- Email: [email protected]
Effect of physiological increments of blood glucose on plasma somatostatin and pancreatic polypeptide levels in dogs
Regulatory Peptides, 2 (1981) 211-218 Elsevier/North-Holland Biomedical Press
211
EFFECT OF PHYSIOLOGICAL INCREMENTS OF BLOOD GLUCOSE ON PLASMA SOMATOSTATINAND PANCREATIC POLYPEPTIDE LEVELS IN DOGS
V. SCHUSDZIARRA, W. STAPELFELDT, M. KLIER, V. MAIER and E.F. PFEIFFER
Department of Internal Medicine I, University of Ulm, Ulm, FederalRepublic of Germany (Received 18 March 1981 ;Accepted for publication 1 April 1981)
SUMMARY
The present study was designed to determine the effects of physiological increments of plasma glucose levels upon basal and stimulated plasma somatostatin and pancreatic polypeptide levels. In seven conscious dogs the elevation of plasma glucose levels by 3 0 - 4 0 mg/dl did not change basal somatostatin and pancreatic polypeptide levels. During stimulation of these two hormones by acetylcholine and the octapeptide of cholecystokinin intravenous infusion of glucose elicited a significant decrease of somatostatin levels by 30 pg/ml and of pancreatic polypeptide levels ~y 300 pg/ml. The present data demonstrate that a physiological elevation of plasma glucose levels inhibits stimulated but not basal somatostatin and pancreatic polypeptide levels which may be of importance for nutrient entry and metabolism. plasma glucose levels; somatostatin; pancreatic polypeptide; physiological increment; dogs
INTRODUCTION Peripheral venous plasma somatostatin-like immunoreactivity o f dogs
increases in response to a meal [ 19,20] and evidence has been accumulated
212
it has been reported that glucose stimulates pancreatic somatostatin release in vitro [8,23] and in vivo [ 18] other studies have shown that in conscious dogs intravenous glucose has an inhibitory effect on basal and meal-stimulated peripheral vein plasma SLI levels [20]~. In all t ~ exl~riments, however, the increase in plasma glucose levels has been rather unphysiological~ high. Therefore, the present study was designed to determine in normal cons.,:~ious dogs the effect of physiological increments of plasma glucose levels upon peripheral vein plasma SLI levels and upon those stimulated by the infusion of acetylcholine [24] and the octapeptide of cholecystokinin [ 16]. Additionally, pancreatic polypeptide levels were determined. MATERIAL AND METHODS
The experiments were performed in 7 conscious dogs (body weight 2 7 - 3 4 kg) after a ! 2 - 1 7 h fast. Each dog received an infusion of either: (I)acetylcholine (Ach; I0 /~g/kg/min) + cholecystokinin-octapeptide (CCK-OP~ 0.8 ng/kg/min) + saline (2) Ach/CCK-OP + glucose (3) saline + glucose. The infusion of Ach/CCK-OP started 30 rain before the onset of the glucose infusion. Glucose (40%) was infused at increasing rates to raise plasma glucose levels stepwise by approx. 10 mg/di to a maximum of 30--40 mg/dl above baseline levels, Plasma glucose concentrations were monitored continuously by means of the Biostator Glucose Controller (Miles Company). All dogs served as their own controls and the experiments were carried out in random order. Frequent samples were drawn from a crural vein before and during the infusion and all blood samples were collected in tubes containing 6 mg EDTA and 500 K.I.U. Trasylol ® per ml blood. The samples were kept chilled in an ice bath until centrifugation at 2000 rpm for 20 rain at 4°C. The separated plasma was stored at -20°C until the time of assay. Plasma levels of insulin [29,6], somato~tatin [5] and pancreatic polypeptide [251 were determined by radioimmunoassay as described elsewhere. Antiserum 80 c for measurement of somatostatin-like immunoreactivity was generously provided by R.H. Unger, Dallas, TX, U.S.A. Standard human pancreatic polypeptide (hPP) and rabbit anti-hPP-serum were a generous gift of R.E. Chance of Lilly Research Lab., Indianapolis, IN, U.S.A. The increments and decrements shown in Figure 1 are the difference from the mean of the three values obtained within the 15 min period immediately before the start of the glucose infusion. For the calculation of statistical significances Student's t-test for paired data was employed and P values of 0.05 or less were considered significant.
