Int. Archs Allergy appl. Immun. 50: 548-554 (1976)
Effect of Insulin and Alloxan Diabetes on Carrageenin Inflammation in Rats A nna O ttlecz , M. K oltai and E lizabeth D ekov Departments of Pathophysiology and Pharmacology, University Medical School of Szeged, Szeged
Abstract. Some hypersensitivity reactions and allergic responses are known to be increased by insulin treatment and decreased in diabetes. In contrast, the present ex periments showed that paw swelling induced by carrageenin in rats was inhibited by insulin. The anti-inflammatory activity, to some extent, paralleled the dose applied and did not appear to be due to hypoglycaemia. Alloxan diabetes in turn increased the vascular response to carrageenin and abolished the anti-inflammatory effect of insulin. The experiments call attention to the possible significance of insulin in the regulation of the acute non-immune inflammatory process.
Introduction
Received: August 1, 1975.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Insulin has been known to influence some hypersensitivity reactions and allergic responses. A single injection of the hormone renders the rat more sensitive to the anaphylactoid reaction evoked by dextran and egg-white [1, 16] and to anaphylactic shock [3, 16]. After sensitisation with Freund’s adjuvant, a positive skin reaction to tuberculin is elicited in the presence of insulin in the rat, a species known to be insensitive to this type of challenge [20]. The hormone also increases the susceptibility of mice to bacterial endotoxin [14]. On the other hand, the lack of insulin considerably decreases histam ine release [11] and oedema formation produced by dextran and eggwhite [2]. Mortality of sensitised rats and mice challenged by the specific antigen is diminished in the diabetic state [6-8, 19]. Arthus and local Shwartzman reactions are also suppressed in diabetes [17, 18]. Adjuvant
Ottlecz/K oltai/D ekov
549
arthritis, supposedly a delayed type reaction, is alleviated in diabetes [4, 13]. Clinical studies have revealed a suppressed cellular immunity in dia betic patients [5,15]. Here, we report some findings indicating that the acute non-immune inflammatory response induced by carrageenin in rats is also altered by insulin treatment and in diabetes.
Materials and Methods Male and female rats of CFY strain weighing 180-220 g and fed a normal pellet diet with water ad libitum were used. Inflammatory response was evoked by 0.1 ml of 0.5 or 1.0°/o carrageenin (Mar ine Colloids) given subcutaneously into the plantar region of the left hind paw. The other foot was injected with isotonic saline. Oedema was measured by mercury dis placement under light ether anaesthesia 2 or 6 h after the administration of the car rageenin. In some cases, the animals were anaesthetised with 40 mg/kg pentobarbital (Mebubarbital, Rhone-Poulenc). Insulin (Novo, Actrapid) was administered subcutaneously 30 min prior to carra geenin. Diabetes was induced by an injection of 40 mg/kg i.v. of alloxan (BDH). Rats with glycosuria and high blood sugar level received 1% salt solution for drink ing. Insulin was not supplemented. Blood sugar level was estimated by orthotoluidine reagent [12], Haematocrit was determined in Wintrobe tubes. The results are expressed by subtracting the saline-treated paw volume from the value of the swollen foot (oedema volume) and then are statistically analysed by the Student’s t test.
Influence of Insulin Treatment on Carrageenin Inflammation When the rats were injected with various doses of insulin, the inflam matory response evoked by carrageenin was suppressed (table I). The ef fect was somewhat more expressed 2 h after the induction of inflamma tion than at the termination of the swelling (6 h). Using amounts of insu lin from 1 to 10 U/kg, a dose-response relationship was observed. When the doses were further increased, the anti-inflammatory activity was de creased. The anti-inflammatory effect of insulin was somewhat less when swelling was produced by 0.1 ml of 1.0% carrageenin. A concomitant intravenous administration of glucose was sufficient to neutralise the blood sugar lowering activity of the hormone but it did not antagonise the antiphlogistic effect (table II). Glucose alone caused a slight but insignificant inhibition,
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Results
Ottlecz/K oltai/D ekov
550
Table I. Effect of insulin on carrageenin inflammation in rats
Treatment with insulin, U/kg s.c.
