Epidemiological study of pancreatic diabetes in Japan in 2005: a nationwide study.

Abstract

There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan.
We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes).
A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers.
We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.

Full text

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Epidemiological Study ofPancreatic Diabetes inJapan in2005
A Nationwide Study
Tetsuhide Ito, MD, PhD,* Makoto Otsuki, MD, PhD,Þ Hisato Igarashi, MD, PhD,*
Yasuyuki Kihara, MD, PhD,Þ Ken Kawabe, MD, PhD,* Taichi Nakamura, MD,* Nao Fujimori, MD,*
Takamasa Oono, MD, PhD,* Ryoichi Takayanagi, MD, PhD,* Tooru Shimosegawa, MD, PhD,þ
and The Research Committee of Intractable Diseases of the Pancreas
Objectives: There have been few epidemiological studies on pancre-
atic diabetes. In this study, we determined the incidence and pathologyof
pancreatic diabetes in Japan.
Methods: We examined the epidemiology of pancreatic diabetes in
Japan in 2005 by using a nationwide stratified random-sampling method.
Especially, we focused on newly developed diabetes in association with
the occurrence of pancreatic disease (true pancreatic diabetes).
Results: A total of 19,500 individuals received treatment for true
pancreatic diabetes, accounting for 0.8% of patients with diabetes. Pre-
valence was estimated to be 15.2 per 100,000 with an annual onset
incidence of 1.1 per 100,000. With regard to the complications in true
pancreatic diabetes, the incidence of retinopathy was lower than that in
types 1 and 2 diabetes. Among true pancreatic diabetes with chronic
pancreatitis, alcoholic pancreatitis was found in the largest sector. Fur-
thermore, as many as 53.7% were continuous drinkers, and 66.7% re-
ceived insulin therapy. The frequency of hypoglycemia was high in
regular drinkers treated with insulin. Hypoglycemia was a major cause
of death in patients who were on insulin and continuous drinkers.
Conclusion: We clarified the epidemiology of pancreatic diabetes in
Japan. Patients with chronic pancreatitisYassociated pancreatic diabetes
should receive lifestyle guidance focused on drinking cessation.
Key Words: pancreatic diabetes, nationwide survey, epidemiology,
diabetic complication, chronic pancreatitis
(Pancreas 2010;39: 829Y835)
D
such as pancreatitis or pancreatic cancer, because this disease
occurs due to pancreatic endocrine dysfunction caused by pro-
gression of pancreatic disorder.1Y4From the endocrinologic
aspects, both insulin synthesis/secretion and glucagon secretion
are affected by the primary disease.3,4Therefore, pathology and
clinical features of pancreatic diabetes are often different from
those of types 1 and 2 diabetes, and its treatment method should
iabetes mellitus with pancreatic disorders (pancreatic dia-
betes) is closely related to progression of a primary disease
be different. In Japan, reports on investigation, diagnosis, and
treatment of pancreatic diabetes were published by Okuno et al5
in 1990 and Koizumi et al6in 1998, but there have been few
comprehensive discussions or epidemiological surveys since
then. We performed a nationwide epidemiological survey on
pancreatic diabetes to determine the incidence, pathology, clini-
cal features, and current treatment status in Japan.
MATERIALS AND METHODS
The survey was conducted on patients with pancreatic
diabetes who were treated from January 1 to December 31,
2005. We obtained the list of all hospitals, including the name,
address, number of beds, and departments in the hospital, from
the Ministry of Health, Labor, and Welfare in Japan. The de-
partments of internal medicine, metabolism, diabetes, endocri-
nology, and surgery in each hospital were listed, and the method
of stratified random sampling was used to select departments
for survey. The sampling rates were 5%, 10%, 20%, 40%, 80%,
100%, and 100%, for the stratum of general hospitals with less
than 100 beds, 100 to 199 beds, 200 to 299 beds, 300 to 399
beds, 400 to 499 beds, 500 or more beds, and the university
hospitals, respectively. To increase the efficiency of this survey,
we added some relevant departments where many patients with
pancreatic diabetes were expected to be treated. They were con-
sidered as a special stratum and were all selected.