213 RESULTS
The infusion of acetylcholine and CCK-OP did not change basal plasma glucose levels for the 30 min before the start of the glucose infusion. The subsequent elevation ~o f plasma glucose levels in response to the stepwise intravenous administration of glucose is shown in Figure 1 No change of
~--~|
I ' =.
GLUCOSE
~
I
I 1
z
I
]
'
I I
=
A,
I
/
I
,,I t
•
O.
~-~00.
:]l
,
_,
10.
~
sahne + glucose
Somato~tatm - 5ke if~ltt,clorea¢ IN#fy
I1.,1~ ~
" ~"
4o
~
~
~Ido"
"41"l,!1
12o
Fig. l. Increments and/or decrements of blood glucose levels, plasma somatostatin (SLI;', insulin (IRD and pancreatic polypeptide (PP) levels during an intravenous infusion of glucose and/or aeetylcholine/CCK-octapeptide. Data represent mean values of ~ven dogs. I, I1 and 111 indicate the stepwise increase after glucose infusion at various tater.
214
v
44
O O l ~-
...., ~
4444
4444
O
If'r4444
-H-H
4"I
OOU'~ +14"I
44+I
O00
r~
•~
0
@
44
o~.~ 0 "~
~
"~ .= ~
o.-
o r ~
ar,,,ar.,,;
"~
215 plasma glucose levels occurred in the dogs receiving Ach/CCK-OP + saline throughout the experimental period. Plasma insulin levels rose in both groups in response to the infusion of acetylcholine/CCK-OP by 1O - 1 2 #U/ml above baseline levels during the 30 r~in before the start o f glucose or sa~line infusion. During the additional saline infusion insulin levels decreased slightly, reaching preinfusion levels of 6 -+ 1 /~U/ml after 30 min. In response to the i.v. glucose infusion insulin levels remained near the plateau of 13 ± 2 ttU/ml that had already been reached during the infusion of acetylcholine/CCK-OP. During the infusion of glucose + saline the increas~ of plasma insulin levels above the mean basal value of 6 ± 1 #U/ml was similar to the one observed in dogs receiving Ach/CCK-OP + glucose (Figure 1). In response to Ach/CCK-OP plasma SLI levels rose from a mean baseline of 70 ± 13 pg/ml to 84 ± 16 pg/ml, decreasing during the infusion of glucose to a nadir of 58 ± 8 pg/ml at 100 min. In the controls SLI levels rose from a mean baseline of 54 ± 11 pg/ml to 74 ± 6 pg/ml in response to Ach/CCK-OP and remained at approximately this level during the subsequent 120 rain of the experimental period (Figure 1). During the infusion of sali'ae + glucose the mean basal plasma SLI level was 64 ± 13 pg/ml and this level did not change significantly during the entire infusion period (Figure 1). Incremental plasma SLI levels during the respective periods of increasing glucose levels are shown in Table I. During the highest elevation of plasma glucose levels a significant decrease of the SLI levels was observed compared to the two other control experiments. In the groups of Ach/CCK-OP + glucose plasma pancreatic ~0olypeptide (PP) levels rose in response to Ach/CCK-OP from a mean baseline of 230 ± 17 pg/ml to 558 ± 126 pg/ml, decreasing thereafter during ti~e infusion of glucose to a nadir of 277 ± 33 pg/ml at 60 rain and remaining at about 330 pg/ml for the following experimental period. In response to Ach/CCK-OP + saline PP levels rose from a mean baseline of 290 ± 30 pg/ml to 530 ± 90 pg/ml decreasing slightly to 404 ± 25 pg/ml at 40 min and increasing thereafter to a maximum of 696 :~ 210 pg/ml at 110 min. During the infusion of saline + glucose basal plasma PP was 242 -* 14 pg/ml increasing slightly, although not significantly, to 330 ± 60 pg/ml at 30 min and remaining at approximately baseline values throughout the subsequent infusion period (Figure 1). Incremental PP levels are shown in Table 1. DISCUSSION
The present study demonstrates that in dogs physiological increments of plasma glucose levels do not affect basal peripheral vein plasr~a somatostatin
216