Inflammatory response measured at 2h oedema, ml inhibi- P (mean ± SE1) tion %
6h oedema, ml (mean ± SE1)
None
0.435 ±0.022 0.365 ±0.02 0.302 ±0.015 0.226±0.013 0.242 ±0.009 0.271 ±0.012 0.378±0.019
0.552 ±0.015 0.480 ±0.025 0.442 ±0.011 0.420 ±0.016 0.356 ±0.008 0.386 ±0.011 0.417±0.024
1.0
2.5 5.0 10.0 20.0 40.0
_
16 31 39 44 38 13
_
n.s. 0.0025 0.0005 0.0005 0.0005 n.s.
inhibition % —
13 20 24 36 31 24
P
_
n.s. 0.01 0.01 0.0025 0.001
0.01
Inflammatory response was evoked by 0.1 ml of 0.5% carrageenin; n.s. = not signi ficant. 1 Obtained from 6 experiments.
Table II. Effect of glucose on the anti-inflammatory effect of insulin on carrageenin in groups of 10 female rats Treatment
Oedema, ml (mean ± SD)
Saline Glucose Saline plus insulin Glucose plus insulin
0.448 ±0.039 0.376 ±0.053 0.210±0.023 0.187 ±0.014
Inhibi tion1, %
_ 16 54 59 (53)
Pl
Blood sugar level mg%
_
94 ±7.5 148 ± 13.1 54 ±5.1 96 ±8.9
n.s. 0.0005 0.0005 (0.005)
Carrageenin Inflammation in Alloxan Diabetic Rats Diabetic rats were carefully selected from a pool of animals injected with alloxan. Their blood sugar level was in the range between 450 and 520 mg°/o. As judged by haematocrit measurements, no rats showing hae-
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Swelling was induced by 500 ng carrageenin and was measured 2 h after the intrapedal injection. Blood sugar was measured at the time when the phlogogen was injected. All treatments were introduced 30 min prior to carrageenin. 1.5 ml isotonic saline or 20% glucose were given i.v. simultaneously with insulin (10 U/kg s.c.). 1 Open values were compared with those of the saline-treated rats, values in parentheses were compared with the glucose-treated group; n.s. =not significant.
Insulin and Carrageenin Inflammation
551
Table III. Carrageenin inflammation and insulin response in groups of 10 male diabetic rats P
Blood sugar mg% (mean ± SE)
_ 0.01
94 ±8.6 480 ±31.8
19
0.05
190 ±23.9
9
n.s.
76 ±10.5
Pro-inflam matory activity, %
Group
Treatment
Oedema, ml (mean ± SD)
Normal Diabetic Diabetic
0 0 insulin (10 U/kg) insulin (40 U/kg)
0.530 ±0.029 0.661 ±0.018
25
0.663 ±0.041 0.582 ±0.052
Diabetic
_
moconcentration were included in the experimental groups. The inflam matory response was tested 6 h, 1, 3, 5 and 9 days following alloxan treatment. In most cases, oedema was measured 6 h after intrapedal injections. Some animals were treated with 10 or 40 U/kg of insulin 30 min before carrageenin. The data obtained in a representative experi ment are included in table III. Alloxan treatment without inducing diabetes did not alter the inflam matory response. 6 h after alloxan had been injected, there was no differ ence in swelling between the untreated, and alloxanised groups. At that time, insulin was able to inhibit the inflammatory response. On the first day of diabetes, the vascular response to carrageenin start ed to increase. A constant pro-inflammatory activity was observed during the period up to the 9th day after alloxanisation. As indicated in table III, doses of insulin partly or completely restored the blood sugar level of dia betic rats, decreased the pro-inflammatory effect of diabetes, but pro duced no anti-inflammatory activity as compared with the control value. In some experiments, 50 ¡ug carrageenin was injected intrapedally and the swelling of the paws was measured under pentobarbital anaesthesia as described by G arcia L eme et al. [9, 10]. Under these conditions, the pro-inflammatory activity of diabetes was even more prominent than in the experiments performed with 500 fig of the phlogogen.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Diabetes was induced 9 days prior to the experiment. Swelling was measured 6 h after carrageenin injection. Blood sugar was estimated at the time when the phlogogen was injected. Insulin was given subcutaneously 30 min before carrageenin. n.s. = not signi ficant.
