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Insulin autoimmune syndrome in Japan
ELSEVIER
Diabetes Research and Clinicai Practice, 24 Suppi. (1994) S153-S157
Insulin autoimmune syndrome in Japan Yukimasa EIirata*, Yasuko Uchigata Emeritus Professor of TLtyo Women’s Medical School, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Iapn
Since 1970,197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantrbodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe ;iilG &r: United States. High levels of the extractable native human insulin and of the characteristic irisulin autoantibodies in the sera of d,.e IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan. Kqwordr: Insulin autoimmune syndrome; Hypoglycemia; HLA-DRBl
1. Intmduction When the lirst patient with spontaneous hypo-
glycemia associated with the production of insulin autoantibodies, so-called insulin autoimmune syndrome (IAS), was reported by Hirata et al. [l] in Japan in 1970, many questions were raised, its differential diagnosis from factitious hypoglycemia, the causes of this syndrome, the mechanisms to produce hypoglycemia in this syndrome and so on. Immediately after the first patient was diagnosed with IAS, several other patients were reported with the same syndrome over five years [2-S], and reports of a total of 197 patients in Japan from 1970 to 1992 have been registered. Besides the analysis of those reports, several studies concerning the causes of IAS and the hypeglycemia have been carried out by us.
*Corresponding author, 2-8-17-401 Momochi, Sawara-ku. Fukuoka 514, Japan.
gene
2. InsuIin autoimmune syudrome as the third leading cause of spontaneous hypoglycemia in Japan
Takayama-Hasumi et al. [6] analyzed the results of questionnaires sent to 2094 large or general hospitals throughout Sapan to investigate the causes of severe spontaneous hypoglycemic attacks from 1979 to 1981. The survey revealed three main causes for the hypoglycemic attacks: insulinoma, extrapancreatic neoplasms and IAS. The second survey carried out 6 years later from 1985 to 1987 gave the same results. 3. Onset age and sex distribution of 197 IAS patients reported in Japan fhm 1970 to 1992 The records of 197 patients with PAS reported
from 1970 to 1992 were carefully examined [7]. Age of onset and sex distribution of the 197 patients are listed in Table 1. The peak age of onset was 60-69 years for both sexes.
0X8-8227/94/$07.00 0 1994 Elsevier Science Ireland Ltd. AU rights reserved SSDI 016&8227(94)00910-M
Y Hinua, X Uchigata /Di&tes
s154
Res. Clin hct.
Table 1 + at onset and sex distribution in Japanese IAS patkm% 1970-1992 Age at oIlSet
IAS patients Male(n)
Female (n)
Total
1 1 12 7 16 19 24 I.4 5 w
1 2 15 17 36 40 46 33 7 197
. -.._
o-9 lo-19 20-29 30-39 40-49 50-59 60-69 70-79 w-89 Total
0 1 3 10 20 21 22 19 2 98
IAS, insulin autoimmune syndrome. The geographic distribution of lAS in Japan showed no characteristic pattern in the areas of residence of the patients.
4. Trigger of onset of IA!3 In Japan, methimazole (MTZ) has been used for the treatment of Graves’ disease and amercaptopropionyl glycine (MPG) for the treatment of chronic hepatitis, dermatitis, ca.aract and rheumatoid arthritis, and glutathion (G’IT) for urticaria. These drugs containing the sulfhydryl (SH) group were found to play a role in triggering the development of IAS [4,8,9]. Among 197 patients with IAS, 44 had been treated with MT2 just before the first attack of hypoglycemia caused by IAS, 34 with MPG, 7 with GlT, and one with captopril[7]. There were 28 IAS patients who had received medication based on non-SH compounds just before the onset of IAS and 83 patients had no history of receiving any medicine just before the onset of IAS. 5. clinical course and treatment in 197 patients WithLQ The duration of hypoglycemic attacks was rela-
tively short. In 62 (31.5%) of the 197 patients the
24 Suppl. &W4) S153-SlS7
period lasted less than one month, and onIy 12 patients had a period of attack longer than one year. Spontaneous remission occurred in 162, while in the remaining 35 patients some specific treatments were introduced as shown in Table 2 [7]. Among these 35 patients 6 patients were misdiagnosed as having insulinoma, and this was followed by partial excision of the pancreas which was effective in reducing attacks. Hyperplasia of the islet B-cells of .Lhe excised part of the pancreas was reported in some IAS patients [1,2]. 6. Insulin in the sera of the patients with IAS The insulin in the sera of IAS patients was native human insulin itself [lo]. Fig. 1 shows total extractable IRI and ‘251-insulin binding % of the sera of patients with IAS. The IRX levels during hypoglycemic attacks were quite enormous [4].