and pancreatic polypeptide levels but have an inhibitory effect upon stimulated hormone levels. Recently, it has been demonstrated that the infusion of glucose, although in supraphysiological quantities, reduces basal and postprandial plasma SLI [20l and b ~ ! PP [ 12] levels. Since it has been shown that an increase o f plasma glucose levels has an inhibitory effect upon various gastrointestinal functions [3,10,11,27] and might therefore result in an attenuation of the intensity of stimulatory factors during the postprandial period we have employed a less ambiguous stimulus of SLI and PP release - acetylcholine and CCK-octapeptide [ 16,24-26]. The exact mechanism by which glucose elicits the reduction in SLI and PP release remains to be established but in view of the studies in vitro [ 14] as well as in normal and insulin-deficient diabetic animals [9,13,15,18,20] there is substantial supportive evidence that the decrease of plasma SLI might be the result of the inhibitory effect of the increasing plasma insulin concentrations. With regard to pancreatic polypeptide secretion i.v. glucose has been shown to have no effect upon basal pp levels in vitro [ 2,7 ]. In vivo glucose has been shown to be either ineffective or to decrease plasma PP levels [ 1,12]. The inhibitory effect upon stimulated PP levels, as shown in the present study can not necessarily be related to insulin secretion, because insulin appears to have no effect on PP release, at least in vitro [28]. In conclusion the present data show that physiological increments of plasma glucose levels reduce pancreatic polypeptide and somatostatin levels during stimulation by neuroendocrine factors. In view of the proposed physiological roles of these two hormones [4,11,21 ] these changes could act to facilitate the rate of nutrient entry from the gut into the circulation emphasizing the importance of the rate of postprandial glucose influx upon the endocrine status [ 17 ]. ACKNOWLEDGEMENTS
The present study was supported by Deutsche Forschungsgemeinschaft SFB 87 G3 and G6. The authors thank W. Friedrich and 1. Zwiebel for expert technical assistance. REFERENCES I Adrian, T.E., Bloom, S.R., Bestermann, H.S., Barnes, A.J., Cooke, T.J.C., Russel, R.C.G. and Faber, R.G., Mechanism of pancreatic polypeptide release in man, Lancet, 1 (1977) 161-163. 2 Adrian, T.E., Bloom, S.R., Hermansen, K. and lversen, J., Pancreatic polypeptide, glucagon, and insulin secretion from the isolated perfused canine pancreas, Diabetologia, 14 (1978) 413-417.
217 3 Dotteval, G. and Muren, A., Effect of intravenous infusion of glucose on gastric secretory responses to feeding in Parlor and Heidenhain pouch dogs, Acta Physiol. Scand., 52 (1961) 234-241. 4 Grcenberg, G.R., McCloy, R.F., Adrian, T.E., Chadwick, V.S., Baron, J.H. and Bloom, S.R., Inhibition of pancreas and gallbladder by pancreatic polypeptide in man, Lancet, 2 (1978) 1280-1282. 5 Harri~ V,, Conlon, J.M., Srikant, C.B., McCorkle, K., Schusdziarra, V., Ipp, E. and Unger, R.H., Measurements o f somatostatin-like immunoreactivity in plasma, Clin. Chim. Acta, 87 (1978) 275-283. 6 Herbert, V., Lau, K.S., Gottlieb, C.W. and Bleicher, S.J., Coated charcoal imm~noa~_~__yof insulin, J. Clin. EndocrinoL Metab., 25 (1965) 1375-i384. 7 Hermausen, K. and Schwartz, T.W., The influence of calcium on the basal and ace~ylcholine stimulated secretion of pancreatic polypeptide, Endocrinology, 105 (1979) 1469-1475. 8 lpp, E., Dobbs, R.E., Arimura, A., Vale, W., Harris, V. and Unger, R.H., Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancrcozymin-cholecystokinin, and tolbutamide, J. Clin. Invest., 60 (1977) 760765. 9 Kazumi, T., Utsumi, M., Yoshino, G., Ishihara, K., Hirose, Y., Makimura, H. and Baba, S., Somatmtatin concentration response to arglnine in portal plasma, Diabetes, 29 (1980) 71-73. !0 MacGregor, I.L., Gueller, R., Watts, H.D. and Meyer, J.H., The effect of acute hyperglycemia on gastric emptying in man, Gastroenterology, 70 (1976) 190-196. 