552
Ottlecz/K oltai/D ekov
Carrageenin paw oedema represents a valuable model for studying the acute inflammatory response in rats [21]. The present experiments show that this type of reaction is influenced by insulin treatment and diabetes in an opposite manner to that involving dextran, egg-white release of his tamine, or some allergic responses. The anti-inflammatory activity of insulin as measured on carrageenin paw swelling shows some correlation with the dose applied, although high amounts exhibit lower activity indicating that a complex mechanism is in volved. Since glucose administration does not alter the antiphlogistic ef fect, it seems unlikely that hypoglycaemia is responsible for the phenome non. The anti-inflammatory activity appears to be more expressed in the early phase of the inflammatory response than at the termination of swell ing. Induction of diabetes in turn increases carrageenin inflammation. Since the vascular response is unchanged 6 h after alloxan or alloxantreatment without inducing diabetes, the chemical is not involved in the pro-inflammatory activity observed. It develops as early as 24 h after a diabetogenic dose of alloxan, at a time when the blood sugar level is al ready elevated. The pro-inflammatory effect is constantly observed dur ing the diabetic state. A single injection of insulin, depending upon the dose applied, tends to normalise the paw swelling in diabetic animals, but it fails to inhibit carrageenin inflammation as compared with the normal animals. Our observations are contrary to those of G arcia L eme et al. [9, 10] who found that the carrageenin-induced inflammatory response (like dextran oedema) is decreased by diabetes. They used, however, alloxanised and depancreatised rats treated with 1 U NPH insulin daily. After the discontinuation of insulin treatment, paw swelling was induced by 50 //g carrageenin under pentobarbital anaesthesia. We always found an increase in carrageenin oedema during diabetes regardless of the dose of the phlogogen injected or whether the animals were anaesthetised or not. The only difference between the two experimental conditions used was that our rats were not given insulin supplementation before the experiments. Since insulin is able to inhibit carrageenin inflammation, one may speculate that the anti-inflammatory effect attributed to diabetes by G arcia L eme et al. [9, 10] is brought about by the long-term insulin treatment. Further studies are being devoted to solve this problem.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Discussion
Insulin and Carrageenin Inflammation
553
The present findings show that insulin is possibly involved in the regu lation of the acute non-immune inflammatory process. It is conceivable that some endogenous anti-inflammatory mechanisms are controlled by the hormone, and, therefore, its lack leads to an increased vascular re sponse to carrageenin. References 1 A damkiewicz , V. W. and L anglois, Y.: Sensitization by insulin to dextran ‘ana phylactoid’ reaction. Can. J. Biochem. 35: 251 (1957). 2 A damkiewicz , V. W. and Adamkiewicz , L. M.: Alloxan diabetes and dextran ‘anaphylactoid’ inflammation. Am. J. Physiol. 197: 377 (1959). 3 A damkiewicz , V. W.; Sacra, P. J., and V entura , J.: Glycemic states and hor se-serum and egg-white anaphylactic shock in rats. J. Immun. 92: 3 (1964). 4 Best, R. and Spencer, P. S. J.: The effect of alloxan diabetes upon adjuvant-in duced arthritis in the rat. J. Pharm. Pharmac. 20: suppl., p, 126 (1968). 5 D elespesse, G.; D uchateau, J.; Bastenie, P. A.; L auvaux, J. P.; C ollet, H., and G ovaerts, A.: Cell-mediated immunity in diabetes mellitus. Clin. exp. Im munol. 18: 461 (1974). 6 D har, H. L. and Sanyal, R. K.: Carbohydrate metabolism and anaphylaxis. J. Pharm. Pharmac. 15: 628 (1963). 7 D har, H. L.; Sanyal, R. K., and W est , G. B.: Anaphylactic shock and the blood sugar level. J. Pharm. Pharmac. 19: 699 (1967). 8 D har, H. L.; Sanyal, R. K., and West, G. B.: The relationship of the blood sug ar level to the severity of anaphylactic shock. Br. J. Pharmac. Chemother. 31: 351 (1967). 9 G arcia L eme, J.; H amamura, L.; Migliorini, R. H., and L eite, M. P.: Influence of diabetes upon the inflammatory response of the rat. A pharmacological anal ysis. Eur. J. Pharmacol. 23: 74 (1973).