7. Insulin autoantibodies of IAS The sera from 24 patients with IAS in Japan were tested by us to determine the immunoglobulin class, the subclass and the light chain types of insulin autoantibodies [l l]. All insulin antibodies belonged to the IgG group. One patient seemed to have monoclonal antibodies such as an IgG, (lambda) single subclass [ll] which had a very low aflinity constant and a quite large binding capacity against human insulin in Scatchard Table 2 Disease course and treatment in 197 Japanese LAS patients, 1970-1992 IAS patients
Spontaneous remission Treatment Steroids Pancreatic surgery Plasmapheresis Azathioprine 6-Mercaptopurine Total
Male (n)
Femak (n 1
Total
84
78
162
5 3 5 1 0 98
17 3 0 0 1 99
22 6 5 1 1 197
IAS, insulin autoimmune syndrome.
Y Hirata. Y Uchigata J Diabetes Res. Clin. Pratt. 24 Suppl. (1994) SI53-S157
analysis [12]. Further studies concerning this particular serum sample were carried out by Wchigata et al. [13]. Scatchard analysis of the serum in another patient with IAS showed an obvious prozone phenomenon of antibodies to human insulin 1141.Besides those two patients mentioned a’bove, even the high affinity site of the antibodies of PAS presented lower afhnity constants and larger binding capacities than insulin antibodies produced by exogenous insulin injection in diabetic patients [14]. 8. Strong association of IA!3 with HLA-DR4
Uchigata et al. [15] reported that serological
typing of 27 patients with IAS showed that all of the patients had DR4, which was presented in 43% of the normal Japanese controls (odds ratio 72.1, P < 2 X 1W6). Table 3 presents the HLA typing of the 32 Japanese JAS patients so far examined [16]. Analysis of the nucleotide sequences showed that all of the patients with JAS had DRJ31* 0406, DQAl+ 0301 and DQBl * 0302 compared with only 14% of the controls having this haplotype (odds ratio 385, P < 1 x 10-‘“). Uchigata et al. [17] reported that all 13 patients with Graves’ disease who developed JAS by MTZ therapy possessed a specific alielic combination, Bw 62/Cw4/DR4 carrying DRBl * 04C6, whereas only one of 50 Graves’ disease patients without
0790
e158
e 143
273 199 e e 143 . .
7*r
e
%
Bound
SB55
0154 0136 mm e
% Bound
Fig. 1. Total extractable immunoreactive insulin, and 12sI-insulin binding % of the sera of male and female patients, immediately after diagnosis of insulin autoimmune syndrome. The methods for the IRI and ‘251-human insulin binding assay have been descriid elsewhere 1111.At diagnosis of IAS, the peak of the hypoglycemic attacks had been passed. The normal range of total IRI and 1251-insulin binding was < 71.8 pmol/l and < 5%, respectively.
I! Himto, Y Uchigata / Diaberes Res. C&L Rzzct. 24 Suppl (1994) S153-S1.57
s156
Table 3 Serological m
Ft. no. 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
typing of Japanese patients with insulin autoimmune syndrome
A
B
C
DR
526 1123 113 224 113 llJ4 ll,11,33 11,31 24,26 24,26 24,26 2433 2,ll 26,24,233 11,24 24,31 2,ll z224 2G% 24,26
40,62 44,62 44,62 51,62 62,60,62 5452 44,62 16,62 35,61 62,62,17,62 61,62 35,54,62 44,35 6,61 62,51,62 46,15,35 35,62 35,62 60,62 55,62 62,54,62 35,62 54,62 62,7,62
w4,w4,w4,w3,w4,w4,wl,w4 w4,w4,w7 w3,w3,w4 w4,w3,w4 w4,w3,wl,w4 w3,w4,w3,w4,wll,w3,w4,w3,w4 w3,w4 wl.w3 wl,w3 wl,w4 w3,w4 w4,w4,w4,w7
4,4,13 499 4,12 4,499 438 499 294 439 2,4 4,436 499 498 4,4,13 4,12 4,12 4,438 499 4,12 2,4 4,496 499
:1: ll,24,31 11,26 11,24 2,ll 11,31
4,-
4,4,438 134
DQ NT
193 NT 3,3,NT 1,3 3,NT NT NT NT 193 3,3,-3,NT 327 337 3,1.3 3,NT 12 NT 1J NT 394 394 3.4 1s NT
HLA typing was performed in various laboratories. NT, not tested.