11 MacGregor, LL., Deveney, C., Way, L.W. and Meyer, J.H., The effect of acute hyperglycemia on meal-stimulated gastric, biliary and pancreatic secretion and serum gastrin, Gastroenterology, 70 (I 976) 197-202. 12 Marco, J., Hedo, J.A. and ViUanueva, M.L., Control of pancreatic polypeptide secretion by glucose in man, J. Clin. EndocrinoL Metab., 46 (1978) 140-145. 13 Patel, Y.C., Wheatley, T., Mallaisse-Lagae, F. and Orci, L., Elevated portal and peripheral blood concentration of immunoreactive $omatostatin in spontaneously diabetic wlstar rats, Diabetes, 29 (1980) 757-761. 14 Rothman, J. and lgnarro, L.J,, Effects of anti-insulin serum in pancreatic somatostatin release, Clin. Res., 26 (1978) 775A. * 15 Rouiller, D., Schu~lziarra, V. and Unger, R.H., Effect of insulin upon pancreatic and ~stric release of somatostatin-like immunoreactivity, Diabetes, 28 (1979) 352. 16 Rouiller, D., Schusdziarra, V., Harris, V. and Unger, R.H., Release of pancreatic and gastric somatostatin-like immunoreactivity in response to the octapeptide of cholecystokinin, secretin, gastric inhibitory polypeptide and gastrin-I 7 in dogs, Endocrinology, 107 (1980) 524-529. 17 Schusdziarra, V., Dangel, G., Klier, M., Henrichs~ 1. and Pfeiffer, E.F, Effect of solid and liquid carbohydrates on pancreatic endocrine function, J. C~in. EndocrinoL Metab., 1981, in press. 18 Schusdziarra, V., Dobbs, R.E., Harris, V. and Unger, R.H., Immuno~eactive somatostatin levels in plasma of normal and alloxan diabetic dogs, FEBS Lett., 81 (1977) 69-72. 19 Schusdziarra, V., ipp, E., Harris, V., Dobbs, R.E., Raskin, P., Orci, L. and Unger, R.H., Studies of the physiology and pathophysiology of the pancreatic D-cell, Metabolism, 27, Suppl. I (1978) 1227-1232.
218 20 Schusdziarra, V., Rouiller, D., Harris, V., Conlon, J.M. and Unser, R.H., The response of plasma somatostatin-like immunoreactivity to nutrients in normal and aUoxan diabetic dogs, Endocrinology, 103 (1978) 2264-2273. 21 Schusdzlarra, V., Harris, V., Arimura, A. and Unger, R.H., Evidence for a role of splanchnic somatostatin in the homeost_a~" of ingested nutrients, Endocrinology, 104 (1979) 1705-1708. 22 Schusdziarra, V., Zyznar, E., Rouiller, D., Boden, G., Brown, J., Arimura, A. and Unger, R.H., Splanchnic somatostatin: a hormonal regulator of nutrient homeostasis, Science, 207 (1980) 530-532. 23 Schauder, P., Mcintosh, C., Arend$, G., Arnold, R., Frerichs, H. and Creutzfeldt, W., Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose, FEBS Lett., 68 (I 976) 225-227. 24 Schusdziarra, V., Rouiller, D., Harris, V., Pfeiffer, E.F. and Unger, R.H., Effect of acetylcholine infusion upon the release of gastric and pancreatic somatostatin-like immunoreactivity, Regul. Peptides, 1, Suppl. 1 (1980)S102. 25 Taylor, I.L., impicciatore, M., Carter, D.C. and Walsh, J.H., Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dogs, An~ J. Physiol., 235 (I 978) 1978. 26 Taylor, I.L., Walsh, J.H., Carter, D.C., Wood, J. and Gromman, M.I., Effect of atropine and bethenachoi on release of pancreatic polypeptide and gastrin by bombesin in dogs, Scand. J. GastroenteroL, 13 (Suppl. 49) (1978) 183. 27 Towne, J.B., Hamilton, R.F. and Stephenson, D.V., Mechanisms of hyperalimentation in the suppression of upper gastrointestinal secretions, Am. J. Surf,, 126 (1973) 714716. 28 Weir, G.C., Samois, E., Loo, S., Patel, Y.C. and Gabbay, K.H., Somatostatin and pancreatic polypeptide secretion. Effects of glucagon, insulin and arginine, Diabetes, 28 (1979) 35-40. 29 Yalow, R.S. and Berson, S.A., lmmunoasuy of endogenous plasma insulin in man, J. Ciin. Invest., 39 (1960) 1157-1175.
