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ORIGINAL
Post-meal endogenous insulin secretion was significantly
lower in head than in body/tail cancer of the pancreas
Hirotaka Shichijo1, Toshio Hosaka2, Fumie Takewaki1, Yoshikazu Sumitani1, Hitoshi Ishida1, and Kazuki Yasuda1
1
Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan, 2Laboratory of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan

Abstract : The aim : Pancreatic cancer, a rapidly progressive malignancy, is often diagnosed in patients withdiabetes. The incidence of pancreatic cancer has risen dramatically over recent decades. Early diagnosis of thismalignancy is generally difficult because the symptoms do not become apparent until the disease has progressed,
generally leading to a poor outcome. To achieve earlier diagnosis, we analyzed the clinical characteristics of pancreatic cancer patients showing deterioration of plasma glucose levels while hospitalized. Method : Thirty-six
cases were divided into 2 groups ; those diagnosed with diabetes more than a year prior to identification of pancreatic cancer and diabetes secondary to pancreatic cancer. These 2 groups were further subdivided according
to the tumor site (head or body / tail), allowing analysis of 4 subgroups. Anthropometric measurements, laboratory values were determined. Results : Both groups with diabetes lost at least 4 kg and showed HbA1c deteriorationof at least 1% within 5 months of the pancreatic cancer diagnosis. The post-meal elevation of serum C-peptide immunoreactivity (CPR) was significantly decreased in the group with cancer of the pancreatic head, and this wasunrelated to tumor size. Conclusion : Characteristically, pancreatic head cancer was associated with decreased
endogenous insulin secretion as compared to body / tail cancer. J. Med. Invest. 70 : 350-354, August, 2023
Keywords : pancreatic cancer, postprandial CPR, diabetes

INTRODUCTION
The incidence of pancreatic cancer is estimated to be 35 per
100,000 people. Pancreatic cancer rates have been rising dramatically for several decades. This malignancy is known to havea poor prognosis. Because early diagnosis of pancreatic cancer isoften difficult, due to symptoms being absent until the disease isadvanced, outcomes are generally poor. Early diagnosis is thus
considered to have a major prognostic impact.
Chari et al. examined 2,122 patients newly diagnosed with diabetes and found that 0.85% developed pancreatic cancers within
3 years after the diabetes had been diagnosed. Pancreatic cancer
is reportedly detected in one of every 100 to 150 people with diabetes. In addition, half of pancreatic cancers are associated withdiabetes and the percentage of new-onset diabetes with rapidly
progressing morbidity is high (1). According to past reports, therisk of pancreatic cancer development in patients with diabetes
is 1.82-fold greater than that in non-diabetic individuals (95%
confidence interval (CI) : 1.66-1.89) (2). Early screening forpancreatic cancer is important for comprehensively managing
patients with diabetes (3).
Various factors possibly underlying the blood glucose increases associated with pancreatic cancer are broadly attributed toeither pancreatic β cell dysfunction or impaired insulin sensitivity. Possible causes of pancreatic β-cell dysfunction include
direct infiltration of tumor cells into pancreatic islets, increased
intraductal pressure due to occlusion of the main pancreatic
duct and concomitant inflammation-induced disorders. Causes
of increased insulin resistance include decreased glucose uptake
Received for publication December 20, 2022 ; accepted March 30,2023.
Address correspondence and reprint requests to Toshio Hosaka, MD,PhD., Laboratory of Clinical Nutrition, School of Food and Nutritional
Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan andE-mail : toshio.hosaka@u-shizuoka-ken.ac.jp

and decreased phosphoinositol-3-kinase activity in muscle (4, 5).
Herein, we retrospectively examined the clinical backgroundsof pancreatic cancer patients with diabetes mellitus by focusing
on the potential for diabetes to serve as a factor allowing early
detection or progression of pancreatic cancer.