11 G oth , A.; N ash, W. L.; N agler, M., and H olman, J.: Inhibition of histamine release in experimental diabetes. Am. J. Physiol. 191: 25 (1957). 12 H ultman, E.: Rapid specific method for determination of aldosaccharides in body fluids. Nature, Lond. 183: 108 (1959). 13 Kellett, D. N.: Suppression of an ‘adjuvant arthritis’ in alloxan-diabetic rats. J. Pharm. Pharmac. 17: 184 (1965). 14 P ieroni, R. E. and L evine, L.: Enhancing effect of insulin on endotoxin lethali ty. Experientia 25: 507 (1969). 15 R agab, A. H.; H azlett, B., and Cowan, D. H.: Response of peripheral lympho cytes from patients with diabetes mellitus to phytohemagglutinin and Candida albicans antigen. Diabetes 21: 906 (1972). 16 Sanyal, R. K.; S pencer , P. S. J., and W est , G. B.: Insulin and hypersensitivity. Nature, Lond. 184: 2020 (1959).
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
10 G arcia L eme, J.; Böhm, G. M.; M igliorini, H., and Souza, M. Z. A.: Possible participation of insulin in the control of vascular permeability. Eur. J. Pharma col. 29: 298 (1974).
554
Ottlecz/K oltai/D ekov
Correspondence to: Dr. A nna O ttlecz , Department of Pathophysiology, University Medical School of Szeged, PO Box 531, H-6701 Szeged (Hungary)
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
17 Szilagyi, T.; Kiss, A., and C saba, B.: Shwartzman phenomenon in diabetic rab bits. Acta physiol, hung. 23: 281 (1963). 18 Szilagyi, T.; Kiss, A., and K avai, M.: Allergic type skin reactions in animals with alloxan diabetes. Acta microbiol. hung. 13: 223 (1966). 19 T hompson , G. E.: Alloxan diabetes and hypersensitivity. Nature, Lond. 190: 822 (1961). 20 T hompson , G. E.: Enhancing effect of insulin on the tuberculin reaction in the albino rat. Nature, Lond. 215: 748 (1967). 21 W inter , C. A.; R isley , E. A., and Nuss, G. W.: Carrageenin-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc. Soc. exp. Biol. Med. I l l : 544 (1962).
Effect of Insulin and Alloxan Diabetes on Carrageenin Inflammation in Rats A nna O ttlecz , M. K oltai and E lizabeth D ekov Departments of Pathophysiology and Pharmacology, University Medical School of Szeged, Szeged
Abstract. Some hypersensitivity reactions and allergic responses are known to be increased by insulin treatment and decreased in diabetes. In contrast, the present ex periments showed that paw swelling induced by carrageenin in rats was inhibited by insulin. The anti-inflammatory activity, to some extent, paralleled the dose applied and did not appear to be due to hypoglycaemia. Alloxan diabetes in turn increased the vascular response to carrageenin and abolished the anti-inflammatory effect of insulin. The experiments call attention to the possible significance of insulin in the regulation of the acute non-immune inflammatory process.
Introduction
Received: August 1, 1975.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Insulin has been known to influence some hypersensitivity reactions and allergic responses. A single injection of the hormone renders the rat more sensitive to the anaphylactoid reaction evoked by dextran and egg-white [1, 16] and to anaphylactic shock [3, 16]. After sensitisation with Freund’s adjuvant, a positive skin reaction to tuberculin is elicited in the presence of insulin in the rat, a species known to be insensitive to this type of challenge [20]. The hormone also increases the susceptibility of mice to bacterial endotoxin [14]. On the other hand, the lack of insulin considerably decreases histam ine release [11] and oedema formation produced by dextran and eggwhite [2]. Mortality of sensitised rats and mice challenged by the specific antigen is diminished in the diabetic state [6-8, 19]. Arthus and local Shwartzman reactions are also suppressed in diabetes [17, 18]. Adjuvant
Ottlecz/K oltai/D ekov
549
arthritis, supposedly a delayed type reaction, is alleviated in diabetes [4, 13]. Clinical studies have revealed a suppressed cellular immunity in dia betic patients [5,15]. Here, we report some findings indicating that the acute non-immune inflammatory response induced by carrageenin in rats is also altered by insulin treatment and in diabetes.