IAS had Bw62/Cw4/DR4 possess DRBl * 04r)6.
and those 50 did not 4
References 5 Hirata, Y., Ishizu, H., Quchi, N. et al. (1970) Insulin autoimmunity in a case of spontaneous hypoglycemia. J. Jpn. Diabetes Sot. 13,312-319 (in Japanese). Hirata, Y. and Arimichi, M. (1972) Insulin autoimmune syndrome - the second case. J. Jpn. Diabetes Sot. 15, 187-192 (in Japanese). F@lling,J. and Norman, N. (1972) Hyperglycemia, hypoglycemic attacks and production of anti-insulin autoantibodies without previous known immunization. Immune_
6
7
logical and functional studies in a patient. Diahetes 21, 814-826. Hirata, Y., Tominaga, M., Ito, J. et al. (1974) Spontaneous hypoglycemia with insulin autoimmunity in Graves’ disease. Ann. Int. Med. 81,214-218. Oneda, A., Matsuda, K., Sato, M. et al. (1974) Hypoglycemia due to apparent autoantibodies to insulin. Characterization of insulin-binding protein. Diabetes 23, 4130. Takayama-Hasumi, S., Eguchi, Y., Sato, A. et al. (1990) Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemic attacks in Japan. Diabetes Res. Clin. Pratt. 10,211-214. Uchigata, Y., Eguchi, Y., Takayama-Hasumi, S. et al. (1994) Insulin autoimmune syndrome (Hiram disease):
Y; iiirata, Y Wchigata /Diabetes Res. Clin. Pratt. 24 Suppl. (1994) S153-S157 Clinical features aud epidemiology in Japan. Diabetes Res. Clin. Pratt., 22, 89-94. 8 Icbihara, K., Shima, IC.,Saito, Y. et al. (1977) Mechanism of hypoglycemia observed in a patient with insulin autoimmune syndrome. Diabetes 26,5OO-506. 9 Hirata, Y. (1983) Methimazoie and insulin autoimmune syndrome with hypoglycemia. Iancet ii, 1037-1038. 10 Wasada, T., Eguchi, Y., Takayama-Hasumi, S. et al. (1988) Reverse phase high performance liquid chromatographic analysis of circulating insulin in the insulin autoimmune syndrome. J. Clin. Endocrmol. Metab. 66, 153-158. S. et al. 11 Uchigata, Y., Eguchi, Y., Takayama-Hasumi, (1983; The immunoglobulin class, the subclass and the ratio of k:A light chain of autoantibodies to human insulin in insulin autoimmune syndrome. Autoimmunity 3, 289-297. S. et al. (1989) 12 Wasada, T., Eguchi, Y., Takayama-Hasumi, InsuIin autoimmune syndrome associated with benign moaoclonal gammopathy. Evidence for monoclonal insulin autoantiiies. Diabetes Care 12, 147-150.
13
14
15
16
17
s157
Uchigata. Y., Takayama-Hasumi, S., Kawanishi, IL et al. (i&X) Inducdon of antibody that mimics ksulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain. Diabetes 40,966-970 Hiram, Y. (1987) Autoimmune insulin syndrome ‘up to date’. In: D. Andreani, V. Marks and P.J. Lefebvre (Eds.), Hypoglycemia. Serono Symposia Publications, Vol. 38, Baven Press, New York, pp. 105-li8. Uchigata, Y., Kuwata, S., Tokunaga, K. et al. (1992) Strong association of insulin autoimmune syndrome with HL4-DR4. Iancet 339,393-394. Uchigata, Y., Omori, Y., Nieda, M. et al. (1992) HLA-DR4 genotype and insulin-process;ng in insulin autoimmune syndrome. Lancet 340,1467. Uchigata, Y., Kuwata, S., Tsushima, T. et al. (1993) Patients with Graves’ disease who developed insulin autoimmune syndrome (Hirata disease) possess HLABw62/Cw4/DR4 carrying DRBl*O406. J. Ch. Endocrinol. Metab. ?7, 249-754.