211
EFFECT OF PHYSIOLOGICAL INCREMENTS OF BLOOD GLUCOSE ON PLASMA SOMATOSTATINAND PANCREATIC POLYPEPTIDE LEVELS IN DOGS
V. SCHUSDZIARRA, W. STAPELFELDT, M. KLIER, V. MAIER and E.F. PFEIFFER
Department of Internal Medicine I, University of Ulm, Ulm, FederalRepublic of Germany (Received 18 March 1981 ;Accepted for publication 1 April 1981)
SUMMARY
The present study was designed to determine the effects of physiological increments of plasma glucose levels upon basal and stimulated plasma somatostatin and pancreatic polypeptide levels. In seven conscious dogs the elevation of plasma glucose levels by 3 0 - 4 0 mg/dl did not change basal somatostatin and pancreatic polypeptide levels. During stimulation of these two hormones by acetylcholine and the octapeptide of cholecystokinin intravenous infusion of glucose elicited a significant decrease of somatostatin levels by 30 pg/ml and of pancreatic polypeptide levels ~y 300 pg/ml. The present data demonstrate that a physiological elevation of plasma glucose levels inhibits stimulated but not basal somatostatin and pancreatic polypeptide levels which may be of importance for nutrient entry and metabolism. plasma glucose levels; somatostatin; pancreatic polypeptide; physiological increment; dogs
INTRODUCTION Peripheral venous plasma somatostatin-like immunoreactivity o f dogs
increases in response to a meal [ 19,20] and evidence has been accumulated
212
it has been reported that glucose stimulates pancreatic somatostatin release in vitro [8,23] and in vivo [ 18] other studies have shown that in conscious dogs intravenous glucose has an inhibitory effect on basal and meal-stimulated peripheral vein plasma SLI levels [20]~. In all t ~ exl~riments, however, the increase in plasma glucose levels has been rather unphysiological~ high. Therefore, the present study was designed to determine in normal cons.,:~ious dogs the effect of physiological increments of plasma glucose levels upon peripheral vein plasma SLI levels and upon those stimulated by the infusion of acetylcholine [24] and the octapeptide of cholecystokinin [ 16]. Additionally, pancreatic polypeptide levels were determined. MATERIAL AND METHODS
The experiments were performed in 7 conscious dogs (body weight 2 7 - 3 4 kg) after a ! 2 - 1 7 h fast. Each dog received an infusion of either: (I)acetylcholine (Ach; I0 /~g/kg/min) + cholecystokinin-octapeptide (CCK-OP~ 0.8 ng/kg/min) + saline (2) Ach/CCK-OP + glucose (3) saline + glucose. The infusion of Ach/CCK-OP started 30 rain before the onset of the glucose infusion. Glucose (40%) was infused at increasing rates to raise plasma glucose levels stepwise by approx. 10 mg/di to a maximum of 30--40 mg/dl above baseline levels, Plasma glucose concentrations were monitored continuously by means of the Biostator Glucose Controller (Miles Company). All dogs served as their own controls and the experiments were carried out in random order. Frequent samples were drawn from a crural vein before and during the infusion and all blood samples were collected in tubes containing 6 mg EDTA and 500 K.I.U. Trasylol ® per ml blood. The samples were kept chilled in an ice bath until centrifugation at 2000 rpm for 20 rain at 4°C. The separated plasma was stored at -20°C until the time of assay. Plasma levels of insulin [29,6], somato~tatin [5] and pancreatic polypeptide [251 were determined by radioimmunoassay as described elsewhere. Antiserum 80 c for measurement of somatostatin-like immunoreactivity was generously provided by R.H. Unger, Dallas, TX, U.S.A. Standard human pancreatic polypeptide (hPP) and rabbit anti-hPP-serum were a generous gift of R.E. Chance of Lilly Research Lab., Indianapolis, IN, U.S.A. The increments and decrements shown in Figure 1 are the difference from the mean of the three values obtained within the 15 min period immediately before the start of the glucose infusion. For the calculation of statistical significances Student's t-test for paired data was employed and P values of 0.05 or less were considered significant.
