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Inhibition of gastric motility elicited by d -glucose anomers in man
Journal of the Autonomic Nervous System, 12 (1985) 347-351 Elsevier
347
JAN 00431
Short C o m m u n i c a t i o n
Inhibition of gastric motility elicited by D-glucose anomers in man T a k e o Sakaguchi, M a s a h i r o Ohtake, Akira Niijima and Kenji T a k i z a w a l Departments of Phvswlogy and J Psychiatry, Ntigata Unwersttv School of Medwme, Nitgata 951 (Japan)
Key word~: blood glucose - gastric motility - glucose anomer - man
It has been accepted that changes in the glucose concentration in the blood influence gastric motility; hypoglycemia causes enhanced motility of the stomach by stimulating the vagal glucose-sensitive mechanisms, whereas the raised motility is depressed by glucose [1,9]. On the other hand, D-glucose dissolved in an aqueous solution exists as an optically equilibrated mixture of its two anomers: 36% a-anomer and 64% fl-anomer [8]. Moreover, almost the same anomeric fraction has been known to exist in the blood of higher animals [2,5]. However, the physiological significance of each anomer remains to be elucidated in humans. Recently, it was observed that D-glucose and its anomers injected into the vein affected the gastric motility in man, respectively. Thirty-two healthy men (18-22 years old) weighing about 56-63 kg were tested. They were divided into 3 groups; the first group of 8 men received no injection, the second group of 12 men received NaCI and equilibrated o-glucose, and the third group of 12 men received or- and fl-D-glucose. They were deprived of food for 12- 16 h before the experiments and the experiments were conducted in the mornings to eliminate any diurnal variation in plasma concentrations of glucose and insulin [4]. The evaluation of gastric motility was made by the balloon methods described earlier [9,11]. Briefly, a Salem Sump tube (Argyle) with a balloon at the tip was introduced into the stomach of a subject through his esophagus and was fixed in position with a tape on his lip. The balloon was inflated with water at body temperature and at an initial pressure of 15-18 kPa. The pressure was recorded by a strain-gauge pressure transducer combined with an ink writing recorder (Nihon Kohden). Throughout the experiment, body temperature of each man was between 36.5 to 36.8°C. The D-glucose and NaCI dissolved in distilled water kept at 25°C were infused through a catheter placed in the cubital vein. The purity of alpha and Correspondence: T. Sakaguchi, Department of Physiology, Niigata University School of Medicine, Niigata 951, Japan. 0165-1838/85/$03.30 4~ 1985 Elsevier Science Publishers B.V. (Biomedical Division)
348 |T'/mM equll. G.glucose
SSSmM equil. D-glucose
0-* 3 rain
Fig. 1. A graph showing the effect of equilibrated D-glucose on enhanced motility of the stomach caused by insulin-hypoglycemia. Equilibrated D-glucose (277 and 555 mM, 100 ml) and NaCI (308 raM, 100 ml) were injected into a vein in the forearm. Arrows show the time of injections.
beta anomers (Nakarai) was more than 96%. Optically equilibrated D-glucose solution consisting of 36% a- and 64% //-D-glucose was obtained by incubating at room temperature (25°C) either a- or/t-o-glucose solution for 22 h to induce the glucose to mutarotate completely. Crystallized D-glucose anomers (a and /3) were dissolved in water at 25°C immediately before use to eliminate mutarotation of the glucose; the time periods required for the two anomers to be dissolved in the same water were about 15 s and the mutarotational half-life of the two anomers was 26.1 5- 0.5 min (n = 5) at 25°C in the same water. A venous injection (100 ml) of test solution was performed for the duration of 90 s. Regular insulin (Novo) was administered, i.v. (0.8 ~tg/kg/h) to stimulate motility of the stomach [3,9]. The concentrations of glucose and insulin in the blood were measured by the methods reported earlier [13,14]. Blood for glucose and insulin estimations was drawn through the same catheter in the vein. Statistical significance of differences between values was determined by t-test: P < 0.05 was taken as indicative of significance between means. When intragastric pressures were recorded during hypoglycemia associated with 0 . 