The study consisted of 2 surveys, each using a different
questionnaire. In the first survey, a simple questionnaire was used
to inquire about the number of patients with pancreatic diabetes
who visited those departments and were treated in 2005. This
questionnaire was directly mailed to the heads of 3459 depart-
ments randomly selected, with the above-mentioned sampling
rate, in January 2005. After the first questionnaire was collected,
the second questionnaire was forwarded to those departments
from which patients with pancreatic diabetes were reported on
the first questionnaire. It requested detailed clinical information
on individual patients treated, including etiology, symptoms, and
procedures for diagnosis of pancreatic diseases as well as dia-
betes, complications, treatments, and prognosis. Because there
are no clear diagnostic criteria for pancreatic diabetes, we used
the Committee Report on Classification and Diagnostic Criteria
of Diabetes Mellitus7compiled by the Committee for Classifi-
cation and Diagnostic Criteria of Diabetes Mellitus, Japan Di-
abetes Society. Pancreatic diabetes is included in BGroup B:
various types of diabetes associated with other diseases and
pathology: (1) pancreatic exocrine disorders (pancreatitis, pan-
creatic injury, pancreatectomy, pancreatic tumor, pancreatic he-
mochromatosis, and miscellaneous).[ Miscellaneous refers to
congenital pancreatic hypoplasia and autoimmune pancreatitis.
Strictly speaking, pancreatic diabetes is a disease associated with
pancreatic disorders, and the patients with preexisting type 1 or
2 diabetes were also included, if their diabetes clearly worsened
ORIGINAL ARTICLE
Pancreas & Volume 39, Number 6, August 2010 www.pancreasjournal.com
829
From the *Department of Medicine and Bioregulatory Science, Graduate
School of Medical Sciences, Kyushu University, Fukuoka; †Department of
Gastroenterology and Metabolism, University of Occupational and Envi-
ronmental Health, School of Medicine, Kitakyushu; and ‡Division of Gas-
troenterology, Department of Internal Medicine, Tohoku University Graduate
School of Medicine, Sendai, Japan.
Received for publication June 14, 2009; accepted October 30, 2009.
Reprints: Tetsuhide Ito, MD, PhD, Department of Medicine and
Bioregulatory Science, Graduate School of Medical Sciences, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
(e-mail: itopapa@intmed3.med.kyushu-u.ac.jp).
This study was supported by the Research Committee of Intractable
Pancreatic Diseases, provided by the Ministry of Health, Labour, and
Welfare, Japan.
Copyright * 2010 by Lippincott Williams & Wilkins
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because of certain pancreatic disorders. Because the incidence of
diabetic complications is influenced by the duration of diabe-
tes,8,9we focused on the analysis of patients who developed
diabetes secondary to pancreatic disorders (true pancreatic dia-
betes). Furthermore, the clinical conditions of patients with true
pancreatic diabetes associated with chronic pancreatitis were also
examined.Themethodofestimationwasbasedontheassumption
that the mean number of patients among the departments that
responded to the survey was equal to that among departments
that did not respond. The total number of patients was then
corrected using the proportions of duplicate cases and inappro-
priate cases. The population of Japan in 2005 reported by the
Japanese government was used to estimate the prevalence rate of
pancreatic diabetes. The guidelines of the Nationwide Epidemi-
ological Survey Manual,10issued by the Research Committee on
the Epidemiological of Intractable Diseases, Ministry of Health,
LabourandWelfare,wasusedtoestimatethecrudeincidencerate,
andtheprevalenceratewasmultipliedbytheproportionofpatients
who were newly diagnosed with pancreatic diabetes in 2005.
RESULTS
Epidemiology of Pancreatic Diabetes in Japan
A national survey was carried out by a stratified random-
sampling method on patients with pancreatic diabetes who were
treated in 2005 (Table 1). On the basis of data derived from the
first survey, the total number of patients treated for pancreatic
diabetes in the year 2005 was estimated at 42,100 (95% con-
fidence interval [CI], 36,328Y51,896), accounting for 1.7% of the
2,469,000 Japanese patients with diabetes in 2005. The overall
prevalence was estimated at 32.9 per 100,000 population (95%
CI, 28.5Y40.7). Furthermore, on the basis of the data obtained in
the second survey, the incidence rate of pancreatic diabetes in
2005 was estimated at 2.4 per 100,000 population (95% CI,
2.1Y2.9). Meanwhile, 19,500 patients (95% CI, 16,854Y24,027)
with true pancreatic diabetes (development of diabetes second-
ary to the onset of a pancreatic disorder) were treated in 2005,
accounting for 0.8% of all patients with diabetes. The overall
prevalence rate was estimated at 15.2 per 100,000 (95% CI,
13.1Y18.7), and the incidence rate was estimated at 1.1 per
100,000 (95% CI, 0.95Y1.36).
