Failure of 6-aminonicotinamide to inhibit the potentiating effect of leucine and arginine on glucose-induced insulin release in vitro

Diabetologia, Dec 1974

Summary 6-aminonicotinamide (6-AN), which decreases the activity of the hexosemonophosphate pathway of pancreatic islets as well as the insulin releasing effect of glucose, was used to determine whether the potentiating effect of leucine and arginine on glucose induced insulin release is dependent upon normal function of the hexosemonophosphate pathway in pancreatic islets. In control islets, at low glucose concentrations (1 mg/ml), or in the absence of glucose, insulin release induced by these amino acids was negligible. At high glucose concentrations (3 mg/ml), which markedly stimulated insulin release (584 μU/5 islets/90 min), 1 and 10 mM leucine and 10 mM arginine increased insulin release by another 250 to 300 μU. Islets from animals treated with 6-AN released significantly less insulin in response to glucose alone or glucose plus leucine or arginine than control islets. However, the potentiating effect of these amino acids on insulin release from islets of animals treated with 6-AN was still similar to that observed in control islets and the total insulin released in the presence of 1 or 10 mM leucine or 10 mM arginine plus 3 mg/ml glucose was about the same as that observed in control islets in the presence of 3 mg/ml glucose alone. The data are consistent with the hypothesis that glucose exerts a permissive effect upon the insulinogenic actions of leucine and arginine, but that glucose oxidation through the hexosemonophosphate pathway is not important for the potentiation of glucose-induced insulin release by these amino acids.

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Failure of 6-aminonicotinamide to inhibit the potentiating effect of leucine and arginine on glucose-induced insulin release in vitro

Failure of 6-Aminonicofinamide to Inhibit the Potentiating Effect of Leueine and Arginine on Glucose-Induced Insulin Release in Vitro* M.J. MacDonald 0 2 H . P . T . Ammon 0 2 T. Patel 0 2 J. Steinke 0 2 0 E.P. Joslin Research Laboratory, Harvard Medical School and Peter Bent Brigham Hospital, and the Elliott 1). Joslin Research Foundation, Inc. , Boston, Mass. , USA and the Dept. of 1)harmacology, University of Erlangen-Nurenberg , W. Germany 1 Supported by U.S.P.H.S. Grants AM 15721 and AM 05077 and the P. Martini Foundation , Frankfurt, W. Germany 2 1Department of Pharmacology, University of Erlangen-Nurenberg , W. Germany. 2 Deceased Summary. 6-aminonicotinamide (6-AN), which de. creases the activity of the hexosemonophosphate pathway of pancreatic islets as well as the insulin releasing effect of glucose, was used to determine whether the potentiating effect of leueine and arginine on glucoseinduced insulin release is dependent upon normal function of the hexosemonophosphate pathway in pancreatic islets. In control islets, at low glucose concentrations (1 mg/ml), or in the absence of glucose, insulin release induced by these amino acids was negligible. At high glucose concentrations (3 mg/ml), which markedly stimulated insulin release (584 fzU/5 islets/90 rain), 1 and 10 mM leucine and 10 m3/I arginine increased insulin release by another 250 to 300 y.U. Islets from animals treated with 6-AN released significantly less insulin in response to glucose alone or glucose plus leueine or arginine than control islets. However, the potentiating effect of these amino acids on insulin release from islets of animals treated with 6-AN was still similar to that observed in control islets and the total insulin released in the presence of 1 or 10 mM leueine or 10 mM arginine plus 3 mg/ml glucose was about the same as that observed in control islets in the presence of 3 mg/ml glucose alone. The data are consistent with the hypothesis tha~ glucose exerts a permissive effect upon the insulinogenie actions of leucine and arginine, but that glucose oxidation through the hexosemonophosphate pathway is not important for the potentiation of glucose-induced insulin release by these amino acids. Glucose; 6-aminonicotinamide; leucine; arginine; insulin release; hexosemonophosphate pathway - Recently it was shown t h a t normal function of the hexosemonophosphate p a t h w a y of the pancreatic beta cell is critical for glucose-induced insulin release. When 6-aminonicotinamide (6-AN), an antimetabolite of pyridine nucleotide synthesis [ 1 ], was administered to rats, they became transiently diabetic. Isolated pancreatic islets from these rats showed a marked decrease in insulin release when challenged with glucose [ 2 ], aminophylline [ 3 ], or cyclic AMP [ 4 ] and a marked decrease in the activity of the hexosemonophosphate p a t