Fulminant type 1 dm

Fulminant Type 1 DM
劇症型1型糖尿病
1

Fulminant type 1 DM
 1型糖尿病の亜型で, 劇症発症するタイプ.
◦ アジアで多く報告されており,
日本国内の急性1型糖尿病の20%がこのタイプ.
◦ ウイルス感染症や妊娠等を契機とし, 1週間以内に急激に発症し,
その際膵酵素上昇が認められることが多い.
膵臓の組織検査では, 炎症性細胞(主にT cell)の浸潤が認められる.
◦ 通常type 1 DMで見られる様な自己抗体は陰性.
(GAD抗体, Islet-cell Ab, 抗インスリン抗体,
Insulinoma-associated antigen 2 Ab).
◦ 症例報告レベルでは陽性例もある.(Internal Medicine 2003;42:517-520)
◦ 遺伝子が関連していると考えられており,
HLA-DR-DQ, HLA-B, CTLA-4とFulminant type 1 DMの関連が示唆
2
Diabetes Metab Res Rev 2011; 27: 959–964.

 Fulminant type 1 DMの診断クライテリア;
◦ 発症早期にDKAやケトン体陽性となり,
その際のHbA1cは低値(<8.5%)
◦ 尿中, 血中C-peptideは抑制されている.
3
Table 1. Criteria for definite diagnosis of fulminant type
1 diabetes
Fulminant type 1 diabetes mellitus is confirmed when all
the following 3 findings are present.
1. Occurrence of diabetic ketosis or ketoacidosis soon
(around 7 days) after the onset of hyperglycaemic
symptoms (elevation of urinary or serum ketone bodies
at first visit)
2. Plasma glucose level ≥288 mg/dL (16.0 mmol) and
haemoglobin A1c level <8.5%a
at first visit
3. Urinary C-peptide excretion <10 µg/day or fasting
serum C-peptide level <0.3 and <0.5 ng/mL after
intravenous glucagon (or meal) load at onset
aShown in JDS value [32].
Epidemiology
By using the criteria, 19.4% of acute-onset type 1 diabetes
belongs to fulminant type 1 diabetes in the national survey
in Japan [3]. This prevalence is concordant with our first
report in which 11 of the 56 patients (19.6%) with acute-
onset type 1 diabetes are fulminant type 1 diabetes.
In Ehime study, regional register study in southwestern
part of Japan, fulminant type 1 diabetes accounted for
0.2% of all new-onset diabetes and 14.8% of acute-onset
type 1 diabetes [10]. In Korea, 7.1% of type 1 diabetes
ratio: 2.9, 2.1). DRB1∗
01:01-DQB1∗
05:01
DQB1*06:01 and DRB1∗
15:02-DQB1∗
06:0
cantly lower (2.7 versus 7.7%, 3.5 versus
versus 11.5%, respectively). The frequenc
gotes with DRB1∗
04:05-DQB1∗
04:01 (13.7
odds ratio 6.7) and DRB1∗
09:01-DQB1∗
03
1.5%, odds ratio 7.0) were significantly hig
with fulminant type 1 diabetes.
These results were concordant with our p
in which DR4-DQ4 was the most frequen
fulminant type 1 diabetes [19] and adde
findings as regard to susceptible or resista
class II HLA in fulminant type 1 diabetes.
In addition, CTLA-4 CT60 polymorph
B∗
4002 are associated with fulminant ty
in recent reports [20,21] (Table 2).
Viral infection
We have several lines of evidence that ind
tion of viral infection to the aetiology of fu
diabetes. They are (1) preceding flu-like sy
were more frequently observed in fulmina
betes, in 71.7%, than in type 1A diabetic pat
[3]; (2) elevation of broad reacting an

4
0
Hypothetical
β-cell
mass
(%)
Insulin-
requiring
state
100
20
<1 week
Time
Years
Fulminant
Autoimmune
Figure 1 Schematic process showing the destruction of the hypothetical β-cell
mass in fulminant type 1 diabetes and type 1A (autoimmune) diabetes.
25
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 2007; 3:37-45

Fulminant Type 1 DMの疫学
 日本国内では急性発症の1型DMの19.4%を占める
◦ 新規発症のDMの0.2%の頻度.
◦ 男女比は1:1と差は無く,
男性例では平均43歳, 女性では35歳が発症年齢.
成人で多く, <20歳での発症は8.7%のみ.
◦ 遺伝子が関連しており, HLA-DR-DQ, HLA-B, CTLA-4が発症に関連している.
5
Fulminant Type 1 Diabetes – an Important Subtype in East Asia 961
Table 2. Genetic factors in Japanese type 1 diabetes
Fulminant Type 1A
HLA DRB1-DQB1 (frequent) ∗04:05-∗04:01, ∗09:01-∗03:03 ∗09:01-∗03:03, ∗04:05-∗04:01, ∗08:02-∗03:02
HLA DRB1-DQB1 (Rare) ∗
15:02-∗
06:01, ∗
01:01-∗
05:01, ∗
08:03-∗
06:01, ∗
15:01-∗
06:02, ∗
15:02-∗
06:01
CTLA-4 CT60 AA GG
HLA-B ∗
4002 None