213 RESULTS
The infusion of acetylcholine and CCK-OP did not change basal plasma glucose levels for the 30 min before the start of the glucose infusion. The subsequent elevation ~o f plasma glucose levels in response to the stepwise intravenous administration of glucose is shown in Figure 1 No change of
~--~|
I ' =.
GLUCOSE
~
I
I 1
z
I
]
'
I I
=
A,
I
/
I
,,I t
•
O.
~-~00.
:]l
,
_,
10.
~
sahne + glucose
Somato~tatm - 5ke if~ltt,clorea¢ IN#fy
I1.,1~ ~
" ~"
4o
~
~
~Ido"
"41"l,!1
12o
Fig. l. Increments and/or decrements of blood glucose levels, plasma somatostatin (SLI;', insulin (IRD and pancreatic polypeptide (PP) levels during an intravenous infusion of glucose and/or aeetylcholine/CCK-octapeptide. Data represent mean values of ~ven dogs. I, I1 and 111 indicate the stepwise increase after glucose infusion at various tater.
214
v
44
O O l ~-
...., ~
4444
4444
O
If'r4444
-H-H
4"I
OOU'~ +14"I
44+I
O00
r~
•~
0
@
44
o~.~ 0 "~
~
"~ .= ~
o.-
o r ~
ar,,,ar.,,;
"~
215 plasma glucose levels occurred in the dogs receiving Ach/CCK-OP + saline throughout the experimental period. Plasma insulin levels rose in both groups in response to the infusion of acetylcholine/CCK-OP by 1O - 1 2 #U/ml above baseline levels during the 30 r~in before the start o f glucose or sa~line infusion. During the additional saline infusion insulin levels decreased slightly, reaching preinfusion levels of 6 -+ 1 /~U/ml after 30 min. In response to the i.v. glucose infusion insulin levels remained near the plateau of 13 ± 2 ttU/ml that had already been reached during the infusion of acetylcholine/CCK-OP. During the infusion of glucose + saline the increas~ of plasma insulin levels above the mean basal value of 6 ± 1 #U/ml was similar to the one observed in dogs receiving Ach/CCK-OP + glucose (Figure 1). In response to Ach/CCK-OP plasma SLI levels rose from a mean baseline of 70 ± 13 pg/ml to 84 ± 16 pg/ml, decreasing during the infusion of glucose to a nadir of 58 ± 8 pg/ml at 100 min. In the controls SLI levels rose from a mean baseline of 54 ± 11 pg/ml to 74 ± 6 pg/ml in response to Ach/CCK-OP and remained at approximately this level during the subsequent 120 rain of the experimental period (Figure 1). During the infusion of sali'ae + glucose the mean basal plasma SLI level was 64 ± 13 pg/ml and this level did not change significantly during the entire infusion period (Figure 1). Incremental plasma SLI levels during the respective periods of increasing glucose levels are shown in Table I. During the highest elevation of plasma glucose levels a significant decrease of the SLI levels was observed compared to the two other control experiments. In the groups of Ach/CCK-OP + glucose plasma pancreatic ~0olypeptide (PP) levels rose in response to Ach/CCK-OP from a mean baseline of 230 ± 17 pg/ml to 558 ± 126 pg/ml, decreasing thereafter during ti~e infusion of glucose to a nadir of 277 ± 33 pg/ml at 60 rain and remaining at about 330 pg/ml for the following experimental period. In response to Ach/CCK-OP + saline PP levels rose from a mean baseline of 290 ± 30 pg/ml to 530 ± 90 pg/ml decreasing slightly to 404 ± 25 pg/ml at 40 min and increasing thereafter to a maximum of 696 :~ 210 pg/ml at 110 min. During the infusion of saline + glucose basal plasma PP was 242 -* 14 pg/ml increasing slightly, although not significantly, to 330 ± 60 pg/ml at 30 min and remaining at approximately baseline values throughout the subsequent infusion period (Figure 1). Incremental PP levels are shown in Table 1. DISCUSSION
The present study demonstrates that in dogs physiological increments of plasma glucose levels do not affect basal peripheral vein plasr~a somatostatin
216