8 / ~ g / k g / h insulin administration, elevated pressures were usually observed 40-100 min after insulin administration (Fig. 1). The injections of 277 and 555 mM (100 ml) equilibrated D-glucose solution into the cubital vein produced an abrupt and substantial decrease in the pressure. The levels (mean 5- S.E.M.) of the pressure 0, 1, 2, 3, 4 and 5 rain after the 277 mM D-glucose (isotonic) were 24.1 5- 1.1, 22.5 + 1.3, 19.8 + 1.4, 20.5 + 1.3, 20.5 5- 1.4 and 21.6 + 2.6 kPa (n = 12), respectively. The levels of the pressure 1, 2, 3 and 4 min after the injection were significantly diminished (P < 0.02-0.001) compared to the level before the injection; the inhibitory response reached its peak in about 2 min and disappeared m 6 rain after the injection. No significant reduction in pressure was elicited after the administration of 100 nil 308 mM NaCl solution which is equitonic to 555 mM D-glucose (Fig. 1). Equilibrated D-glUCOSe solutions of 3 different concentrations (138, 277 and 555 raM) were injected in the vein to examine the relationship of concentration to the pressure decrease (Fig. 2). Although the 138 mM D-glucose injection failed to cause a response, the 277 and 555 mM D-glucose injections produced a significant decrease
349
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Oj
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r---J
!- s.0] 2.5
o~0
,-,
20
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o@o
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I
II
III
IV
Fig. 2. The effect of venous injections of 138 ( O : n = 12), 277 ( ~ : n = 12) and 555 (e: n = 12) mM equilibrated D-glucose on the intragastric pressure provoked by 0.8 # g / k g insulin. A square in the center shows duration of the venous injection. Values are means_+ S.E.M. * P < 0.05. ** P < 0.01 and *** P < 0.00l : significantly different from the value just before injection. F i g 3. The intragastric pressures 2 rain after administering 154 mM NaCI (I), 277 m M a-D-glucose (11). 277 mM equilibrated D-glucose (III), and 277 m M ,8-D-glucose (IV). Values are means + S.E.M. N u m b e r s in parentheses represent the n u m b e r of samples, a, P < 0.02 vs N a C h b, P < 0.001 vs N a C h c, P < 0.05 vs c~-D-glucose or equilibrated D-glucose.
( P < 0 . 0 5 - 0 . 0 0 1 ) in the pressure relative to the level before injection. Plasma concentrations of glucose were not significantly different from each other either just before or 9 min after the 3 injections. However, the concentrations 3 and 6 rain after the 277 and 555 mM D-glucose administrations increased significantly ( P < 0.05-0.001) compared to the level before injection (Fig. 2). Plasma concentration (mean __+S.E.M.) of insulin just before the venous test administration was 391 _+ 18 (n = 31) pM. The levels (mean _+ S.E.M.) of pressure 2 min after the 154 mM NaC1, 277 mM a-D-glucose, 277 mM equilibrated D-glucose and 277 mM B-D-glucose injections were 24.1 + 0.8 (n - 9), 20.6 + 1,6 (n = 9), 19.8 + 1.3 (n = 8) and 16.8 _+ 1.4 (n = 9) kPa, respectively (Fig. 3). Statistically, the magnitude of the pressure drop after the B-D-glucose injection was greater than that after the equilibrated D-glucose ( P < 0.05) or the a-D-glucose ( P < 0.05) injections. Atropin (10 ~g/kg, s.c.) blocked these glucose responses (n = 3). Although elevated motility of the stomach evoked by insulin has been shown to be reduced through vagal action by glucose [9,11], only a few researchers have reported the relation between intragastric pressure and the concentration of glucose in the blood during insulin-hypoglycemia [11,15 I. In the present study, equilibrated D-glucose injected into the vein transiently suppressed the elevated motility of the stomach caused by insulin-hypoglycemia and the inhibitory response by the D-glucose solutions was not reproduced by hypertonic NaCI solutions, suggesting.that the response is not due to osmotic effects (Fig. 1). The 3 different doses of the D-glucose injected into the vein appeared to induce a dose-dependent reduction in intragastric pressure (Fig. 2); we conclude that increasing the concentration of glucose in the