 遺伝子型とFulminant type発症のOR
6
FIGURE 1. OR for the genotypic combination of DR4-DQ4 and DR9-DQ3 in fulmi-
nant type 1 diabetes.12 X, neither DR4-DQ4 nor DR9-DQ3.
DR9-DQ3 is strongly associated with the susceptibility to fulminant type 1
diabetes (OR = 10.0, 95% CI: 2.0–49.0, P = 0.0007), even though the clin-
ical phenotypes of these patients are almost the same as those whose onset
were not associated with pregnancy. These results suggest that a differential
Ann. N.Y. Acad. Sci. 1079: 24–30 (2006).

 発症年齢分布.
◦ 白; 男性例
灰色; 女性例
明灰; 妊娠例
7
is 39.1±15.7 years (mean±SD; Table 1).Among
161 patients, only 14 (8.7%) were under 20 years
of age,indicating that more than 90% of patients
Numberofpatients
Age (years)
25
20
15
10
5
0
0–9
10–19
20–29
30–39
40–49
50–59
60–69
70–79
80+Figure 2 Distribution of ages at onset of fulminant type 1 diabetes. The
white columns depict males and the gray columns depict females. The light
gray bars show pregnant patients or those who recently gave birth. Adapted,
with permission, from Hanafusa et al.16 Permission obtained from the Japan
Diabetes Society © Hanafusa T et al. (2005) J Japan Diab Soc 48 (Suppl 1):
A1–A13.

8
発症の季節性;
夏, 冬に多い傾向
(ウイルス感染に関連？)
REVIEW
www.nature.com/clinicalpractice/endmet
Numberofpatients
Month
20
15
10
5
0
Jan
Feb
M
ar
Apr
M
ay
Jun
Jul
Aug
Sep
O
ct
N
ov
D
ec
Figure 4 Seasonal variation of fulminant type 1 diabetes. Numbers of patients
include both patients seen in 10 diabetes centers and those reported from
other hospitals. Adapted, with permission, from Hanafusa et al.16 Permission
obtained from the Japan Diabetes Society © Hanafusa T et al. (2005) J Japan
Diab Soc 48 (Suppl 1): A1–A13.
Box 1 The human leukocyte antigen system.

臨床経過
 急性ウイルス感染症を契機とした発症が有名で,
◦ Fulminant type 1 DMの71.7%で孔するFlu-like symptomがある.
(通常のType 1 DMでは26.9%)
◦ 抗Enterovirus IgAの上昇も認められることが多い.
他にはHHV-6, Influenza B, Mumps, Coxackie, HAV, CMV, EBVに対する
抗体が上昇している報告例があり, 発症に関連している可能性がある.
9

10
Figure 1. Cellular inﬁltration in the serial sections of a patient with fulminant type 1 diabetes. (a) Insulin, (b) glucagon, (c) CD3 (T
cell) and (d) CD68 (macrophage) [29]
ntofcellularinfiltration
Viral infection
-several virus
+ Genetic Factors+ Genetic Factors
-Class I and II HLA, CTLA-4-Class I and II HLA, CTLA-4
Accelerated antiviral immune reaction
膵臓の組織所見ではインスリン分泌細胞の減少,
T-cellの浸潤が認められる.

日本国内のSurvey
 222名のType 1 DM患者の解析.
◦ 43名(19.4%)がFulminant type 1 DM患者であった.
それ以外に日本国内で報告された118名のFulminant type 1 DM患者を加えて
161例を解析.
11
Diabetes Care 26:2345–2352, 2003
Table 1—Proﬁles of fulminant and autoimmune type 1 diabetic patients
Fulminant Autoimmune
n 161 137
Clinical characteristics
Duration of symptoms (days) 4.4 Ϯ 3.1 36.4 Ϯ 25.1
Age (years) 39.1 Ϯ 15.7 30.1 Ϯ 16.2
BMI (kg/m2
) 20.7 Ϯ 3.9 18.8 Ϯ 2.8
Family history of type 1 diabetes 1/160 2/135
Other autoimmune disease 9/85 17/51
Laboratory data 1
HbAlc (%) 6.4 Ϯ 0.9 12.2 Ϯ 2.2
Urinary C-peptide (␮g/day) 4.3 Ϯ 4.0 21.0 Ϯ 14.8
Fasting serum C-peptide (nmol/l) 0.10 Ϯ 0.07 0.23 Ϯ 0.13
Peak serum C-peptide (nmol/l) 0.10 Ϯ 0.10 0.40 Ϯ 0.26
Increment of serum C-peptide (nmol/l) 0.03 Ϯ 0.03 0.20 Ϯ 0.20
Fulminant type 1 diabetes in Japan