Materials and Methods Male and female rats of CFY strain weighing 180-220 g and fed a normal pellet diet with water ad libitum were used. Inflammatory response was evoked by 0.1 ml of 0.5 or 1.0°/o carrageenin (Mar ine Colloids) given subcutaneously into the plantar region of the left hind paw. The other foot was injected with isotonic saline. Oedema was measured by mercury dis placement under light ether anaesthesia 2 or 6 h after the administration of the car rageenin. In some cases, the animals were anaesthetised with 40 mg/kg pentobarbital (Mebubarbital, Rhone-Poulenc). Insulin (Novo, Actrapid) was administered subcutaneously 30 min prior to carra geenin. Diabetes was induced by an injection of 40 mg/kg i.v. of alloxan (BDH). Rats with glycosuria and high blood sugar level received 1% salt solution for drink ing. Insulin was not supplemented. Blood sugar level was estimated by orthotoluidine reagent [12], Haematocrit was determined in Wintrobe tubes. The results are expressed by subtracting the saline-treated paw volume from the value of the swollen foot (oedema volume) and then are statistically analysed by the Student’s t test.
Influence of Insulin Treatment on Carrageenin Inflammation When the rats were injected with various doses of insulin, the inflam matory response evoked by carrageenin was suppressed (table I). The ef fect was somewhat more expressed 2 h after the induction of inflamma tion than at the termination of the swelling (6 h). Using amounts of insu lin from 1 to 10 U/kg, a dose-response relationship was observed. When the doses were further increased, the anti-inflammatory activity was de creased. The anti-inflammatory effect of insulin was somewhat less when swelling was produced by 0.1 ml of 1.0% carrageenin. A concomitant intravenous administration of glucose was sufficient to neutralise the blood sugar lowering activity of the hormone but it did not antagonise the antiphlogistic effect (table II). Glucose alone caused a slight but insignificant inhibition,
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Results
Ottlecz/K oltai/D ekov
550
Table I. Effect of insulin on carrageenin inflammation in rats
Treatment with insulin, U/kg s.c.
Inflammatory response measured at 2h oedema, ml inhibi- P (mean ± SE1) tion %
6h oedema, ml (mean ± SE1)
None
0.435 ±0.022 0.365 ±0.02 0.302 ±0.015 0.226±0.013 0.242 ±0.009 0.271 ±0.012 0.378±0.019
0.552 ±0.015 0.480 ±0.025 0.442 ±0.011 0.420 ±0.016 0.356 ±0.008 0.386 ±0.011 0.417±0.024
1.0
2.5 5.0 10.0 20.0 40.0
_
16 31 39 44 38 13
_
n.s. 0.0025 0.0005 0.0005 0.0005 n.s.
inhibition % —
13 20 24 36 31 24
P
_
n.s. 0.01 0.01 0.0025 0.001
0.01
Inflammatory response was evoked by 0.1 ml of 0.5% carrageenin; n.s. = not signi ficant. 1 Obtained from 6 experiments.
Table II. Effect of glucose on the anti-inflammatory effect of insulin on carrageenin in groups of 10 female rats Treatment
Oedema, ml (mean ± SD)
Saline Glucose Saline plus insulin Glucose plus insulin
0.448 ±0.039 0.376 ±0.053 0.210±0.023 0.187 ±0.014
Inhibi tion1, %
_ 16 54 59 (53)
Pl
Blood sugar level mg%
_
94 ±7.5 148 ± 13.1 54 ±5.1 96 ±8.9
n.s. 0.0005 0.0005 (0.005)
Carrageenin Inflammation in Alloxan Diabetic Rats Diabetic rats were carefully selected from a pool of animals injected with alloxan. Their blood sugar level was in the range between 450 and 520 mg°/o. As judged by haematocrit measurements, no rats showing hae-
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Swelling was induced by 500 ng carrageenin and was measured 2 h after the intrapedal injection. Blood sugar was measured at the time when the phlogogen was injected. All treatments were introduced 30 min prior to carrageenin. 1.5 ml isotonic saline or 20% glucose were given i.v. simultaneously with insulin (10 U/kg s.c.). 1 Open values were compared with those of the saline-treated rats, values in parentheses were compared with the glucose-treated group; n.s. =not significant.
Insulin and Carrageenin Inflammation
551
Table III. Carrageenin inflammation and insulin response in groups of 10 male diabetic rats P
Blood sugar mg% (mean ± SE)
_ 0.01
94 ±8.6 480 ±31.8
19
0.05
190 ±23.9
9
n.s.
