse, W. J., Ionic mechanism of diphenylhydantoin action on glucose-induced insulin release, Eur. J. Pharmacol., 73 (2-3): 189-97, 1981.

Siegel, Janjic and Wollheim, Diabetes (1982),2952 studied the inhibition of insulin release by PHT in rat pancreatic islet culture. PHT (80 µM), added during the second phase of glucose-induced biphasic insulin release, resulted in marked and rapid inhibition. PHT also significantly reduced glucose-induced calcium uptake of islet cells. The authors suggest that PHT inhibits glucose-stimulated insulin release by regulating voltage-dependent calcium channels.

2952. Seigel, E. G., Janjic, D., Wollheim, C. B., Phenytoin inhibition of insulin release: studies on the involvement of Ca+ fluxes in rat pancreatic islets, Diabetes, 31: 265-9, 1982.