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Effect of Glucose/Sulfonylurea Interaction on Release of Insulin

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Effect of Glucose/Sulfonylurea Interaction on Release of Insulin Proc. Nati. Acad. Sci. USA Vol. 76, No. 11, pp. 5901-5904, November 1979 Medical Sciences Effect of glucose/sulfonylurea interaction on release of insulin, glucagon, and somatostatin from isolated perfused rat pancreas (glibenclamide) SUAD EFENDIt*, FRANZ ENZMANNf, ANITA NYLtN*, KERSTIN UVNAS-WALLENSTENt, AND ROLF LUFT* *Department of Endocrinology, Karolinska Hospital, 104 01 Stockholm; tDepartment of Pharmacology, Karolinska Institute, 104 01 Stockholm, Sweden; and tHoechst Aktiengesellschaft, Medizinische Abteilung, Frankfurt, West Germany Contributed by Rolf Luft, July 27, 1979 ABSTRACT The effect of a sulfonylurea, glibenclamide, method and separated on CM-cellulose column. The antibodies on the release of insulin, glucagon, and somatostatin was studied produced in our laboratory were used at a final dilution of 1: in the isolated perfused rat pancreas. At concentrations glucose 56,000. Crossreactivity of the antibody was less than 0.01% with of 1.1 mM or less, the drug stimulated somatostatin release, whereas glucagon release, after 2-3 min of increase, was insulin, glucagon, substance P, luliberin, vasopressin, and ox- markedly inhibited. Insulin release was moderately stimulated, ytocin. The antigenic specificity of the antibodies was deter- and maximal release occurred relatively late. A moderate glu- mined by using somatostatin analogues (11). Phosphate buffer cose load (6.7 mM) inhibited glibenclamide-induced release of (0.04 M, pH 7.4) containing 1% bovine serum albumin was used somatostatin, whereas the two in combination exerted an ad- as the diluent for all components in this radioimmunoassay. ditive action on insulin release. Greater glucose loads, which by themselves would stimulate somatostatin release, only Incubations were for 48 hr at 4°C. Separation of bound from marginally suppressed glibenclamide-induced somatostatin free tracer was on dextran-coated charcoal (12). Dilution of release. The insulinogenic effect of these glucose levels was not perfusates demonstrated binding parallel to that of the synthetic modified by glibenclamide. Glibenclamide may thus stimulate standard. The sensitivity of the assay was 5 pg/ml (13). both the alpha and beta as well as delta cells of the pancreas, depending on glucose concentration. We suggest a paracrine (local) interaction of somatostatin with the alpha and Cta cells, RESULTS which has an important role in the kinetics of insulin and glu- cagon release induced by sulfonylureas. Effect of Glucose Concentration on Responsiveness to Glibenclamide by Beta, Alpha, and Delta Cells of the Pan- Sulfonylurea compounds stimulate the release of insulin and creatic Islets. After isolation, each pancreas was equilibrated somatostatin from the pancreas (1-3). Their effect on insulin for 10 min with a medium containing 3.3 mM glucose and then release is dependent upon the prevailing glucose concentration perfused with either 0, 1.1, 3.3, or 4.4 mM glucose. Twenty (4, 5). There are contradictory reports regarding the effect of minutes after the start of these infusions, glibenclamide at 1 sulfonylureas on glucagon release: they have been considered ,ug/ml was added to the infusion medium (Fig. 1). Before the to either stimulate (6) or inhibit this function (2, 7, 8). addition of glibenclamide, the amount of insulin and soma- The present study demonstrates that the effect of one such tostatin in the perfusate increased with increasing glucose sulfonylurea, glibenclamide, on somatostatin and glucagon concentrations, whereas the amount of glucagon decreased (Fig. release is glucose dependent as well and suggests a paracrine 1). action of somatostatin on the alpha and beta cells of the is- The insulin release by glibenclamide was considerably more lets. pronounced at glucose concentrations of 3.3 and 4.4 mM than MATERIAL AND METHODS 0-and 1.1 mM. In contrast, the release of somatostatin after glibenclamide addition was more pronounced at glucose con- The pancreas was removed from fasting (18 hr) Sprague- centrations of 0-3.3 mM than at 4.4 mM. Dawley rats (Cimex, Stockholm) and attached by the coeliac The elevated levels of glucagon appearing at glucose con- artery to an open-circuit perfusion system. The glands were centrations of 0 and 1.1 mM were markedly inhibited by gli- perfused with a Krebs-Ringer bicarbonate solution (5) con- taining 2% bovine serum albumin, to which the various con- centrations of were an glucose added. After initial equilibration Table 1. Effect of interaction of glibenclamide and glucose on