76 ±10.5
Pro-inflam matory activity, %
Group
Treatment
Oedema, ml (mean ± SD)
Normal Diabetic Diabetic
0 0 insulin (10 U/kg) insulin (40 U/kg)
0.530 ±0.029 0.661 ±0.018
25
0.663 ±0.041 0.582 ±0.052
Diabetic
_
moconcentration were included in the experimental groups. The inflam matory response was tested 6 h, 1, 3, 5 and 9 days following alloxan treatment. In most cases, oedema was measured 6 h after intrapedal injections. Some animals were treated with 10 or 40 U/kg of insulin 30 min before carrageenin. The data obtained in a representative experi ment are included in table III. Alloxan treatment without inducing diabetes did not alter the inflam matory response. 6 h after alloxan had been injected, there was no differ ence in swelling between the untreated, and alloxanised groups. At that time, insulin was able to inhibit the inflammatory response. On the first day of diabetes, the vascular response to carrageenin start ed to increase. A constant pro-inflammatory activity was observed during the period up to the 9th day after alloxanisation. As indicated in table III, doses of insulin partly or completely restored the blood sugar level of dia betic rats, decreased the pro-inflammatory effect of diabetes, but pro duced no anti-inflammatory activity as compared with the control value. In some experiments, 50 ¡ug carrageenin was injected intrapedally and the swelling of the paws was measured under pentobarbital anaesthesia as described by G arcia L eme et al. [9, 10]. Under these conditions, the pro-inflammatory activity of diabetes was even more prominent than in the experiments performed with 500 fig of the phlogogen.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Diabetes was induced 9 days prior to the experiment. Swelling was measured 6 h after carrageenin injection. Blood sugar was estimated at the time when the phlogogen was injected. Insulin was given subcutaneously 30 min before carrageenin. n.s. = not signi ficant.
552
Ottlecz/K oltai/D ekov
Carrageenin paw oedema represents a valuable model for studying the acute inflammatory response in rats [21]. The present experiments show that this type of reaction is influenced by insulin treatment and diabetes in an opposite manner to that involving dextran, egg-white release of his tamine, or some allergic responses. The anti-inflammatory activity of insulin as measured on carrageenin paw swelling shows some correlation with the dose applied, although high amounts exhibit lower activity indicating that a complex mechanism is in volved. Since glucose administration does not alter the antiphlogistic ef fect, it seems unlikely that hypoglycaemia is responsible for the phenome non. The anti-inflammatory activity appears to be more expressed in the early phase of the inflammatory response than at the termination of swell ing. Induction of diabetes in turn increases carrageenin inflammation. Since the vascular response is unchanged 6 h after alloxan or alloxantreatment without inducing diabetes, the chemical is not involved in the pro-inflammatory activity observed. It develops as early as 24 h after a diabetogenic dose of alloxan, at a time when the blood sugar level is al ready elevated. The pro-inflammatory effect is constantly observed dur ing the diabetic state. A single injection of insulin, depending upon the dose applied, tends to normalise the paw swelling in diabetic animals, but it fails to inhibit carrageenin inflammation as compared with the normal animals. Our observations are contrary to those of G arcia L eme et al. [9, 10] who found that the carrageenin-induced inflammatory response (like dextran oedema) is decreased by diabetes. They used, however, alloxanised and depancreatised rats treated with 1 U NPH insulin daily. After the discontinuation of insulin treatment, paw swelling was induced by 50 //g carrageenin under pentobarbital anaesthesia. We always found an increase in carrageenin oedema during diabetes regardless of the dose of the phlogogen injected or whether the animals were anaesthetised or not. The only difference between the two experimental conditions used was that our rats were not given insulin supplementation before the experiments. Since insulin is able to inhibit carrageenin inflammation, one may speculate that the anti-inflammatory effect attributed to diabetes by G arcia L eme et al. [9, 10] is brought about by the long-term insulin treatment. Further studies are being devoted to solve this problem.