Diabetes Research and Clinicai Practice, 24 Suppi. (1994) S153-S157
Insulin autoimmune syndrome in Japan Yukimasa EIirata*, Yasuko Uchigata Emeritus Professor of TLtyo Women’s Medical School, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Iapn
Since 1970,197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantrbodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe ;iilG &r: United States. High levels of the extractable native human insulin and of the characteristic irisulin autoantibodies in the sera of d,.e IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan. Kqwordr: Insulin autoimmune syndrome; Hypoglycemia; HLA-DRBl
1. Intmduction When the lirst patient with spontaneous hypo-
glycemia associated with the production of insulin autoantibodies, so-called insulin autoimmune syndrome (IAS), was reported by Hirata et al. [l] in Japan in 1970, many questions were raised, its differential diagnosis from factitious hypoglycemia, the causes of this syndrome, the mechanisms to produce hypoglycemia in this syndrome and so on. Immediately after the first patient was diagnosed with IAS, several other patients were reported with the same syndrome over five years [2-S], and reports of a total of 197 patients in Japan from 1970 to 1992 have been registered. Besides the analysis of those reports, several studies concerning the causes of IAS and the hypeglycemia have been carried out by us.
*Corresponding author, 2-8-17-401 Momochi, Sawara-ku. Fukuoka 514, Japan.
gene
2. InsuIin autoimmune syudrome as the third leading cause of spontaneous hypoglycemia in Japan
Takayama-Hasumi et al. [6] analyzed the results of questionnaires sent to 2094 large or general hospitals throughout Sapan to investigate the causes of severe spontaneous hypoglycemic attacks from 1979 to 1981. The survey revealed three main causes for the hypoglycemic attacks: insulinoma, extrapancreatic neoplasms and IAS. The second survey carried out 6 years later from 1985 to 1987 gave the same results. 3. Onset age and sex distribution of 197 IAS patients reported in Japan fhm 1970 to 1992 The records of 197 patients with PAS reported
from 1970 to 1992 were carefully examined [7]. Age of onset and sex distribution of the 197 patients are listed in Table 1. The peak age of onset was 60-69 years for both sexes.
0X8-8227/94/$07.00 0 1994 Elsevier Science Ireland Ltd. AU rights reserved SSDI 016&8227(94)00910-M
Y Hinua, X Uchigata /Di&tes
s154
Res. Clin hct.
Table 1 + at onset and sex distribution in Japanese IAS patkm% 1970-1992 Age at oIlSet
IAS patients Male(n)
Female (n)
Total
1 1 12 7 16 19 24 I.4 5 w
1 2 15 17 36 40 46 33 7 197
. -.._
o-9 lo-19 20-29 30-39 40-49 50-59 60-69 70-79 w-89 Total
0 1 3 10 20 21 22 19 2 98
IAS, insulin autoimmune syndrome. The geographic distribution of lAS in Japan showed no characteristic pattern in the areas of residence of the patients.
4. Trigger of onset of IA!3 In Japan, methimazole (MTZ) has been used for the treatment of Graves’ disease and amercaptopropionyl glycine (MPG) for the treatment of chronic hepatitis, dermatitis, ca.aract and rheumatoid arthritis, and glutathion (G’IT) for urticaria. These drugs containing the sulfhydryl (SH) group were found to play a role in triggering the development of IAS [4,8,9]. Among 197 patients with IAS, 44 had been treated with MT2 just before the first attack of hypoglycemia caused by IAS, 34 with MPG, 7 with GlT, and one with captopril[7]. There were 28 IAS patients who had received medication based on non-SH compounds just before the onset of IAS and 83 patients had no history of receiving any medicine just before the onset of IAS. 5. clinical course and treatment in 197 patients WithLQ The duration of hypoglycemic attacks was rela-
tively short. In 62 (31.5%) of the 197 patients the
24 Suppl. &W4) S153-SlS7
period lasted less than one month, and onIy 12 patients had a period of attack longer than one year. Spontaneous remission occurred in 162, while in the remaining 35 patients some specific treatments were introduced as shown in Table 2 [7]. Among these 35 patients 6 patients were misdiagnosed as having insulinoma, and this was followed by partial excision of the pancreas which was effective in reducing attacks. Hyperplasia of the islet B-cells of .Lhe excised part of the pancreas was reported in some IAS patients [1,2]. 6. Insulin in the sera of the patients with IAS The insulin in the sera of IAS patients was native human insulin itself [lo]. Fig. 1 shows total extractable IRI and ‘251-insulin binding % of the sera of patients with IAS. The IRX levels during hypoglycemic attacks were quite enormous [4].