Relationship Between Prevalence of Etiology
and Onset of Diabetes
According to the second survey, the causal factors of pan-
creatic diabetes were chronic pancreatitis (40.0%), pancreatic
cancer (24.6%), pancreatectomy (10.2%), acute pancreatitis
(7.5%), and autoimmune pancreatitis (6.1%) (Table 2). Chronic
pancreatitis was the most frequent factor for pancreatic diabetes.
Among the patients with true pancreatic diabetes (initial onset of
diabetes secondary to the development of a pancreatic disorder),
chronic pancreatitis (46.3%), pancreatic cancer (33.7%), pan-
createctomy (65.2%), and acute pancreatitis (47.6%) were the
main factors.
Prevalence of Diabetic Complications in Patients
With True Pancreatic Diabetes
The mean duration of diabetes was 10 years and 2 months
in true pancreatic diabetes (Fig. 1). With regard to microangio-
pathy, retinopathy, neuropathy, and nephropathy were found in
20.9%, 34.9%, and 22.1% of patients, respectively. With regard
to macroangiopathy, cerebrovascular disorder and cardiovas-
cular diseases were observed in 4.7% and. 7.6% of patients,
respectively. Compared with the prevalence of diabetic compli-
cations in patients with types 1 and 2 diabetes with a disease
duration of 11years,theincidence of concurrent retinopathy was
lower in patients with true pancreatic diabetes with a disease
duration of 10 years and 2 months.
Prevalence of Complications in True Pancreatic
Diabetes by Disease Duration
It is known that the duration of diabetes and the status
of blood glucose control are substantial factors for the develop-
ment of diabetic complications in patients with pancreatic di-
abetes, as in the case of patients with type 1 or 2 diabetes.8,9
Therefore, it is considered important to assess complications and
monitor clinical conditions of pancreatic diabetes over time.2Y4
We examined the prevalence of complications in true pancre-
atic diabetes by disease duration and compared it with the data
for types 1 and 2 diabetes.
TABLE 1. Epidemiology of Pancreatic Diabetes in Japan (2005)
Total Pancreatic DiabetesTrue Pancreatic Diabetes
Total no. patients treated during the year
Percentage of total patients with diabetes
Overall prevalence (per 100,000 population)
Incidence rate (per 100,000 population)
42,100 (95% CI, 36,328Y51,896)
1.7%
32.9 (95% CI, 28.5Y40.7)
2.4 (95% CI, 2.1Y2.9)
19,500 (95% CI, 16,854Y24,027)
0.8%
15.2 (95% CI, 13.1Y18.7)
1.1 (95% CI, 0.95Y1.36)
TABLE 2. Prevalence of Pancreatic Diabetes by Causal
Factor and Relationship With Onset of Diabetes
Etiology
No.
Patients%
Onset of Diabetes
Secondary to
Pancreatic Disorder, %
Chronic pancreatitis
Acute pancreatitis
Autoimmune
pancreatitis
Pancreatic injury
Pancreatic cancer
Pancreatic endocrine
tumor
Pancreatic cystic
tumor
Other tumors
After
pancreatectomy
Pancreatic
hemochromatosis
Pancreatic
hypoplasia
Miscellaneous
Total
684
129
105
40.0
7.5
6.1
46.3
47.6
43.3
130.8
24.6
1.1
66.7
33.7
38.9
421
18
117 6.838.6
150.9
10.2
60.0
65.2 174
8 0.571.4
10.10
25 1.5 45.8
44.51,710 100
Ito et al
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Prevalence of Concurrent Retinopathy
by Diabetes Duration
The prevalence of concurrent retinopathy in true pancreatic
diabetes was 29.4% in patients with a 10- to 14-year history of
diabetes and 50.0% in patients with a 20-year or longer history
of diabetes (Fig. 2). Meanwhile, the prevalence of concurrent
retinopathy in types 2 and 1 diabetes was 47.0% and 78.0%,
respectively, in patients with a 10- to 14-year history of diabetes
and 65.0% and 95.0%, respectively, in patients with a 20-year or
longer history of diabetes. Compared with patients with types
1 and 2 diabetes, the prevalence of concurrent retinopathy in
patients with true pancreatic diabetes was lower according to the
duration of the disease.