METHODPatients

Fifty-two diabetic patients, who had not yet received pancreatic cancer treatment, were admitted to Kyorin University
Hospital during the period from April 2007 to September 2016
(Figure1). Diabetes was diagnosed based on the established criteria (6). Thirty-six patients with diabetes (24 males, 12 females)
were analyzed after excluding 16 who rejected pancreatic cancer
treatment and could not undergo detailed examinations, such as
CPR measurement, or were lost to follow-up. The patients included in this analysis had relatively well-maintained insulin secretion, although some required insulin treatment and had neither
renal dysfunction nor metastasis involving other organs. Though
the precise onset time of pancreatic cancer was unknown, thosewith pancreatic cancer were divided into two groups ; Group A
subjects had been diagnosed with diabetes more than a yearprior to identification of pancreatic cancer, such that no patientsdeveloping pancreatic cancer within one year after the diagnosis
of diabetes mellitus were included in this group, while in group
B subjects the diabetes had developed after or been diagnosed
concurrently with the detection of pancreatic cancer (diabetes
secondary to pancreatic cancer).
The subjects consumed almost all daily meals, calculatedon the basis of standard body weight. The study protocol wasapproved by the ethics committee of Kyorin University School ofMedicine (No. 1545). Consent for this study was obtained by theopt-out method, allowing the content to be presented on the hospital homepage or in outpatient settings. All procedures followed

The Journal of Medical Investigation Vol. 70 2023

The Journal of Medical Investigation Vol. 70 August 2023
were in accordance with the ethical standards of the responsible
committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2021.

Parameters
Age, sex, height, body mass index (BMI), family history ofdiabetes mellitus, history of smoking, alcohol consumption, family history of malignant disease, duration of diabetes, HbA1c,fasting plasma glucose, the serum and urinary C-peptide immunoreactivity (CPR) levels, CPR index, weight loss amountand duration, treatments (oral hypoglycemic agent/insulin/both), tumor marker (CA19-9), tumor diameter (long diameter oftumor as measured by computed tomography), pancreatic cancer
development site and cancer treatments were examined. We
determined ΔHbA1c, indicating HbA1c elevation at the time ofpancreatic cancer diagnosis as compared to the most recent priormeasurement, and weight loss within 5 months before the cancer
diagnosis at a clinic or hospital.

351RESULTS
There were 23 group A cases (16 males, 7 females) and 13
group B cases (8 males, 5 females) (Figure 1 and Table 1). The
characteristics and comparisons of these patients are shown in
Table 1. ΔHbA1c was more than 2 % in both groups and weightloss exceeded 4 kg in both groups. There was no difference in insulin secretion between the groups according to measurements

Statistical analyses
Fisher’s test, Spearman’s rank correlation coefficient, the ttest, or the Wilcoxon test was used for all statistical analyses.
p < 0.05 was considered to indicate a statistically significant
difference. Statistical analysis and data management wereconducted using statistical software ; JMP® version 11.1.1 (SASInstitute Inc. Cary NC USA).

Figure 1. Flow chart showing inclusion and exclusion criteria

We obtained informed consent from 52 patients enrolled in the study.
However, 16 cases could not be followed up and were thus excluded.

Table 1. Characteristics of patients with diabetes diagnosed more than a year prior to identification of pancreatic cancer (A) and diabetes
secondary to pancreatic cancer (B)Sex (male / female)
AgeGroup A (n = 23)

Group B (n = 13)P

15 / 89/4

1.00#

68.5 ± 5.6

71.9 ± 4.3

0.07
0.97

Height (cm)

161 ± 9.0

162 ± 9.0

BMI (kg / m2)

22.3 ± 4.3

20.9 ± 2.3

0.27

Family history of diabetes mellitus (%)

13(56.5%)5 (38.5%)

0.49 #

History of smoking (%)

12(52.2%)

6(46.2%)1.00 #

Alcohol (%)

15(65.2%)8(61.5%)

1.00#

Family history of malignant disease (%)

9(39.1%)5(38.5%)1.00 #

15.0 [8.0-19.5]

1.0 [1.0-1.0]< 0.001$, &Duration of diabetes (year)
Fasting plasma glucose (mg / dL)