350 blood consistently inhibits the raised pressure of the stomach. However, the action site of D-glucose on the pressure is not simple to explain. Because glucose-sensitive mechanisms vagally controlling gastric motility have been well-documented in the central nervous regions [12,15] and in the hepatic portal regions [11], the inhibitory responses observed are thus derived from a mechanism in the brain or in the hepatic portal vein or from both mechanisms. Unfortunately, the present data did not shed light on this problem. There have been numerous investigations of the uptake and utilization of o-glucose, but only a few reports have dealt with the uptake and utilization of a- and fl-D-glucose in humans. It has been rather difficult to study the physiological significance of anomers of D-glucose because of the rapid mutarotation of the two anomers. In the present study, mutarotational half-life of the two anomers in distilled water kept at 25°C was about 27 min and a venous administration of D-glucose anomers was completed in 2 rain. Moreover, it should be noted that half-life of the two anomers in h u m a n blood was found to be 2.7 rain at 37°C (unpublished data). So the experiment could provide understanding to the physiological function of D-glucose anomer in h u m a n s based on the fact that the inhibitory response reached its peak in about 2 min (Figs. 1 and 2). Concerning the physiological function of the glucose anomers, several works have suggested that fl-D-glucose is more rapidly transported and metabolized by various nerve cells than a-D-glucose [6,7,10]. In this study, fl-D-glUCOSe was most potent in reducing the intragastric pressure (Fig. 3); anomeric preference is expected to be valid in the vagal mechanism detecting D-glucose. Although more definite experiments are needed to determine the exact action site of anomeric predominancy, the present data suggest that fl-D-glBcose in the blood may play an important role in activating the mechanisms vagally controlling gastric motility in humans.
References 1 Bachrach. W.H., Action of insulin hypoglycemia on motor and secretory functions of the digestive tract, Physiol. gev., 33 (1953) 566-592. 2 Hill, J.B. and Cowart, D.S., Mutarotase and glucose anomers, Biochem. Med., 1 (1967) 62-86. 3 Hollander, F., The insulin test for the presence of intact nerve fibers after vagal operations for peptic ulcer, Gastroenterology, 7 (1946) 607-614. 4 Jarrett, R.J., Rhythms in insulin and glucose. In D.T. Krieger (Ed.), Endocrine Rhythms, Raven Press. New York, 1979, pp. 247-258. 5 Miwa, I., Maeda, K. and Okuda, J., Anomeric compositions of D-glucose in tissues and blo~xl of rat, Experientia, 34 (1978) 167-169. 6 Nagata, Y., Nanba, T., Ando, M., Miwa, I. and Okuda, J., Anomeric preferences of D-glucoseuptake and utilization by cerebral cortex slices of rats, Neurochem. Res.. 4 (1979) 505-516. 70kuda, J., Miwa, 1., Sato, M. and Murata, T., Uptake of D-glucose anomers by rat retina, Experientia. 33 (1977) 19-20. 8 Pigman, W. and Isbell0 H.S., Mutarotation of sugars in solution. Part I Histor3', basic kinetics and composition of sugar solutions, Adv. Carbohyd. Chem., 23 (1968) 11-57. 9 Quigley, J.P. and Templeton, R.D., Action of insulin on the motility of the gastrointestinal tract. IV. Action on the stomach following double vagotomy. Amer. J. Physiol., 91 (1930) 482-487.
351 10 Sakaguchi, T. and lwanaga, M., Effects of D-glucose anomers on afferent discharge in the hepatic vagus nerve, Experientia, 38 (19821 475-476. 11 Sakaguchi, T. and Shimojo, E., Inhibition of gastric motility induced by hepatic portal injections of i~-glucose and its anomers. J. Physiol. (Lond.), 351 (19841 573- 581. 12 Sakaguchi, T.. Taguchi, T. and Okuda, J., Different effects of D-glucose anomers on enhanced motility of the stomach, Biochem. Int., 7 (1983) 299-305. 13 Sakaguchi, T. and Yamaguchi, K., Effects of vagal stimulation, vagotomy and adrenalectomy on release of insulin in the rat, J. Endocrinol., 85 (19801 131 136. 14 Salomon, L.L. and Johnson. J.E., Enzymatic microdetermination of glucose in blc,od and urine. Analyt. Chem., 31 (19591 453-456. 15 Sharma, K.N., Anand, B.K.. Dua, S. and Baldev Singh., Role of stomach in regulation of activities of hypothalamic feeding centers, Amer. J. Physiol., 201 (19611 593-598.