and pancreatic polypeptide levels but have an inhibitory effect upon stimulated hormone levels. Recently, it has been demonstrated that the infusion of glucose, although in supraphysiological quantities, reduces basal and postprandial plasma SLI [20l and b ~ ! PP [ 12] levels. Since it has been shown that an increase o f plasma glucose levels has an inhibitory effect upon various gastrointestinal functions [3,10,11,27] and might therefore result in an attenuation of the intensity of stimulatory factors during the postprandial period we have employed a less ambiguous stimulus of SLI and PP release - acetylcholine and CCK-octapeptide [ 16,24-26]. The exact mechanism by which glucose elicits the reduction in SLI and PP release remains to be established but in view of the studies in vitro [ 14] as well as in normal and insulin-deficient diabetic animals [9,13,15,18,20] there is substantial supportive evidence that the decrease of plasma SLI might be the result of the inhibitory effect of the increasing plasma insulin concentrations. With regard to pancreatic polypeptide secretion i.v. glucose has been shown to have no effect upon basal pp levels in vitro [ 2,7 ]. In vivo glucose has been shown to be either ineffective or to decrease plasma PP levels [ 1,12]. The inhibitory effect upon stimulated PP levels, as shown in the present study can not necessarily be related to insulin secretion, because insulin appears to have no effect on PP release, at least in vitro [28]. In conclusion the present data show that physiological increments of plasma glucose levels reduce pancreatic polypeptide and somatostatin levels during stimulation by neuroendocrine factors. In view of the proposed physiological roles of these two hormones [4,11,21 ] these changes could act to facilitate the rate of nutrient entry from the gut into the circulation emphasizing the importance of the rate of postprandial glucose influx upon the endocrine status [ 17 ]. ACKNOWLEDGEMENTS
The present study was supported by Deutsche Forschungsgemeinschaft SFB 87 G3 and G6. The authors thank W. Friedrich and 1. Zwiebel for expert technical assistance. REFERENCES I Adrian, T.E., Bloom, S.R., Bestermann, H.S., Barnes, A.J., Cooke, T.J.C., Russel, R.C.G. and Faber, R.G., Mechanism of pancreatic polypeptide release in man, Lancet, 1 (1977) 161-163. 2 Adrian, T.E., Bloom, S.R., Hermansen, K. and lversen, J., Pancreatic polypeptide, glucagon, and insulin secretion from the isolated perfused canine pancreas, Diabetologia, 14 (1978) 413-417.
217 3 Dotteval, G. and Muren, A., Effect of intravenous infusion of glucose on gastric secretory responses to feeding in Parlor and Heidenhain pouch dogs, Acta Physiol. Scand., 52 (1961) 234-241. 4 Grcenberg, G.R., McCloy, R.F., Adrian, T.E., Chadwick, V.S., Baron, J.H. and Bloom, S.R., Inhibition of pancreas and gallbladder by pancreatic polypeptide in man, Lancet, 2 (1978) 1280-1282. 5 Harri~ V,, Conlon, J.M., Srikant, C.B., McCorkle, K., Schusdziarra, V., Ipp, E. and Unger, R.H., Measurements o f somatostatin-like immunoreactivity in plasma, Clin. Chim. Acta, 87 (1978) 275-283. 6 Herbert, V., Lau, K.S., Gottlieb, C.W. and Bleicher, S.J., Coated charcoal imm~noa~_~__yof insulin, J. Clin. EndocrinoL Metab., 25 (1965) 1375-i384. 7 Hermausen, K. and Schwartz, T.W., The influence of calcium on the basal and ace~ylcholine stimulated secretion of pancreatic polypeptide, Endocrinology, 105 (1979) 1469-1475. 8 lpp, E., Dobbs, R.E., Arimura, A., Vale, W., Harris, V. and Unger, R.H., Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancrcozymin-cholecystokinin, and tolbutamide, J. Clin. Invest., 60 (1977) 760765. 9 Kazumi, T., Utsumi, M., Yoshino, G., Ishihara, K., Hirose, Y., Makimura, H. and Baba, S., Somatmtatin concentration response to arglnine in portal plasma, Diabetes, 29 (1980) 71-73. !0 MacGregor, I.L., Gueller, R., Watts, H.D. and Meyer, J.H., The effect of acute hyperglycemia on gastric emptying in man, Gastroenterology, 70 (1976) 190-196. 