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Diabetes Care 26:1640-1641, 2003
© 2003 by the American Diabetes Association, Inc.

Letters: Observations
Letter

HLA-DR-DQ Haplotype in Rapid-Onset Type 1 Diabetes in Japanese

Tomoatsu Nakamura, MD, Shoichiro Nagasaka, MD, Ikuyo Kusaka, MD, Toshimitsu Yatagai, MD, Jianmei Yang, MD and Shun Ishibashi, MD

From the Division of Endocrinology and Metabolism, Jichi Medical School, Tochigi, Japan

Type 1 diabetes is characterized by the presence of insulitis and autoantibodies, at least in the earlier course of the disease. It is well known that HLA locus confers strong genetic susceptibility to the disease. Imagawa et al. (1) described a unique subtype of type 1 diabetes that shows a rapid and fulminant onset of the disease but lacks evidence of insulitis and autoantibodies. Although the etiology of this unique subtype of type 1 diabetes is unclear at present, Tanaka et al. (2) very recently reported that specific HLA-DQ genotypes may be associated with this subtype of type 1 diabetes. Here, we report clinical characteristics of subjects with type 1 diabetes of a rapid and fulminant onset who were collected from the registration of type 1 diabetes in our institution.

We identified 19 type 1 diabetic subjects showing an acute and abrupt onset of diabetes (duration of hyperglycemic symptoms 6 ± 3 days [mean ± SD], range 1–10) accompanied by low HbA1c levels (6.8 ± 0.9%, 5.4–8.2). The subjects consisted of 11 men and 8 women aged 38 ± 17 years (range 16–66) with BMI of 22.2 ± 3.2 kg/m2 (17.1–27.7). Family history of diabetes (possibly type 2 diabetes) was recorded in three subjects (16%). Among eight women, four manifested diabetes during gestation (n = 2) or just after delivery (n = 2). History of preceding upper respiratory infection was noted in nine subjects (47%). Despite short duration of subjective symptoms and low HbA1c levels, their initial concentrations of plasma glucose was as high as 34.1 ± 13.2 mmol/l (range 13.6–72.4), indicating a fulminant onset of diabetes. In fact, 14 subjects showed diabetic ketoacidosis at their initial presentation (arterial pH 7.14 ± 0.17, 6.80–7.34), and the remaining five had marked ketosis and hyperglycemia. GAD autoantibodies, measured by commercial RIA kits (Cosmic Corporation, Tokyo) (3), were negative in 18 of the 19 subjects (<1.5 units/ml), but a single subject showed a weakly positive level (5.6 units/ml). Insulinoma-associated protein 2 (IA2) autoantibody and anti-thyroperoxidase and -thyroglobulin antibodies were negative in all subjects. Fasting serum level and urinary excretion of C-peptide were decreased to 0.10 ± 0.07 nmol/l (0–0.26) and 2.2 ± 2.1 µmol/day (0.2–6.9), respectively, and they did not show any signs of remission of insulin dependency during the observation period.

As for HLA status, HLA-DRB1-DQB1 genotypes were determined and compared with those in autoantibody (GAD and/or IA2 autoantibodies)-positive subjects with significant type 1A diabetes (n = 87) derived from our registration. Frequency of HLA-DRB1*0405-DQB1*0401 haplotype in a homozygous manner was significantly higher in the rapid-onset group (5 of 19, 26%) than the type 1A group (4 of 87, 5%, P = 0.009 by Fisher’s exact probability). The frequency was also far higher than that of nondiabetic Japanese subjects reported in the literature (1 of 84, P < 0.001 [2] and 6 of 157, P = 0.003 [4]). Frequency of other susceptible haplotypes (DRB1*0405-DQB1*0401 in a heterozygous manner and DRB1*0901-DQB1*0303 in a homozygous manner) (4) did not differ between the rapid-onset group and type 1A group (data not shown).

In our experience, homozygous HLA-DRB1*0405-DQB1*0401 haplotype confers genetic susceptibility to rapid-onset type 1 diabetes in Japanese, consistent with the recent report by Tanaka et al. (2). Frequency of GAD autoantibodies was actually low in this subgroup of type 1 diabetes (1,2), but a single subject showed a positive result at the onset of diabetes. There was also a case report in which GAD autoantibodies turned positive 1 year after the fulminant onset of type 1 diabetes (5). Tanaka et al. (6) also demonstrated presence of insulitis in a case of rapid-onset type 1 diabetes. Collectively, it is suggested that rapid-onset type 1 diabetes could share autoimmune etiology with type 1A diabetes (7). Of interest is that half of the female patients developed diabetes during or just after pregnancy. There have been many studies reporting altered immune response during pregnancy (8,9), and pregnancy is considered to be a precipitating factor for type 1 diabetes (10). We hypothesize that altered immune response to unknown stimulus may be causative of rapid and aggressive ß-cell loss, together with the genetic susceptibility, at least in part, determined by HLA-DR-DQ haplotypes.

Footnotes

Address correspondence to Shoichiro Nagasaka, MD, Division of Endocrinology and Metabolism, Jichi Medical School, Yakushiji 3311-1, Minamikawachi, Tochigi 329-0498, Japan. E-mail: sngsk{at}jichi.ac.jp.

References

  1. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y: A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med 342:301–307, 2000[Abstract/Free Full Text]
  2. Tanaka S, Kobayashi T, Nakanishi K, Koyama R, Okubo M, Murase T, Odawara M, Inoko H: Association of HLA-DQ genotype in autoantibody-negative and rapid-onset type 1 diabetes. Diabetes Care 25:2302–2307, 2002[Abstract/Free Full Text]
  3. Akamine H, Komiya I, Shimabukuro T, Asawa T, Tanaka H, Yagi N, Taira T, Nagata K, Arakaki K, Wakugami T, Takasu N, Powell MJ, Furmaniak J, Smith BR: High prevalence of GAD65 (and IA-2) antibodies in Japanese IDDM patients by a new immunoprecipitation assay based on recombinant human GAD65. Diabet Med 14:778–784, 1997[Medline]
  4. Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M, Nishino M, Uchigata Y, Lee I, Ogihara T: Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51:545–551, 2002[Abstract/Free Full Text]
  5. Shimada A, Oikawa Y, Shigihara T, Senda T, Kodama K: A case of fulminant type 1 diabetes with strong evidence of autoimmunity (Letter). Diabetes Care 25:1482–1483, 2002[Free Full Text]
  6. Tanaka S, Kobayashi T, Momotsu T: A novel subtype of type 1 diabetes mellitus. N Engl J Med 342:1835–1837, 2000[Free Full Text]
  7. Lernmark A: Rapid-onset type 1 diabetes with pancreatic excorine dysfunction. N Engl J Med 342:344–345, 2000[Free Full Text]
  8. Whitacre CC, Reingold SC, O’Looney PA: A gender gap in autoimmunity. Science 283:1277–1278
  9. Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP: IL-12, TNF-{alpha}, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 86:4933–4938, 2001[Abstract/Free Full Text]
  10. Buschard K, Buch I, Molsted-Pedersen L, Hougaad P, Kuhl C: Increased incidence of true type 1 diabetes acquired during pregnancy. BMJ 294:275–279, 1987

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