12
tients (35.1 Ϯ 15.8)
at onset of fulmin
from 1 year to 80
adolescent onset o
(onset before age 20
patients (3 male and
adult onset was obse
147 patients.
The mean BMI a
betes was 20.7 in ful
patients, which wa
than that in autoim
patients. There was
ence in the presenc
type 1 and type 2 d
relatives between fu
mune diabetes, but
other than type 1 di
quently observed in
tes than in fulminan
Thirst was the m
tom accompanying
and was observed i
minant and autoim
patients. Lower bod
served in fulminant
immune diabetes.
Flu-like sympto
toms, and drowsin
n 161 137
Age (years) 39.1 Ϯ 15.7 30.1 Ϯ 16.2
BMI (kg/m2
) 20.7 Ϯ 3.9 18.8 Ϯ 2.8
Laboratory data 1
HbAlc (%) 6.4 Ϯ 0.9 12.2 Ϯ 2.2
Accompanying symptoms
Thirst 93.7 93.3
Body weight loss (kg) 3.5 Ϯ 2.7 5.5 Ϯ 3.7
Flu-like symptoms (total) 71.7 26.9
Fever 60.0 ND
Headache 11.5 ND
Sore throat 25.2 ND
Cough 12.0 ND
Rhinorrhea 7.9 ND
Joint pain 5.5 ND
Abdominal symptoms (total) 72.5 7.5
patients. There was n
ence in the presence
type 1 and type 2 dia
relatives between fulm
mune diabetes, but au
other than type 1 diab
quently observed in
tes than in fulminant
Thirst was the m
tom accompanying th
and was observed in
minant and autoimm
patients. Lower body
served in fulminant d
immune diabetes.
Flu-like symptom
toms, and drowsine
quently observed in t
than in the autoimmu
onset (P Ͻ 0.0001) (T
ﬂu-like symptoms, f
common and was ob
patients. Nausea, vom
also frequent and wer
of patients.
Of the 14 patien
diabetes during or aft
study, 13 belonged to
(Table 1). Their onse
in one patient, the 22
Laboratory data 1
HbAlc (%) 6.4 Ϯ 0.9 12.2 Ϯ 2.2
Thirst 93.7 93.3
Fever 60.0 ND
Headache 11.5 ND
Sore throat 25.2 ND
Cough 12.0 ND
Rhinorrhea 7.9 ND
Joint pain 5.5 ND
Nausea, Vomiting 65.4 ND
Upper abdominal pain 39.2 ND
Lower abdominal pain 11.0 ND
Diarrhea 5.5 ND
Drowsiness 45.2 5.3
Pregnancy† 21.0 1.5
Laboratory data 2
Plasma glucose level (mmol/l) 44.4 Ϯ 20.0 24.1 Ϯ 11.8
Arterial pH 7.125 Ϯ 0.125 7.309 Ϯ 0.124
Serum exocrine pancreatic enzyme level 98/2 17/26
Amylase 74/54 11/81
Elastase-1 54/9 1/37
Lipase 50/9 5/38
Diabetes Care 26:2345–2352, 2003