11 MacGregor, LL., Deveney, C., Way, L.W. and Meyer, J.H., The effect of acute hyperglycemia on meal-stimulated gastric, biliary and pancreatic secretion and serum gastrin, Gastroenterology, 70 (I 976) 197-202. 12 Marco, J., Hedo, J.A. and ViUanueva, M.L., Control of pancreatic polypeptide secretion by glucose in man, J. Clin. EndocrinoL Metab., 46 (1978) 140-145. 13 Patel, Y.C., Wheatley, T., Mallaisse-Lagae, F. and Orci, L., Elevated portal and peripheral blood concentration of immunoreactive $omatostatin in spontaneously diabetic wlstar rats, Diabetes, 29 (1980) 757-761. 14 Rothman, J. and lgnarro, L.J,, Effects of anti-insulin serum in pancreatic somatostatin release, Clin. Res., 26 (1978) 775A. * 15 Rouiller, D., Schu~lziarra, V. and Unger, R.H., Effect of insulin upon pancreatic and ~stric release of somatostatin-like immunoreactivity, Diabetes, 28 (1979) 352. 16 Rouiller, D., Schusdziarra, V., Harris, V. and Unger, R.H., Release of pancreatic and gastric somatostatin-like immunoreactivity in response to the octapeptide of cholecystokinin, secretin, gastric inhibitory polypeptide and gastrin-I 7 in dogs, Endocrinology, 107 (1980) 524-529. 17 Schusdziarra, V., Dangel, G., Klier, M., Henrichs~ 1. and Pfeiffer, E.F, Effect of solid and liquid carbohydrates on pancreatic endocrine function, J. C~in. EndocrinoL Metab., 1981, in press. 18 Schusdziarra, V., Dobbs, R.E., Harris, V. and Unger, R.H., Immuno~eactive somatostatin levels in plasma of normal and alloxan diabetic dogs, FEBS Lett., 81 (1977) 69-72. 19 Schusdziarra, V., ipp, E., Harris, V., Dobbs, R.E., Raskin, P., Orci, L. and Unger, R.H., Studies of the physiology and pathophysiology of the pancreatic D-cell, Metabolism, 27, Suppl. I (1978) 1227-1232.
218 20 Schusdziarra, V., Rouiller, D., Harris, V., Conlon, J.M. and Unser, R.H., The response of plasma somatostatin-like immunoreactivity to nutrients in normal and aUoxan diabetic dogs, Endocrinology, 103 (1978) 2264-2273. 21 Schusdzlarra, V., Harris, V., Arimura, A. and Unger, R.H., Evidence for a role of splanchnic somatostatin in the homeost_a~" of ingested nutrients, Endocrinology, 104 (1979) 1705-1708. 22 Schusdziarra, V., Zyznar, E., Rouiller, D., Boden, G., Brown, J., Arimura, A. and Unger, R.H., Splanchnic somatostatin: a hormonal regulator of nutrient homeostasis, Science, 207 (1980) 530-532. 23 Schauder, P., Mcintosh, C., Arend$, G., Arnold, R., Frerichs, H. and Creutzfeldt, W., Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose, FEBS Lett., 68 (I 976) 225-227. 24 Schusdziarra, V., Rouiller, D., Harris, V., Pfeiffer, E.F. and Unger, R.H., Effect of acetylcholine infusion upon the release of gastric and pancreatic somatostatin-like immunoreactivity, Regul. Peptides, 1, Suppl. 1 (1980)S102. 25 Taylor, I.L., impicciatore, M., Carter, D.C. and Walsh, J.H., Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dogs, An~ J. Physiol., 235 (I 978) 1978. 26 Taylor, I.L., Walsh, J.H., Carter, D.C., Wood, J. and Gromman, M.I., Effect of atropine and bethenachoi on release of pancreatic polypeptide and gastrin by bombesin in dogs, Scand. J. GastroenteroL, 13 (Suppl. 49) (1978) 183. 27 Towne, J.B., Hamilton, R.F. and Stephenson, D.V., Mechanisms of hyperalimentation in the suppression of upper gastrointestinal secretions, Am. J. Surf,, 126 (1973) 714716. 28 Weir, G.C., Samois, E., Loo, S., Patel, Y.C. and Gabbay, K.H., Somatostatin and pancreatic polypeptide secretion. Effects of glucagon, insulin and arginine, Diabetes, 28 (1979) 35-40. 29 Yalow, R.S. and Berson, S.A., lmmunoasuy of endogenous plasma insulin in man, J. Ciin. Invest., 39 (1960) 1157-1175.