h w a y as evidenced b y decreased oxidation of 1-1aCglucose to luCCa, whereas t h a t from 6-14C-glucose was essentially unchanged [ 3 ]. Tolbutamide, however, is able to overcome the block in insulin secretion without overcoming the block in the oxidation of glucose at C-1 caused b y 6-AN, suggesting t h a t normal function of the hexosemonophosphate p a t h w a y is not necessary for insulin release by tolbutamide [ 3 ]. I t has been well documented t h a t leucine and arginine stimulate insulin release in vitro [5--10] and in vivo [11--17]. There is also evidence t h a t insulin release from the isolated pancreatic islet stimulated b y leucine and arginine is dependent on the glucose concentration, but leueine seems to be less dependent upon glucose in this respect t h a n is arginine [ 5, 10, 18, 19 ]. Since leucine and arginine, similar to tolbutamide, are most effective in stimulating insulin release in the presence of high glucose concentrations, but since the the activity of the hexosemonophosphate p a t h w a y of the pancreatic islet is independent of the glucose concentration [ 20, 21 ], it is possible t h a t the stimulation of insulin release b y leucine and arginine is also independent of the activity of the hexosemonophosphate pathway. To test this hypothesis we investigated[ the effect of leucine and arginine on insulin release and glucose oxidation b y isolated islets of rats treated with 6-AN. The data indicate t h a t potentiation of glucoseinduced insulin release by these amino acids is not affected b y 6-AN and t h a t a normal rate of glucose oxidation through the hexosemonophosphate p a t h w a y is not necessary for these amino acids to potentiate insulin release. Materials and Methods Exloerimental Procedure Female rats, weighing about 200 g, of the Charles River CD strain were used. They were allowed free access to standard Purina chow and tap water. Rats, injected with 6-aminonieotinamide (Aldrich Chemical Co., Inc., Milwaukee, Wis.) 35 mg/kg intraperitoneally six hours before t h e y were sacrificed, and control rats were studied. Their pancreata were removed under ether anesthesia and the pancreatic islets isolated using a collagenase (Worthington Biochemical Corp., Freehold, N . J . ) technique [ 22 ]. The t t a n k ' s solution used for isolation of islets from the 6-aminonieotinamide t r e a t e d rats contained 3.5 mg/100 ml 6-aminonieotinamide. Insulin Release Insulin release studies were performed with an incubation medium containing 2% albumin (bovine albumin powder fraction V, Armour Pharmaceutical Co., Chicago, Illinois) in Krebs-Ringer bicarbonate buffer, p H 7.4, alone or with glucose i mg/ml or 3 rag/ ml, leucine i or 10 raM, or arginine 1 or 10 raM. The incubation m e d i u m used for islets of the 6-AN t r e a t e d animals also contained 6-AN, 3.5 rag/ 100 ml. Five islets per flask, in 1.0 mt medium were incubated in a Dubnoff metabolic shaker at 37~ for 90 rain and gassed with 95~o 0 2 : 5 % C02. Insulin released into the medium was measured b y a double a n t i b o d y imm u n o a s s a y [ 23 ], employing proinsulin-free rat insulin as a standard (courtesy of N e r o Laboratories). Glucose Oxidation For the studies with ~4C labelled glucose 17 t o 20 islets were placed into center wells of scintillation counter vials containing 0.2 ml of the incubation medium used for insulin release studies, except t h g t all solutions contained 3 mg/ml glucose labelled at, C-1 or C-6 with a specific radioactivity of 1 ~Ci/mg and the desired concentrations of 6-AN, leucine or arginine. The scintillation vials were stoppered and incubated at 37~C for three hours in a Dubnoffmetabotie shaker. The vials were gassed with 95% O2:5~ CO~ for the first five minutes of the incubation. The reaction was term i n a t e d b y injecting 0.2 ml 10 N I{pSO4 into the center wells. The C0= was collected overnight in 1 ml hyamine injected into the vials and the 14C0~ counted in 10 ml of scintillation fluid (42 ml Liquiflor, New England Nuclear, Boston, Mass. in 1 1 of toluene) in an automarie scintillation counter (Isoeap 300, Nuclear Chicago). Blanks were made b y placing incubation media with labelled glucose into center wells without islets. The epm obtained from the blanks were s u b t r a c t e d from the epm of the center wells containing islets. Calculations Insulin release is expressed as ~U immunoreaetive insulin released into 1.0 ml m e d i u m per five islets per 90 min incubation period. The glucose oxidation d a t a are expressed as percentages, defining the average 1~C0~ epm metabolized from glucose alone during the same series of experiments as 100~ . Student's t t e s t was used for statistical analysis. Values are expressed as means :J: SEM. lOOO .c_ oE800 c~ The stimulation of insulin release b y 1 or 10 mM leucine and 1 or 10 mM arginine in the absence of glucose was negligible (Figs. 1 and 2). I n the presence of 1 m g / m l glucose, only i0 mM leucine stimulated insulin release (23 :j: 4 vs. 79 :j: 12 FU/5 islets/90 rain, p < 0.02). I n control islets insulin release, stimulated b y 3 mg/ml glucose, was 584 :L73 and 516 :L 52 ~U for the leucine and arginine experiments respectively. The further addition of leucine to make concentrations of 1 and 10 m ~ significantly increased insulin release, in the presence of 3 mg/ml glucose, to 836 ~: 58 (p 0.02) and 892 ~: 65 ~U (p < 0.01, compared to 3 mg/ml glucose alone), respectively. The addition of arginine to m a k e a concentration of 1 mM did not increase insulin enm ~ m ~ m ~ Buffer Iron IOmM lmglml ling/mr ling/mr 3mglml 3mg/ml 3mg/rnl Arginine Arginino Glucose Glucose Glucose Glucose Glucose Glucose h+nIjroinnine A+rIOgimninMe A+rligningine A+rfgOinruinMe Fig. 2. Effect of arginine with and without glueose on insulin release from isolated pancreatic islets from control rats and rats treated with 6-aminonieotinamide Results are expressed as FU immunoreaetive insulin ( I g I ) released into the medium per 5 islets per 90 rain incubation time, (N = 17-- 18), mean~_SEM. release, but insulin release b y 10 m N arginine in the presence of 3 mg/ml glucose was 790 =~ 101 ~zU (p < 0.01, compared to 3 mg/ml glucose alone). Effect of 6-Aminonieotinamide on Insulin .Release by Glucose, Leucine and Arginine 6-AN reduced insulin release b y 3 mg/ml glucose to 190 ~ 38 ~U in the leueine experiments and to 100 ~= 8 ~U in the arginine experiments (p < 0.01). The reduction of insulin release b y 6-AN was a b o u t 400 ~zU in all experiments with the amino acids, as well as with glucose, suggesting t h a t 6-AN affected a process separate from the insulinogenie effect of the amino acids. Likewise, the potentiation of insulin release b y leueine and arginine was the same, and a p p r o x i m a t e l y additive to t h a t of 3 m g / m l glucose, regardless of whether control islets or islets from 6-AN-treated animals were employed, suggesting t h a t the potentiating effect of these amino acids was not via the metabolism of glucose through the hexosemonophosphate pathway. P o t e n t i a t i o n of insulin release b y 1 mFI leueine was 252 ~zU in the absence of 6-AN and 271 9U in the presence of 6-AN. With 10 mM leucine, it was 308 9U in the absence of 6-AN and 423 ~zU in presence of 6-AN (Fig. 1). 1 m N arginine did not p o t e n t i a t e insulin release in the presence or absence of 6-AN, but 10 mM arginine p o t e n t i a t e d insulin release b y 274 y.U in the absence of 6-AN and 308 ~U in the presence of 6-AN (Fig. 2). Discussion 6-AN has been shown to m a r k e d l y decrease the a c t i v i t y of the hexosemonophosphate p a t h w a y i n brain, kidney, and the islets of Langerhans [ 2, 24, 25, 26 ]. 6-AN is incorporated into N A D P and N A D forming 6-amino-NADP and 6-amino-NAD, which do not transfer hydrogen. I n addition, 6-AN decreases N A D P and NAD synthesis. 6-amino-NADP is a competitive inhibitor of N A D P - d e p e n d e n t enzymes such as glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reduetase [ 1, 27, 28 ]. However, no inhibition of NAD-dependent enzymes has yet been observed [ 29 ]. I n isolated pancreatic islets of rats t r e a t e d with 6-AN the concentrations of N A D P and N A D P H are decreased 30 ~o, whereas the concentrations of N A D and N A D t I are normal [ 4, 26 ]. Insulin release b y 3 mg/ml glucose was reduced about 70% b y the addition of 6-AN. The further addition of leucine to make a concentration of 1 or 10 raM, or arginine to make a concentration of 10 raM, restored insulin release to values similar to those observed in control islets with 3 mg/ml glucose. To eliminate the possibility t h a t leucine or arginine restored insulin release b y increasing the a c t i v i t y of the hexosemonophosphate p a t h w a y , the effect of these amino acids on 1~C02 production from ~4C-1 and 14C-6 glucose was studied. No significant change in the activity of the hexosemonophosphate p a t h w a y could be observed, indicating t h a t leucine and argininc do not potentiate C-1 Results are expressed as cpm/10 islets/3 hrs incubation and as percentages of the controls, means~zSEM, p w~lues represent the significance compared to glucose q- 6-AN. Incubation media contained 3 mg/ml glucose, specific radioactivity 1 izCi/mg plus the agents shown. (n = 1 1 - 1 8 ) Effect of 6-Aminonicotinamide on Glucose Oxidation The rate of oxidation of 1-14C-glucose to 14C0~ b y islets from 6-AN-treated rats was only 49~:8~o of t h a t of islets from control rats (p < 0.01), whereas