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
Discussion
Insulin and Carrageenin Inflammation
553
The present findings show that insulin is possibly involved in the regu lation of the acute non-immune inflammatory process. It is conceivable that some endogenous anti-inflammatory mechanisms are controlled by the hormone, and, therefore, its lack leads to an increased vascular re sponse to carrageenin. References 1 A damkiewicz , V. W. and L anglois, Y.: Sensitization by insulin to dextran ‘ana phylactoid’ reaction. Can. J. Biochem. 35: 251 (1957). 2 A damkiewicz , V. W. and Adamkiewicz , L. M.: Alloxan diabetes and dextran ‘anaphylactoid’ inflammation. Am. J. Physiol. 197: 377 (1959). 3 A damkiewicz , V. W.; Sacra, P. J., and V entura , J.: Glycemic states and hor se-serum and egg-white anaphylactic shock in rats. J. Immun. 92: 3 (1964). 4 Best, R. and Spencer, P. S. J.: The effect of alloxan diabetes upon adjuvant-in duced arthritis in the rat. J. Pharm. Pharmac. 20: suppl., p, 126 (1968). 5 D elespesse, G.; D uchateau, J.; Bastenie, P. A.; L auvaux, J. P.; C ollet, H., and G ovaerts, A.: Cell-mediated immunity in diabetes mellitus. Clin. exp. Im munol. 18: 461 (1974). 6 D har, H. L. and Sanyal, R. K.: Carbohydrate metabolism and anaphylaxis. J. Pharm. Pharmac. 15: 628 (1963). 7 D har, H. L.; Sanyal, R. K., and W est , G. B.: Anaphylactic shock and the blood sugar level. J. Pharm. Pharmac. 19: 699 (1967). 8 D har, H. L.; Sanyal, R. K., and West, G. B.: The relationship of the blood sug ar level to the severity of anaphylactic shock. Br. J. Pharmac. Chemother. 31: 351 (1967). 9 G arcia L eme, J.; H amamura, L.; Migliorini, R. H., and L eite, M. P.: Influence of diabetes upon the inflammatory response of the rat. A pharmacological anal ysis. Eur. J. Pharmacol. 23: 74 (1973).
11 G oth , A.; N ash, W. L.; N agler, M., and H olman, J.: Inhibition of histamine release in experimental diabetes. Am. J. Physiol. 191: 25 (1957). 12 H ultman, E.: Rapid specific method for determination of aldosaccharides in body fluids. Nature, Lond. 183: 108 (1959). 13 Kellett, D. N.: Suppression of an ‘adjuvant arthritis’ in alloxan-diabetic rats. J. Pharm. Pharmac. 17: 184 (1965). 14 P ieroni, R. E. and L evine, L.: Enhancing effect of insulin on endotoxin lethali ty. Experientia 25: 507 (1969). 15 R agab, A. H.; H azlett, B., and Cowan, D. H.: Response of peripheral lympho cytes from patients with diabetes mellitus to phytohemagglutinin and Candida albicans antigen. Diabetes 21: 906 (1972). 16 Sanyal, R. K.; S pencer , P. S. J., and W est , G. B.: Insulin and hypersensitivity. Nature, Lond. 184: 2020 (1959).
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
10 G arcia L eme, J.; Böhm, G. M.; M igliorini, H., and Souza, M. Z. A.: Possible participation of insulin in the control of vascular permeability. Eur. J. Pharma col. 29: 298 (1974).
554
Ottlecz/K oltai/D ekov
Correspondence to: Dr. A nna O ttlecz , Department of Pathophysiology, University Medical School of Szeged, PO Box 531, H-6701 Szeged (Hungary)
Downloaded by: Boston University 128.197.229.194 - 1/20/2020 7:39:08 PM
17 Szilagyi, T.; Kiss, A., and C saba, B.: Shwartzman phenomenon in diabetic rab bits. Acta physiol, hung. 23: 281 (1963). 18 Szilagyi, T.; Kiss, A., and K avai, M.: Allergic type skin reactions in animals with alloxan diabetes. Acta microbiol. hung. 13: 223 (1966). 19 T hompson , G. E.: Alloxan diabetes and hypersensitivity. Nature, Lond. 190: 822 (1961). 20 T hompson , G. E.: Enhancing effect of insulin on the tuberculin reaction in the albino rat. Nature, Lond. 215: 748 (1967). 21 W inter , C. A.; R isley , E. A., and Nuss, G. W.: Carrageenin-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc. Soc. exp. Biol. Med. I l l : 544 (1962).