347
JAN 00431
Short C o m m u n i c a t i o n
Inhibition of gastric motility elicited by D-glucose anomers in man T a k e o Sakaguchi, M a s a h i r o Ohtake, Akira Niijima and Kenji T a k i z a w a l Departments of Phvswlogy and J Psychiatry, Ntigata Unwersttv School of Medwme, Nitgata 951 (Japan)
Key word~: blood glucose - gastric motility - glucose anomer - man
It has been accepted that changes in the glucose concentration in the blood influence gastric motility; hypoglycemia causes enhanced motility of the stomach by stimulating the vagal glucose-sensitive mechanisms, whereas the raised motility is depressed by glucose [1,9]. On the other hand, D-glucose dissolved in an aqueous solution exists as an optically equilibrated mixture of its two anomers: 36% a-anomer and 64% fl-anomer [8]. Moreover, almost the same anomeric fraction has been known to exist in the blood of higher animals [2,5]. However, the physiological significance of each anomer remains to be elucidated in humans. Recently, it was observed that D-glucose and its anomers injected into the vein affected the gastric motility in man, respectively. Thirty-two healthy men (18-22 years old) weighing about 56-63 kg were tested. They were divided into 3 groups; the first group of 8 men received no injection, the second group of 12 men received NaCI and equilibrated o-glucose, and the third group of 12 men received or- and fl-D-glucose. They were deprived of food for 12- 16 h before the experiments and the experiments were conducted in the mornings to eliminate any diurnal variation in plasma concentrations of glucose and insulin [4]. The evaluation of gastric motility was made by the balloon methods described earlier [9,11]. Briefly, a Salem Sump tube (Argyle) with a balloon at the tip was introduced into the stomach of a subject through his esophagus and was fixed in position with a tape on his lip. The balloon was inflated with water at body temperature and at an initial pressure of 15-18 kPa. The pressure was recorded by a strain-gauge pressure transducer combined with an ink writing recorder (Nihon Kohden). Throughout the experiment, body temperature of each man was between 36.5 to 36.8°C. The D-glucose and NaCI dissolved in distilled water kept at 25°C were infused through a catheter placed in the cubital vein. The purity of alpha and Correspondence: T. Sakaguchi, Department of Physiology, Niigata University School of Medicine, Niigata 951, Japan. 0165-1838/85/$03.30 4~ 1985 Elsevier Science Publishers B.V. (Biomedical Division)
348 |T'/mM equll. G.glucose
SSSmM equil. D-glucose
0-* 3 rain
Fig. 1. A graph showing the effect of equilibrated D-glucose on enhanced motility of the stomach caused by insulin-hypoglycemia. Equilibrated D-glucose (277 and 555 mM, 100 ml) and NaCI (308 raM, 100 ml) were injected into a vein in the forearm. Arrows show the time of injections.
beta anomers (Nakarai) was more than 96%. Optically equilibrated D-glucose solution consisting of 36% a- and 64% //-D-glucose was obtained by incubating at room temperature (25°C) either a- or/t-o-glucose solution for 22 h to induce the glucose to mutarotate completely. Crystallized D-glucose anomers (a and /3) were dissolved in water at 25°C immediately before use to eliminate mutarotation of the glucose; the time periods required for the two anomers to be dissolved in the same water were about 15 s and the mutarotational half-life of the two anomers was 26.1 5- 0.5 min (n = 5) at 25°C in the same water. A venous injection (100 ml) of test solution was performed for the duration of 90 s. Regular insulin (Novo) was administered, i.v. (0.8 ~tg/kg/h) to stimulate motility of the stomach [3,9]. The concentrations of glucose and insulin in the blood were measured by the methods reported earlier [13,14]. Blood for glucose and insulin estimations was drawn through the same catheter in the vein. Statistical significance of differences between values was determined by t-test: P < 0.05 was taken as indicative of significance between means. When intragastric pressures were recorded during hypoglycemia associated with 0 . 8 / ~ g / k g / h insulin administration, elevated pressures were usually observed 40-100 min after insulin administration (Fig. 1). The injections of 277 and 555 mM (100 ml) equilibrated D-glucose solution into the cubital vein produced an abrupt and substantial decrease in the pressure. The levels (mean 5- S.E.M.) of the pressure 0, 1, 2, 3, 4 and 5 rain after the 277 mM D-glucose (isotonic) were 24.1 5- 1.1, 22.5 + 1.3, 19.8 + 1.4, 20.5 + 1.3, 20.5 5- 1.4 and 21.6 + 2.6 kPa (n = 12), respectively. The levels of the pressure 1, 2, 3 and 4 min after the injection were significantly diminished (P < 0.02-0.001) compared to the level before the injection; the inhibitory response reached its peak in about 2 min and disappeared m 6 rain after the injection. No significant reduction in pressure was elicited after the administration of 100 nil 308 mM NaCl solution which is equitonic to 555 mM D-glucose (Fig. 1). Equilibrated D-glUCOSe solutions of 3 different concentrations (138, 277 and 555 raM) were injected in the vein to examine the relationship of concentration to the pressure decrease (Fig. 2). Although the 138 mM D-glucose injection failed to cause a response, the 277 and 555 mM D-glucose injections produced a significant decrease
349
~
20
o(])o 0 ~ o
0~o.