tients (35.1 Ϯ 15.8)
at onset of fulmin
from 1 year to 80
adolescent onset o
(onset before age 20
patients (3 male and
adult onset was obse
147 patients.
The mean BMI a
betes was 20.7 in ful
patients, which wa
than that in autoim
patients. There was
ence in the presenc
type 1 and type 2 d
relatives between fu
mune diabetes, but
other than type 1 di
quently observed in
tes than in fulminan
Thirst was the m
tom accompanying
and was observed i
minant and autoim
patients. Lower bod
served in fulminant
immune diabetes.
Flu-like sympto
toms, and drowsin
n 161 137
Age (years) 39.1 Ϯ 15.7 30.1 Ϯ 16.2
BMI (kg/m2
) 20.7 Ϯ 3.9 18.8 Ϯ 2.8
Laboratory data 1
HbAlc (%) 6.4 Ϯ 0.9 12.2 Ϯ 2.2
Thirst 93.7 93.3
Fever 60.0 ND
Headache 11.5 ND
Sore throat 25.2 ND
Cough 12.0 ND
Rhinorrhea 7.9 ND
Joint pain 5.5 ND
quently observed in
than in the autoimm
onset (P Ͻ 0.0001) (
flu-like symptoms,
common and was o
patients. Nausea, vo
also frequent and we
of patients.
Of the 14 patie
diabetes during or af
study, 13 belonged
(Table 1). Their onse
in one patient, the 2
tient, the 26th week
29th week in one pa
in three patients, th
patient, the 35th we
36th week in two p
week after delivery i
Compared to au
tients, fulminant typ
markedly higher pla
trations and signific
pH at the first visit (T
of three serum exo
zyme levels—amy
lipase—was increas
range in 98 patient
diabetes group, only
mal levels of all these
Nausea, Vomiting 65.4 ND
Upper abdominal pain 39.2 ND
Lower abdominal pain 11.0 ND
Diarrhea 5.5 ND
Drowsiness 45.2 5.3
Pregnancy† 21.0 1.5
Laboratory data 2
Plasma glucose level (mmol/l) 44.4 Ϯ 20.0 24.1 Ϯ 11.8
Arterial pH 7.125 Ϯ 0.125 7.309 Ϯ 0.124
Serum exocrine pancreatic enzyme level 98/2 17/26
Amylase 74/54 11/81
Elastase-1 54/9 1/37
Lipase 50/9 5/38
Serum sodium level (mEq/l) 131 Ϯ 9 137 Ϯ 4
Serum potassium level (mEq/l) 5.5 Ϯ 1.2 4.3 Ϯ 0.8
Serum chloride level (mEq/l) 94 Ϯ 10 101 Ϯ 5
Serum AST level (IU/l) 49 Ϯ 83 22 Ϯ 17
Serum ALT level (IU/l) 44 Ϯ 51 26 Ϯ 33
Serum total cholesterol level (mmol/l) 5.1 Ϯ 1.6 5.5 Ϯ 1.7
Serum triglycerides (mmol/l) 2.0 Ϯ 1.8 1.3 Ϯ 1.0
Autoantibodies
Anti-GAD antibody 7/138 114/14
Anti–IA-2 antibody 0/43 31/24
Anti-thyroglobulin antibody 5/63 13/64
Anti–thyroid microsomal antibody 6/59 24/64
Data are means Ϯ SD, %, or n (positive/negative). Family history of type 1 or type 2 diabetes given for
first-degree relatives. Pregnancy indicates percent female subjects ages 13–49 years who had type 1 diabetes
during or after pregnancy in this study (13 of 62 fulminant diabetic subjects and 1 of 68 autoimmune diabetic
subjects). Data for serum enzyme levels give number of patients with elevated value of at least one of the three
enzymes/patients with no elevated value of the three enzymes. ND, not determined.
Diabetes Care 26:2345–2352, 2003

 Fulminant typeでは,
インスリン必要量は
初期より多い.
◦ 0.7 U/kg/d程必要となる
14
tients showed elevated serum levels of at
least one of these enzymes and 26 patients
showed normal levels of all these
enzymes.
As shown in Table 1, fulminant pa-
reported previously (16). None of the au-
toimmune type 1 diabetic patients suf-
fered from such episodes. The other
fulminant and autoimmune type 1 diabe-
tes patients survived the metabolic disor-
sis at onset; 2) few patients were children
or adolescents, and Ͼ90% of patients
were adults; 3) male patients accounted
for ϳ50% of all cases; 4) ﬂu-like symp-
toms, especially fever, were frequently
observed at onset; and 5) almost all female
patients who developed type 1 diabetes
during pregnancy had the fulminant type.
This nationwide survey indicated that
fulminant type 1 diabetes is a major sub-
type in Japan. Several cases similar to ful-
minant type 1 diabetes have been
reported in Japan after (16–23) and even
before (8–12) Imagawa et al. proposed
this novel subtype. However, few cases
have been reported from Western coun-
tries (24–27). The number of fulminant
type 1 diabetes in Caucasians might be
relatively small, and therefore this sub-
type might have been disregarded among
the majority of autoimmune type diabetes
cases; however, the fulminant subtype
does not appear to be rare, at least in the
Japanese population.
Second, Ͼ90% of fulminant type 1
diabetic patients were adults and no sex
difference was observed among cases. The
incidence of type 1 diabetes in Japanese
children is 0.8 people/10,000 person-
years and lower than the incidence in Eu-
ropean countries (28); however, type 1
diabetes is not a rare disease. Nonetheless,
few cases of fulminant diabetes were re-
ported in the Japanese children or adoles-
cents in this study. These ﬁndings
suggested that fulminant type 1 diabetes
is most likely an adult-onset disease. Fe-
male sex was predominant in autoim-
Figure 3—Changes in HbA1c levels and insulin injection dosages in fulminant (F) and autoim-
mune (A) type 1 diabetes during 12 months after the onset. f, F, fulminant patients; Ⅺ, E,
autoimmune patients. P Ͻ 0.05 for a vs. b, c, d, and e; b vs. d; e vs. f, g, and h; f vs. g; bЈ vs. dЈ and
fЈ; cЈ vs. dЈ and gЈ; dЈ vs. hЈ; and fЈ vs. hЈ.
Diabetes Care 26:2345–2352, 2003

Fulminant type 1 dm

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