period (20-40 min) with basal glucose concentration, gliben- release of insulin and somatostatin clamide (Daonil; final concentration, 1 Mug/ml) or glucose (to give 6.7-33.3 mM) was added. The perfusion system was op- Hormone Glucose Glibenclamide (1 Ag/ml) mM - erated at a flow rate of 2.5 ml/min. released* load, + Insulin was determined by a double-antibody radioimmu- Insulin, 3.3 0 2,955 ± 184 noassay (9), using an insulin reagent kit (Radiochemical Centre, itU min-' mlh' 6.7 1,260 + 147 4,887 + 380 Amersham). Glucagon was assayed by the charcoal separation 16.7 12,965 + 1129 10,532 i 1060 technique, using an antibody specific for pancreatic glucagon 33.3 20,649 i 2176 20,656 ± 2741 (10). Somatostatin was measured with a radioimmunoassay. Somatostatin, 3.3 -86 i 37 507 + 115 Tyr-somatostatin was labeled with 125I by the lactoperoxidase pg min-I ml-, 6.7 -31 + 37 108 i 42 16.7 97 + 62 308 + 57 The publication costs of this article were defrayed in part by page 33.3 142 i 72 390 i 102 charge payment. This article must therefore be hereby marked "ad- AU, microunit. vertisement" in accordance with 18 U. S. C. §1734 solely to indicate * Insulin and somatostatin responses are expressed as incremental this fact. areas from 0 to 20 min (see Fig. 2). Values are given as mean i SEM. 5901 Downloaded by guest on September 28, 2021 5902 Medical Sciences: Efendic et al. Proc. Natl. Acad. Sci. USA 76 (1979) 500 mM 1.1 mM 3.3 mM 4.4 mM C: 400- D 300 .: 200 c 100 .---0 8000' 7000' 6000- c E1 5000 C 4000 0 , 3000 2000 1000 I 0 I -i 40 c 30- .E CLcx - 20' 0 00E en1o10. -20-10 0 10 20 30-20-10 0 10 20 30-20-1 00 10 20 30-20-o 0 10o 20 30 Time, min FIG. 1. Effect of glibenclamide (1 ,gg/ml) (V////l) on the release of inrulin, glucagon, and somatostatin from the isolated rat pancreas perfused with 0 (n = 6), 1.1 (n = 8), 3.3 (n = 9), and 4.4 (n = 5) mM glucose (solid line). Hatched areas between the curves denote control experiments without glibenclamide. Values are given as mean i SEM. U, unit. benclamide. This latter effect become apparent 4-5 min after produced an additive effect on insulin release. The drug had the glibenclamide infusion was started. In addition, gliben- no effect on the insulin release stimulated by'16.7 and 33.3 mM clamide seemed to exert a stimulatory effect on glucagon re- glucose. lease during the first 2 min. The increase in somatostatin release by glibenclamide was Effect of Glibenclamide on Release of Insulin and So- markedly inhibited by 6.7 mM glucose (P < 0.005). The inhi- matostatin with Increasing Glucose Loads. In these experi- bition was less pronounced at 16.7 mM glucose (P > 0.05) and for 20 min with 3.3 mM almost absent at 33.3 mM glucose (P > 0.05) (Table 1). ments, the pancreas was equilibrated This complex interaction between glucose concentration, glucose and then stimulated with increasing amounts of glucose glibenclamide, and the release of insulin and somatostatin was in the absence or presence of glibenclamide (Fig. 2, Table 1). confirmed by another series of experiments (Fig. 3). Again, The lowest glucose load applied, 6.7 mM, clearly stimulated glibenclamide enhanced the insulmiogenic effect of 6.7 mM but insulin relepse. This was even more pronounced with 16.7 mM not of 16.7 mM glucose. Furthermore, 6.7 mM glucose itself had glucose, whereas infusion of 33.3 mM glucose was accompanied no effect on somatostatin release but markedly inhibited gli- by only a minor further increase. Somatostatin release was not benclamide-induced release of somatostatin. Conversely, 16.7 affected by 6.7 mM glucose whereas glucose at 16.7 and 33.3 mM glucose stimulated somatostatin release while somewhat mM was stimulatory. inhibiting the effect of glibenclamide on somatostatin re- Infusion of 1 gg of glibenclamide per ml with 6.7 mM glucose lease. Downloaded by guest on September 28, 2021 Medical Sciences: Efendic" et al. Proc. Natl. Acad. Sci. USA 76 (1979) 5903 2000 40- n = 4 II = 9 30' 1000- 20 101-3 3.3 3.3 3.3 a.- 200CI. 40 n = 8 30 looc 20 10 - 3.3 6.7 3.'3 6. 3.3 6.7 ._, m = 2000 Xl4C40 'U cC ln = 7 n = 8 3C 1000. 20 10 16.7 3.3 16.7 3.3 16.7 3.3 , 16.7 1 3.3 2000 401- n =8 n= 8 30 1000. 20 10l I I 3.3 33.3 3.3 33.3 3.3 L 33 33 -i 3.3 33.3, Glucose, mM -20-10 0 10 20-20-10 0 10 20 -20-10 0 10 20-20-10 0 10 20 Time, min FIG. 2. Effect of interaction of glibenclamide (1 tig/ml) C777Z=1) and increasing glucose loads (6.7, 16.7, and 33.3 mM) on insulin and so- matostatin release from the isolated perfused rat pancreas. Hormones were measured in 1-min samples. Values are given as mean + SEM. U, unit. DISCUSSION rapid increase in somatostatin release, implies that somatostatin may have mediated the inhibition of glucagon release.
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