O~ 0
a.,~
10 c --
Oj
,.°~
r---J
!- s.0] 2.5
o~0
,-,
20
d<~6""o<).e'-o<)6 .,.'~,~"
o@o
3 nlin
I
II
III
IV
Fig. 2. The effect of venous injections of 138 ( O : n = 12), 277 ( ~ : n = 12) and 555 (e: n = 12) mM equilibrated D-glucose on the intragastric pressure provoked by 0.8 # g / k g insulin. A square in the center shows duration of the venous injection. Values are means_+ S.E.M. * P < 0.05. ** P < 0.01 and *** P < 0.00l : significantly different from the value just before injection. F i g 3. The intragastric pressures 2 rain after administering 154 mM NaCI (I), 277 m M a-D-glucose (11). 277 mM equilibrated D-glucose (III), and 277 m M ,8-D-glucose (IV). Values are means + S.E.M. N u m b e r s in parentheses represent the n u m b e r of samples, a, P < 0.02 vs N a C h b, P < 0.001 vs N a C h c, P < 0.05 vs c~-D-glucose or equilibrated D-glucose.
( P < 0 . 0 5 - 0 . 0 0 1 ) in the pressure relative to the level before injection. Plasma concentrations of glucose were not significantly different from each other either just before or 9 min after the 3 injections. However, the concentrations 3 and 6 rain after the 277 and 555 mM D-glucose administrations increased significantly ( P < 0.05-0.001) compared to the level before injection (Fig. 2). Plasma concentration (mean __+S.E.M.) of insulin just before the venous test administration was 391 _+ 18 (n = 31) pM. The levels (mean _+ S.E.M.) of pressure 2 min after the 154 mM NaC1, 277 mM a-D-glucose, 277 mM equilibrated D-glucose and 277 mM B-D-glucose injections were 24.1 + 0.8 (n - 9), 20.6 + 1,6 (n = 9), 19.8 + 1.3 (n = 8) and 16.8 _+ 1.4 (n = 9) kPa, respectively (Fig. 3). Statistically, the magnitude of the pressure drop after the B-D-glucose injection was greater than that after the equilibrated D-glucose ( P < 0.05) or the a-D-glucose ( P < 0.05) injections. Atropin (10 ~g/kg, s.c.) blocked these glucose responses (n = 3). Although elevated motility of the stomach evoked by insulin has been shown to be reduced through vagal action by glucose [9,11], only a few researchers have reported the relation between intragastric pressure and the concentration of glucose in the blood during insulin-hypoglycemia [11,15 I. In the present study, equilibrated D-glucose injected into the vein transiently suppressed the elevated motility of the stomach caused by insulin-hypoglycemia and the inhibitory response by the D-glucose solutions was not reproduced by hypertonic NaCI solutions, suggesting.that the response is not due to osmotic effects (Fig. 1). The 3 different doses of the D-glucose injected into the vein appeared to induce a dose-dependent reduction in intragastric pressure (Fig. 2); we conclude that increasing the concentration of glucose in the
350 blood consistently inhibits the raised pressure of the stomach. However, the action site of D-glucose on the pressure is not simple to explain. Because glucose-sensitive mechanisms vagally controlling gastric motility have been well-documented in the central nervous regions [12,15] and in the hepatic portal regions [11], the inhibitory responses observed are thus derived from a mechanism in the brain or in the hepatic portal vein or from both mechanisms. Unfortunately, the present data did not shed light on this problem. There have been numerous investigations of the uptake and utilization of o-glucose, but only a few reports have dealt with the uptake and utilization of a- and fl-D-glucose in humans. It has been rather difficult to study the physiological significance of anomers