Prevalence of Concurrent Neuropathy
by Diabetes Duration
The prevalence of concurrent neuropathy in true pancreatic
diabetes was 38.2% in patients with a 10- to 14-year history of
diabetes and 58.3% in patients with a 20-year or longer history
of diabetes (Fig. 3). Meanwhile, the prevalence of concurrent
neuropathy in types 2 and 1 diabetes was 40.0% and 59.0%,
respectively, in patients with a 10- to 14-year history of dia-
betes and 59.0% and 74.0%, respectively, in patients with a
20-year or longer history of diabetes. The prevalence of con-
current neuropathy in true pancreatic diabetes was comparable
to that of type 2 diabetes.
Prevalence of Concurrent Nephropathy
by Disease Duration
The prevalence of concurrent nephropathy in true pancre-
atic diabetes was 20.0% in patients with a 10- to 14-year history
of diabetes and 32.0% in patients with a 20-year or longer
history of diabetes (Fig. 4). Meanwhile, the prevalence of con-
current nephropathy in types 2 and 1 diabetes was 26.5% and
36.0%, respectively, in patients with a 10- to 14-year history of
diabetes and 41.7% and 52.0%, respectively, in patients with
a 20-year or longer history of diabetes. The prevalence of con-
current nephropathy in true pancreatic diabetes was comparable
to that of both types 1 and 2 diabetes.
Prevalence of Concurrent Cardiovascular and
Cerebrovascular Disorders by Disease Duration
The prevalence of concurrent cerebrovascular and cardio-
vascular disorders in true pancreatic diabetes was 8.8% each in
patients with a 10- to 14-year history of diabetes and 16.7% each
in patients with a 20-year or longer history of diabetes (Fig. 5).
Pathology of True Pancreatic Diabetes Associated
With Chronic Pancreatitis
From the second survey, 761 patients with true pancreatic
diabetes and 317 patients with true pancreatic diabetes with
chronic pancreatitis were collected, but actually, 623 patients with
true pancreatic diabetes and 299 patients with true pancreatic
diabetes with chronic pancreatitis were examined in detail.
FIGURE 1. Prevalence of diabetic complications in true
pancreatic diabetes.
FIGURE 2. Prevalence of concurrent retinopathy by
diabetes duration.
FIGURE 3. Prevalence of neuropathy by diabetes duration.
FIGURE 4. Prevalence of concurrent nephropathy by diabetes
duration.
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Family History, Causal Factors, and Coexistence
of Pancreatic Stone
Two hundred ninety-nine patients with true pancreatic dia-
betes also had chronic pancreatitis, representing 48% (299/623)
of all patients in this group. Seventeen percent of patients in
this group had a family history of diabetes. Causal factors for
chronic pancreatitis in patients with true pancreatic diabetes
were alcohol consumption (77.3%, 231/299), idiopathic (14.4%,
43/299), gallstone (2.0%, 6/299), and etiology unknown (5.4%,
16/299). There were no responses in the answer column for
1.0% (3/299) (Fig. 6). Pancreatic stones coexisted in 62.5%
(187/299) of patients in this group, and the highest incidence
of concurrent pancreatic stones was found in patients with al-
coholic pancreatitis (68.0%) (Table 3).
Mortality and Cause of Death
Seven pancreatic diabetes patients died in 2005 (2.3%,
7/299). All the deceased patients had alcoholic chronic pancre-
atitis and received enzyme supplement therapy. Hypoglycemia
was the cause of death in 4 patients with alcoholic pancreati-
tis, including a suspected case (57.1%) (Table 4). All these 4
patients were treated with insulin, and most of them were
regular drinkers.