152 ± 17160 ± 18

0.19

HbA1c (%)

9.8 ± 2.1

9.4 ± 2.1

0.56

ΔHbA1c (%)

2.2 ± 1.5

2.6 ± 2.0

0.45

4.0 [3.0-6.0]

3.0 [2.0-6.0]

0.67$

Pre-meal CPR (ng / mL)

1.5 ± 1.2

1.4 ± 0.8

0.77

CPR 2 hours after meal (ng / mL)

3.2 ± 2.6

3.0 ± 1.80.88

ΔCPR (ng / mL)

2.0 [0.1-2.5]

1.6 [0.52-2.24]

0.98$

CPR index (Pre-meal)

0.9 [0.31-1.41]

0.76 [0.51-1.14]

0.76$

Urine CPR (mg / day)

49.8 [15.4-68.4]

49.8 [26.6-83.0]

0.34$

Weight loss (kg)3.0 [0.0-6.5]

4.0 [3.0-6.0]

0.55$

Weight loss duration (months)

3.0 [0.0-6.0]

3.5 [2.75-5.25]

0.67$

Treatment (Diet only / Oral hypoglycemic agent / Insulin / both) (n)0 / 11 / 10 / 2

7/2/4/00.001#, &25.0 [20.0-35.0]

25.0 [20.0-35.0]

0.97$

9/7/7

6/5/2

0.74#

118.5 [13.7-742.7]

380 [73.8-2650]

0.13$

15 / 89/4

1.00 #

HbA1c deterioration period (months)

Pancreatic tumor diameter (mm)Pancreatic cancer site (Head / Body / Tail) (n)CA19-9 (U / mL)
Cancer treatment (Surgery / chemotherapy)

Fisher’s test ( # ), the t-test, or the Wilcoxon test ( $ ) was used&
denotes significant difference between groups A and B
Values are means ± SD or medians [interquartile range]

352

H. Shichijo, et al. Pancreatic tumor insulin responsivenessof pre-meal and post-meal CPR or post-meal elevation of CPR(ΔCPR), as an indicator of endogenous insulin secretion. Dietaryintake amounts were not the same at each of the CPR determinations. The sites of pancreatic cancer occurrence, visualizedon magnetic resonance images, were the head in 9, the body in
7 and the tail in 7 of the group A patients, and were the head in6, the body in 5 and the tail in 2 of the group B patients. Then,groups A and B were each further divided into 2 subgroups
according to the pancreatic cancer site (body / tail and head).

ΔHbA1c did not differ between the subgroups in either group Aor group B (data not shown). The 2-hour postprandial CPR levelin group B and the ΔCPR level in both group A and group B weresignificantly lower for the head site than for the body / tail site ofpancreatic cancer (Figures 2A, 2B).
On the other hand, tumor size was not related to all CPR conditions at all tumor sites (Figure 3). According to cancer stage
classified by TNM, (I : 4 cases, II : 14 cases, III : 13 cases, IV : 6cases), there were no significant differences in the timing of CPR

Figure 2. Comparison of pre-meal CPR, post-meal 2-hour CPR and ΔCPR between the two groups

2A Pre- and 2-hour post-meal CPR in each subgroup
2B ΔCPR in each subgroup
Data are expressed as means ± standard deviation (2A and group B in 2B) and as medians [interquartile range] withthe smallest or largest observation (group A in 2B).
A : Diabetes diagnosed more than a year prior to identification of pancreatic cancer
B : Diabetes secondary to pancreatic cancer

The Journal of Medical Investigation Vol. 70 August 2023

353

Figure 3. Correlations pancreatic tumor size with CPR and ΔCPR(a), (b), and (c) show head site, (d), (e), and (f) show body/tail site, while (g), (h), and (i) show total pancreatic tumor sites.
Black circle : group A, unfilled circle : group B
X-axis : tumor diameterY-axis : Serum C-peptide levels

determination among the stages (data not shown), though the tumors had not been clinically classified as advanced or early-stage
pancreatic cancer.