7. Insulin autoantibodies of IAS The sera from 24 patients with IAS in Japan were tested by us to determine the immunoglobulin class, the subclass and the light chain types of insulin autoantibodies [l l]. All insulin antibodies belonged to the IgG group. One patient seemed to have monoclonal antibodies such as an IgG, (lambda) single subclass [ll] which had a very low aflinity constant and a quite large binding capacity against human insulin in Scatchard Table 2 Disease course and treatment in 197 Japanese LAS patients, 1970-1992 IAS patients
Spontaneous remission Treatment Steroids Pancreatic surgery Plasmapheresis Azathioprine 6-Mercaptopurine Total
Male (n)
Femak (n 1
Total
84
78
162
5 3 5 1 0 98
17 3 0 0 1 99
22 6 5 1 1 197
IAS, insulin autoimmune syndrome.
Y Hirata. Y Uchigata J Diabetes Res. Clin. Pratt. 24 Suppl. (1994) SI53-S157
analysis [12]. Further studies concerning this particular serum sample were carried out by Wchigata et al. [13]. Scatchard analysis of the serum in another patient with IAS showed an obvious prozone phenomenon of antibodies to human insulin 1141.Besides those two patients mentioned a’bove, even the high affinity site of the antibodies of PAS presented lower afhnity constants and larger binding capacities than insulin antibodies produced by exogenous insulin injection in diabetic patients [14]. 8. Strong association of IA!3 with HLA-DR4
Uchigata et al. [15] reported that serological
typing of 27 patients with IAS showed that all of the patients had DR4, which was presented in 43% of the normal Japanese controls (odds ratio 72.1, P < 2 X 1W6). Table 3 presents the HLA typing of the 32 Japanese JAS patients so far examined [16]. Analysis of the nucleotide sequences showed that all of the patients with JAS had DRJ31* 0406, DQAl+ 0301 and DQBl * 0302 compared with only 14% of the controls having this haplotype (odds ratio 385, P < 1 x 10-‘“). Uchigata et al. [17] reported that all 13 patients with Graves’ disease who developed JAS by MTZ therapy possessed a specific alielic combination, Bw 62/Cw4/DR4 carrying DRBl * 04C6, whereas only one of 50 Graves’ disease patients without
0790
e158
e 143
273 199 e e 143 . .
7*r
e
%
Bound
SB55
0154 0136 mm e
% Bound
Fig. 1. Total extractable immunoreactive insulin, and 12sI-insulin binding % of the sera of male and female patients, immediately after diagnosis of insulin autoimmune syndrome. The methods for the IRI and ‘251-human insulin binding assay have been descriid elsewhere 1111.At diagnosis of IAS, the peak of the hypoglycemic attacks had been passed. The normal range of total IRI and 1251-insulin binding was < 71.8 pmol/l and < 5%, respectively.
I! Himto, Y Uchigata / Diaberes Res. C&L Rzzct. 24 Suppl (1994) S153-S1.57
s156
Table 3 Serological m
Ft. no. 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
typing of Japanese patients with insulin autoimmune syndrome
A
B
C
DR
526 1123 113 224 113 llJ4 ll,11,33 11,31 24,26 24,26 24,26 2433 2,ll 26,24,233 11,24 24,31 2,ll z224 2G% 24,26
40,62 44,62 44,62 51,62 62,60,62 5452 44,62 16,62 35,61 62,62,17,62 61,62 35,54,62 44,35 6,61 62,51,62 46,15,35 35,62 35,62 60,62 55,62 62,54,62 35,62 54,62 62,7,62
w4,w4,w4,w3,w4,w4,wl,w4 w4,w4,w7 w3,w3,w4 w4,w3,w4 w4,w3,wl,w4 w3,w4,w3,w4,wll,w3,w4,w3,w4 w3,w4 wl.w3 wl,w3 wl,w4 w3,w4 w4,w4,w4,w7
4,4,13 499 4,12 4,499 438 499 294 439 2,4 4,436 499 498 4,4,13 4,12 4,12 4,438 499 4,12 2,4 4,496 499
:1: ll,24,31 11,26 11,24 2,ll 11,31
4,-
4,4,438 134
DQ NT
193 NT 3,3,NT 1,3 3,NT NT NT NT 193 3,3,-3,NT 327 337 3,1.3 3,NT 12 NT 1J NT 394 394 3.4 1s NT
HLA typing was performed in various laboratories. NT, not tested.