Pathology of True Pancreatic Diabetes Associated
With Alcoholic Chronic Pancreatitis
Drinking habits, medical treatment, and onset of hypo-
glycemia were examined in 231 patients with true pancreatic
diabetes associated with alcoholic chronic pancreatitis. A total
of 53.7% of patients continued to drink alcohol (Fig. 7A): 34
patients (14.7%) continuously drank the same amount of alco-
hol, and 90(39.0%) continuously drank a reduced amount of
alcohol. With regard to medical treatment, 154 (66.7%) patients
received insulin therapy (Fig. 7B). Among 154 patients on in-
sulin therapy, 21 (13.6%) did not change their drinking habit,
61 (39.6%) reduced the amount of alcohol but continued to
drink, and a total of 53.2% continued with no change in their
drinking habits (Fig. 7C). Furthermore, we examined the fre-
quency of hypoglycemia in patients who continued to drink and
patients who stopped drinking. Among the patients who did not
change their drinking habits, the frequency of hypoglycemia
was high: more than 3 times a week in 4.8% of patients and
1 to 2 times a week in 52.4% of patients (Fig. 8A). Meanwhile,
the frequency of hypoglycemia decreased in patients who re-
duced or stopped drinking: more than 3 times a week in 1.6%
and 1.7% of patients, respectively, and 1 to 2 times a week in
14.8% and 8.5% of patients, respectively (Figs. 8B, C). The
frequency of hypoglycemia (at least once a week) was clearly
higher in the group whose drinking habits remained un-
changed (Fig. 8D).
DISCUSSION
Pancreatic diabetes is defined as Bdiabetes induced by pan-
creatic disorders, including pancreatic diseases such as chronic
pancreatitis and cancer, as well as abnormal exocrine pan-
creas[2Y4; however, general clinicians do not fully understand its
pathology or clinical features. For instance, when patients with
chronic pancreatitis who have insufficient digestive and absorp-
tive functions are not treated with a sufficient quantity of pan-
creatic digestive enzyme, their nutritional status will worsen
and their immunity will be impaired, although their blood glu-
cose level may seem to be under control. Moreover, glucagon
secretion is often insufficient in many insulin-treated patients
who are likely to suffer hypoglycemia. Unlike types 1 and 2
diabetes, pancreatic diabetes presents with different pathology
and clinical features, thus requiring different treatment.3,4
In this study, a national survey was conducted in 2005 by
a stratified random-sampling method aiming to determine the
incidence, pathology, clinical features, and treatment status of
pancreatic diabetes in Japan. Because the prevalence of diabetic
complications is influenced by the duration of diabetes, the
patients who developed diabetes secondary to pancreatic dis-
orders (true pancreatic diabetes) were analyzed for the final
report. Furthermore, the pathology of true pancreatic diabetes
associated with chronic pancreatitis was also examined. In the
FIGURE 5. Prevalence of concurrent cardiovascular and
cerebrovascular diseases in patients with true pancreatic
diabetes by diabetes duration.
FIGURE 6. Etiology of true pancreatic diabetes secondary to
chronic pancreatitis in 299 cases.
TABLE 3. Coexistence of Pancreatic Stones in True
Pancreatic Diabetes Secondary to Chronic Pancreatitis
EtiologyNo. Patients%
Alcoholic
Gallstone
Idiopathic
Unknown
No answer
Total
157/231
3/6
22/43
5/16
0/3
187/299
68.0
50.0
51.2
31.3
0
62.5
Ito et al
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Page 5

first survey, 4117 cases were collected. In 2005, 42,100 pan-
creatic diabetes patients were treated, representing 1.7% of all
patients with diabetes (2,469,000) in 2005. The number of
patients with preexisting pancreatic diabetes was estimated at
32.9 per 100,000; the number of new patients with pancreatic
diabetes was estimated at 2.4 per 100,000. Meanwhile, among
the patients who developed diabetes secondary to pancreatic
disorders (true pancreatic diabetes), 19,500 were treated in
2005, representing 0.8% of total patients with diabetes. The
number of patients with preexisting disease (true pancreatic
diabetes) was estimated at 15.2 per 100,000; the number of
new patients with pancreatic diabetes was estimated at 1.1 per
100,000. The present result is the first finding on pancreatic
diabetes in Japan; therefore, its publication is considered to
have academic and social significance.