the rate of oxidation of 6-14C-glucose to 14C02 b y islets from 6-AN-treated rats was 83  9~o of t h a t of islets from control rats, which was not a statistically significant decrease. Leucine and arginine did not significantly alter the effect of 6-AN upon glucose oxidation at C-1 or C-6 (Table 1). glucose-induced insulin release b y overcoming the block in the hexosemonophosphate p a t h w a y caused b y 6-AN. I n the absence of glucose, leucine and arginine did not stimulate insulin release. When 1 mg/ml glucose was employed, 10 mM leueine stimulated insulin release, but only slightly. I n the presence of 3 mg/ml glucose, 1 and 10 m N leucine and 10 mM arginine greatly p o t e n t i a t e d insulin release. These findings are similar to those of others who observed slight or no insulin release in the absence of glucose or in the presence of low glucose [ 6, 7, 10, 18 ] and marked potentiation of insulin release by these amino acids in the presence of high glucose [ 7, 11, 12 ]. These data suggest t h a t although it is possible t h a t leucine and arginine stimulate insulin release b y a mechanism of their own, the major insulinogenic effect of these amino acids is to further increase glucose-induced insulin release. The potentiation of insulin release b y leucine and arginine was the same in the presence of 6-AN as in the absence of 6-AN. This demonstrates t h a t the potentiating effect of leueine and arginine on glucose-induced insulin release, in contrast to the stimulatory effect of glucose alone, is still present when the activity of the hexosemonophosphate p a t h w a y is decreased and when the level of N A D P H of the B-cell is decreased. I t is unlikely t h a t the potentiating effect of these amino acids on insulin release is related to a fuel function of glucose or of these amino acids because, as this s t u d y and others have shown [ 19, 30 ], these amino acids do not significantly affect glucose oxidation b y the beta cell. Furthermore, if the B-cell required a fuel to be responsive to leueine, leucine itself could serve as its own fuel, because leucine is oxidized b y the pancreatic islet at a rate sufficient to provide any energy necessary to support insulin release [19]. Since leueine itself did not stimulate insulin release in the absence of glucose it is unlikely t h a t leucine acts as an insulin secretagogue b y a mechanism involving its metabolism. Arginine cannot potentiate insulin release by its complete catabolism because it is not oxidized to COs b y the pancreatic islet [ 19 ]. When glucose phosphorylation is inhibited in pieces of pancreas b y mannoheptulose in the presence of 3 mg/ml glucose, 10 mM leucine still stimulates insulin release [ 10 ]. These data and the data of this study suggest t h a t leueine and arginine potentiate glucose-induced insulin secretion b y a mechanism largely independent of the metabolism of glucose and their own metabolism. Therefore, these data are consistent with the hypothesis t h a t these amino acids potentiate insulin release b y interacting with receptors which have been postulated to exist on the membrane of the beta cell [ 11, 31 ]. The above viewpoint should not obscure the possibility t h a t 6-AN affects insulin release in such a complex way t h a t it cannot be fully explained b y an effect on the hexosemonophosphate pathway. For example, the present results do not completely exclude the possibility t h a t 6-AN alters the redox state of the B-cell in a general, nonspecific way; or t h a t an altered redox state interferes with the action of membrane sulfhydryl groups which have been implicated in insulin release [ 32 ]. 1. Dietrich , L.S. , Friedland , J.M. , Kaplan , A. : Pyridine nucleotide metabolism: Mechanism of action of the niacin antagonist, 6-aminonicotinamide . J. biol. Chem . 233 , 964 -- 968 ( 1958 ) 2. Ammon , tI.P.T., Steinke , J.: 6-aminonicotinamide (6-AIq) as a diabetogenie agent: I n vitro and in vivo studies in the rat . Diabetes 21 , 143 -- 148 ( 1972 ) 3. Ammon , tI.P.T., Steinke , J. : Effect of 6-aminonieotinamide on insulin release and C-14-glueose oxidation by isolated pancreatic rat islets: Difference between glucose, tolbutamide and aminophylline . Endocrinology 91 , 33 -- 38 ( 1972 ) 4. Ammon , I-I.P. T. : Unpublished observations 5. 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Joslin Research Laboratory, H a r v a r d Medical School, 170 Pilgrim R o a d Boston , Mass. 02215


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M. J. MacDonald, H. P. T. Ammon, T. Patel, J. Steinke. Failure of 6-aminonicotinamide to inhibit the potentiating effect of leucine and arginine on glucose-induced insulin release in vitro, Diabetologia, 1974, 761-765, DOI: 10.1007/BF01219538