IAS had Bw62/Cw4/DR4 possess DRBl * 04r)6.
and those 50 did not 4
References 5 Hirata, Y., Ishizu, H., Quchi, N. et al. (1970) Insulin autoimmunity in a case of spontaneous hypoglycemia. J. Jpn. Diabetes Sot. 13,312-319 (in Japanese). Hirata, Y. and Arimichi, M. (1972) Insulin autoimmune syndrome - the second case. J. Jpn. Diabetes Sot. 15, 187-192 (in Japanese). F@lling,J. and Norman, N. (1972) Hyperglycemia, hypoglycemic attacks and production of anti-insulin autoantibodies without previous known immunization. Immune_
6
7
logical and functional studies in a patient. Diahetes 21, 814-826. Hirata, Y., Tominaga, M., Ito, J. et al. (1974) Spontaneous hypoglycemia with insulin autoimmunity in Graves’ disease. Ann. Int. Med. 81,214-218. Oneda, A., Matsuda, K., Sato, M. et al. (1974) Hypoglycemia due to apparent autoantibodies to insulin. Characterization of insulin-binding protein. Diabetes 23, 4130. Takayama-Hasumi, S., Eguchi, Y., Sato, A. et al. (1990) Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemic attacks in Japan. Diabetes Res. Clin. Pratt. 10,211-214. Uchigata, Y., Eguchi, Y., Takayama-Hasumi, S. et al. (1994) Insulin autoimmune syndrome (Hiram disease):
Y; iiirata, Y Wchigata /Diabetes Res. Clin. Pratt. 24 Suppl. (1994) S153-S157 Clinical features aud epidemiology in Japan. Diabetes Res. Clin. Pratt., 22, 89-94. 8 Icbihara, K., Shima, IC.,Saito, Y. et al. (1977) Mechanism of hypoglycemia observed in a patient with insulin autoimmune syndrome. Diabetes 26,5OO-506. 9 Hirata, Y. (1983) Methimazoie and insulin autoimmune syndrome with hypoglycemia. Iancet ii, 1037-1038. 10 Wasada, T., Eguchi, Y., Takayama-Hasumi, S. et al. (1988) Reverse phase high performance liquid chromatographic analysis of circulating insulin in the insulin autoimmune syndrome. J. Clin. Endocrmol. Metab. 66, 153-158. S. et al. 11 Uchigata, Y., Eguchi, Y., Takayama-Hasumi, (1983; The immunoglobulin class, the subclass and the ratio of k:A light chain of autoantibodies to human insulin in insulin autoimmune syndrome. Autoimmunity 3, 289-297. S. et al. (1989) 12 Wasada, T., Eguchi, Y., Takayama-Hasumi, InsuIin autoimmune syndrome associated with benign moaoclonal gammopathy. Evidence for monoclonal insulin autoantiiies. Diabetes Care 12, 147-150.
13
14
15
16
17
s157
Uchigata. Y., Takayama-Hasumi, S., Kawanishi, IL et al. (i&X) Inducdon of antibody that mimics ksulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain. Diabetes 40,966-970 Hiram, Y. (1987) Autoimmune insulin syndrome ‘up to date’. In: D. Andreani, V. Marks and P.J. Lefebvre (Eds.), Hypoglycemia. Serono Symposia Publications, Vol. 38, Baven Press, New York, pp. 105-li8. Uchigata, Y., Kuwata, S., Tokunaga, K. et al. (1992) Strong association of insulin autoimmune syndrome with HL4-DR4. Iancet 339,393-394. Uchigata, Y., Omori, Y., Nieda, M. et al. (1992) HLA-DR4 genotype and insulin-process;ng in insulin autoimmune syndrome. Lancet 340,1467. Uchigata, Y., Kuwata, S., Tsushima, T. et al. (1993) Patients with Graves’ disease who developed insulin autoimmune syndrome (Hirata disease) possess HLABw62/Cw4/DR4 carrying DRBl*O406. J. Ch. Endocrinol. Metab. ?7, 249-754.