With regard to diabetic complications of true pancreatic
diabetes, the incidence of microangiopathy was 20.9% for reti-
nopathy, 34.9% for neuropathy, and 22.1% for nephropathy
(Fig. 1). The incidence of macroangiopathy was 4.7% for cere-
brovascular disorders and 7.6% for cardiovascular diseases.
The incidence of diabetic complications was compared between
patients with types 1 and 2 diabetes and those with true pan-
creatic diabetes by adjusting the mean duration of disease. The
incidence of concurrent retinopathy was lower in patients with
true pancreatic diabetes. Comparison in frequency of diabetic
complications by diabetic duration showed that only retinopa-
thy was less common in patients with true pancreatic diabetes
than in patients with types 1 and 2 diabetes. The incidence of
diabetic complications in pancreatic diabetes was previously
considered to be low, but recent reports suggest no difference
in the incidence of diabetic complications between types 1 and
2 diabetes and pancreatic diabetes. For instance, concurrent dia-
betic retinopathy was reported in 20% to 40%11,12and diabetic
nephropathy was reported in approximately 30%13of patients
with pancreatic diabetes. However, with regard to diabetic neu-
ropathy in pancreatic diabetes, the incidence of peripheral neu-
ropathy was reported to be higher than that of retinopathy or
nephropathy because of the influence of alcohol in patients with
TABLE 4. Cause of Death of Patients With Pancreatic Diabetes Secondary to Chronic Pancreatitis
EtiologyCause of DeathDrinkingDiabetic TherapyHemoglobin A1c, %
6.6Y7.5
Q7.6
Q7.6
Q7.6
5.5Y6.5
5.5Y6.5
5.5Y6.5
Alcoholic
Alcoholic
Alcoholic
Alcoholic
Alcoholic
Alcoholic
Alcoholic
Hypoglycemia
Hypoglycemia
Hypoglycemia
Hypoglycemia (suspected)
Pancreatic cancer
Pancreatic cancer
Hepatic insufficiency
Continued
Continued
Unknown
Continued
Continued
Stopped
Stopped
Insulin (dose unknown)
Insulin (16 U)
Insulin (14 U)
Insulin (52 U)
Insulin (40 U)
Diet therapy only
Insulin (6 U)
FIGURE 7. Drinking habits and treatment situation in patients with true pancreatic diabetes secondary to alcoholic chronic
pancreatitis: drinking situation (A), treatment situation (B), and drinking situation in patients with insulin therapy (C).
Pancreas & Volume 39, Number 6, August 2010Pancreatic Diabetes in Japan
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Page 6

alcohol-induced chronic pancreatitis or because of undernutri-
tion caused by insufficient digestive/absorptive function.4,14,15
In our survey, the incidence of retinopathy in patients with true
pancreatic diabetes secondary to pancreatic disorders was lower
than that in patients with types 1 and 2 diabetes. Complication
of hyperlipidemia in patients with pancreatic diabetes is low,
and the lipid in blood is rather low because of the malnutri-
tion.3Thus, it is speculated that the difference of the lipid me-
tabolism greatly takes part in the incidence of the retinopathy
compared with types 1 and 2 diabetes.