of D-glucose because of the rapid mutarotation of the two anomers. In the present study, mutarotational half-life of the two anomers in distilled water kept at 25°C was about 27 min and a venous administration of D-glucose anomers was completed in 2 rain. Moreover, it should be noted that half-life of the two anomers in h u m a n blood was found to be 2.7 rain at 37°C (unpublished data). So the experiment could provide understanding to the physiological function of D-glucose anomer in h u m a n s based on the fact that the inhibitory response reached its peak in about 2 min (Figs. 1 and 2). Concerning the physiological function of the glucose anomers, several works have suggested that fl-D-glucose is more rapidly transported and metabolized by various nerve cells than a-D-glucose [6,7,10]. In this study, fl-D-glUCOSe was most potent in reducing the intragastric pressure (Fig. 3); anomeric preference is expected to be valid in the vagal mechanism detecting D-glucose. Although more definite experiments are needed to determine the exact action site of anomeric predominancy, the present data suggest that fl-D-glBcose in the blood may play an important role in activating the mechanisms vagally controlling gastric motility in humans.
References 1 Bachrach. W.H., Action of insulin hypoglycemia on motor and secretory functions of the digestive tract, Physiol. gev., 33 (1953) 566-592. 2 Hill, J.B. and Cowart, D.S., Mutarotase and glucose anomers, Biochem. Med., 1 (1967) 62-86. 3 Hollander, F., The insulin test for the presence of intact nerve fibers after vagal operations for peptic ulcer, Gastroenterology, 7 (1946) 607-614. 4 Jarrett, R.J., Rhythms in insulin and glucose. In D.T. Krieger (Ed.), Endocrine Rhythms, Raven Press. New York, 1979, pp. 247-258. 5 Miwa, I., Maeda, K. and Okuda, J., Anomeric compositions of D-glucose in tissues and blo~xl of rat, Experientia, 34 (1978) 167-169. 6 Nagata, Y., Nanba, T., Ando, M., Miwa, I. and Okuda, J., Anomeric preferences of D-glucoseuptake and utilization by cerebral cortex slices of rats, Neurochem. Res.. 4 (1979) 505-516. 70kuda, J., Miwa, 1., Sato, M. and Murata, T., Uptake of D-glucose anomers by rat retina, Experientia. 33 (1977) 19-20. 8 Pigman, W. and Isbell0 H.S., Mutarotation of sugars in solution. Part I Histor3', basic kinetics and composition of sugar solutions, Adv. Carbohyd. Chem., 23 (1968) 11-57. 9 Quigley, J.P. and Templeton, R.D., Action of insulin on the motility of the gastrointestinal tract. IV. Action on the stomach following double vagotomy. Amer. J. Physiol., 91 (1930) 482-487.
351 10 Sakaguchi, T. and lwanaga, M., Effects of D-glucose anomers on afferent discharge in the hepatic vagus nerve, Experientia, 38 (19821 475-476. 11 Sakaguchi, T. and Shimojo, E., Inhibition of gastric motility induced by hepatic portal injections of i~-glucose and its anomers. J. Physiol. (Lond.), 351 (19841 573- 581. 12 Sakaguchi, T.. Taguchi, T. and Okuda, J., Different effects of D-glucose anomers on enhanced motility of the stomach, Biochem. Int., 7 (1983) 299-305. 13 Sakaguchi, T. and Yamaguchi, K., Effects of vagal stimulation, vagotomy and adrenalectomy on release of insulin in the rat, J. Endocrinol., 85 (19801 131 136. 14 Salomon, L.L. and Johnson. J.E., Enzymatic microdetermination of glucose in blc,od and urine. Analyt. Chem., 31 (19591 453-456. 15 Sharma, K.N., Anand, B.K.. Dua, S. and Baldev Singh., Role of stomach in regulation of activities of hypothalamic feeding centers, Amer. J. Physiol., 201 (19611 593-598.