DISCUSSION
There were no significant differences in characteristics, suchas age and BMI, between groups A and B. Weight loss of 4 kg or
more and HbA1c deterioration by more than 2% were observed
within 5 months of the pancreatic cancer diagnosis in bothgroups. In order to avoid missing pancreatic cancers in patients
without a diabetes history, Lee et al. advocated that pancreaticcancer be suspected in those with one or more of the following
risk factors : a family history of diabetes, older than age 65 years,
weight loss over 2 kg, and BMI under 25 prior to cancer symptom

onset (7). In addition, Yuan et al. reported that diabetes found in
the wake of weight loss has a higher risk of being associated withpancreatic cancer development, and has a frequency 6.75 times
higher in diabetic patients with a weight loss of 8 pounds than inthose without weight loss (95% confidence interval : 4.55-10.00)(8). Consistent with their report, our present study also showed
weight loss and deterioration of HbA1c, especially in those withweight loss of 4 kg or more and HbA1c deterioration of 1% ormore, to generally be observed within 5 months of the diagnosisof pancreatic cancer.
The risk of pancreatic cancer approximately doubled when thefasting blood glucose level before the onset was 140 mg / dL andwas more than 2.15-fold at 200 mg / dL or higher (9). However, to
our knowledge, there have been no studies comparing CPR justbefore versus after the diagnosis of pancreatic cancer.
Contrary to our speculations regarding β-cell function, this354

H. Shichijo, et al. Pancreatic tumor insulin responsivenessstudy clearly demonstrated the body and tail site of pancreaticcancer to be associated with significantly preserved endogenous
insulin secretion as compared to the head site, based on postprandial blood CPR and Δ CPR, regardless of diabetes history
and tumor size (Figure 3). This observation might be explainedby reports describing secondary effects of pancreatic duct obstruction due to pancreatic head cancer as strongly impairing
pancreatic β-cell function (4, 5), though body and tail cancer also
show partial direct invasion into β-cells.
As a limitation of this study, we acknowledge that while it
might be possible to diagnose pancreatic head cancer at an earlystage by testing CPR before and after a meal, it is somewhat
difficult to perform pre- and post-meal CPR measurements inall patients in an outpatient setting. However, the major limitation of this study is that neither historical nor imaging analyses
such as cholangiopancreatography were performed to confirm
pancreatic duct obstruction, which is related to impaired pancreatic β-cell function. Moreover, we did not examine whether
endogenous insulin secretion shows any association with the progression of pancreatic cancer or reflects postoperative changes.
Adrenomedullin has been suggested as a possible mediatorof pancreatic β-cell dysfunction and was reportedly detected
at higher levels in pancreatic cancer patients than in healthycontrols (10). Islet amyloid polypeptide was also suggested to bea mediator of insulin resistance and its elevation was observedin patients with pancreatic cancer complicated by diabetes (11).
Further analysis, including cytokine measurements, might
be needed to confirm the evidence obtained herein suggesting
reduced residual insulin secretion associated with pancreaticcancer-related diabetes.

IN CONCLUSION
Pancreatic cancer patients experienced not only marked
weight loss, but also HbA1c elevation within 5 months of diagnosis. Notably, we demonstrated for the first time that a poor postprandial CPR response, after the pancreatic cancer diagnosis,
might suggest the tumor to be in the head of the pancreas.

ACKNOWLEDGMENTS
Not applicable

COMPLIANCE WITH ETHICAL STANDARDS
Ethics approval
This study was conducted according to the guidelines laid
down in the Declaration of Helsinki, and all procedures involving
human subjects / patients were approved by the Kyorin University School of Medicine (approval number : 1545, 2020 / 7 / 20) ; theprotocol was registered at the University Hospital Medical Information Network Centre clinical trial registry (Registry No.

UMIN000047330, 2020 / 8 / 3). Informed consent was obtained by
the opt-out method in all subjects.
Conflicts of interest / Competing interests : HS, TH, FT, YS,
HI and KY have no conflicts of interest to declare.

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