We also studied the pathology of true pancreatic diabetes
associated with chronic pancreatitis. Family history of diabetes
was found in a small number of patients (17.0%). A majority of
these patients (77.3%) had an alcoholic factor, and 68.0% had
concurrent pancreatic stones. In general, 60% to 70% of patients
with chronic calcifying pancreatitis concurrently had diabetes
according to previous reports,16,17and we obtained a similar
result. Malka et al18reported a more than 3-fold increase in the
risk of diabetes after the onset of pancreatic calcification in a
follow-up studyof chronic pancreatitis over a mean period of 7.7
years. However, recent our study demonstrated that the risk of
diabetes in Japan increased approximately 1.32-fold after the
onset of pancreatic calcification over an 8-year period.19These
reports suggested that it might be controversial whether the risk
for the development of diabetes in chronic pancreatitis is closely
related to pancreatic stones. The mortality was 2.3% in the
surveyed cases. Alcoholic pancreatitis was found in all deceased
patients. Hypoglycemia was the most frequent cause of death,
and many of the deceased patients were treated with insulin but
continued to drink alcohol. Therefore, we analyzed the
pathology of true pancreatic diabetes associated with alcoholic
chronic pancreatitis. We found that 54.7% were continuous
drinkers, and 66.7% were treated with insulin. Among 154
patients on insulin, 53.2% were continuous drinkers. Further-
more,thefrequencyofhypoglycemiainpatientswhocontinuedto
drink was clearly higher than that in patients who had stopped
drinking. Recently, we performed a long-term follow-up survey
on chronic pancreatic patients over 8 years.19During the 8 years,
pancreatic diabeteswas observed in28.9% ofpatients,andinsulin
therapy became mandatory for 34.7%. We found that continued
drinking was the greatest risk factor for the onset of diabetes.19
According to our survey, alcohol and continued drinking were the
causal factors for chronic pancreatitis in patients with true
pancreatic diabetes, and when insulin therapy was added, the
frequency of hypoglycemia increased and many died of hy-
poglycemia. Therefore, cessation of drinking should be the pri-
mary lifestyle guidance for patients with panreatic diabetes
secondary to chronic pancreatitis. Insulin profiles in healthy in-
dividuals are characterized by relatively constant basal secre-
tion with postprandial peaks. On the other hand, patients with
pancreatic diabetes show a lack or defect in both basal and
postprandial insulin secretion. To mimic physiological insulin
secretion and achieve appropriate glycemic control in the
patients with pancreatic diabetes, it should be recognized that
sufficient basal insulin supplementation is important.3The
ideal basal insulin preparations are considered to provide a
constant and reliable 24-hour basal insulin supply. The available
intermediate-acting human neutral protamine hagedorn (NPH)
insulin is frequently used in insulin regimens. However, NPH
insulin concentrations rise to a peak after 4 to 6 hours and then
steadily decline. Although we did not investigate the kinds of
insulin used in patients with pancreatic diabetes, it is reported that
NPH insulin treatment often results in nocturnal hypoglycemia
events because inappropriate plasma insulin peaks occur at
night.20,21However, new long-acting human insulin analogs,
glargine and detemir, have characteristics of no pronounced peak
FIGURE 8. Frequency of hypoglycemia in patients with true pancreatic diabetes treated with insulin therapy: patients with no change
in drinking habits (n = 21) (A); patients who reduced but continued drinking (n = 61) (B); and patients who stopped drinking (n = 59) (C).
D, Frequency of hypoglycemia at least once a week in patients with no change in drinking habits (group A), patients who reduced
but continued drinking (group B), and patients who stopped drinking (group C).
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Page 7

and a 24-hour time-action profile22Y26and may be ideally suited
to the constant basal insulin supplementation in patients with
pancreatic diabetes. Intensive insulin therapy using long-acting
insulin analogs is effective and useful for achieving better gly-
cemic control and reduction of severe frequent hypoglycemia in
patients with pancreatic diabetes.3However, the management
of patients with pancreatic diabetes, leading to improved diges-
tion and absorption, requires high doses of oral pancreatic en-
zyme supplements27,28to prevent the onset of hypoglycemia. The
intimaterelationshipbetweentheexocrineandendocrinepancreas
is highlighted by experimental studies. After induction of acute
necrotizing pancreatitis in rat, the peri-insular acini remained in-
tact for long times.29Y31The close proximity of the islets of
Langerhans protects the acinar cells and also accelerates the
regenerative process after pancreatic tissue damage. On the other
hand,hypoinsulinemiawasshowntocausepancreaticatrophyand
fatty infiltration of the exocrine pancreas in guinea pigs.32These
results provide confirmation of the key role of insulin in the
regulation of the exocrine pancreatic structure and function.
Therefore, intensive insulin therapy in patients with pancreatic
diabetes is not only important to control the blood glucose level,
but also a very important factor in the regulation of the exocrine
pancreas.3
This survey yielded a new finding on pancreatic diabetes
in Japan. On the basis of the result obtained, clear diagnostic
criteria and treatment guideline will be compiled to enable
general clinicians to effectively treat patients with pancreatic
diabetes.
ACKNOWLEDGMENTS
The authors thank the doctors who responded to the
questionnaires.
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Pancreas & Volume 39, Number 6, August 2010Pancreatic Diabetes in Japan
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