diabetes research and clinical practice 1 2 4 ( 2 0 1 7 ) 6 6 –7 1

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
journa l home page: www.e lse vier.com/locate/diabres

Optimal glycemic target level for colon cancer

patients with diabetes

Shin Jun Lee, Jae Hyun Kim, Seun Ja Park, So Young Ock, Su Kyoung Kwon, Young Sik Choi,
Bu Kyung Kim *
Department of Internal Medicine, Kosin University College of Medicine, Gamcheonro 262, Seogu, Busan, South Korea

A R T I C L E I N F O A B S T R A C T

Article history: Aims: The aim of this study was to evaluate the differences in mortality among colon can-
Received 6 October 2016 cer patients with or without diabetes and to determine optimal glycemic target level for
Received in revised form colon cancer patients with diabetes.
30 November 2016 Methods: A total of 741 patients with colon cancer between April 1999 and December 2010
Accepted 8 December 2016 were reviewed. The non-diabetes group had a fasting plasma glucose <126 mg/dL, and the
Available online 23 December 2016 diabetes group had a fasting plasma glucose P126 mg/dL. Patients with diabetes were fur-
ther divided based on glycemic control into either the uncontrolled subgroup (HbA1c P8%)
or the well-controlled subgroup (HbA1c <8%).
Keywords:
Results: Patients with diabetes had significantly shorter overall survival and median sur-
Diabetes mellitus
vival than non-diabetes patients. Uncontrolled diabetes patients had significantly shorter
Glycemic control
overall survival and median survival than well-controlled diabetes patients. The relative
Mortality
risk of mortality for diabetes patients was higher than non-diabetes patients (relative risk
Colon cancer
1.17). The relative risk of mortality in uncontrolled diabetes patients was significantly
higher than in well-controlled diabetes patients (relative risk 4.58). The area under the
curve for mortality and HbA1c level was 0.73. The cut off HbA1c level was 7.75%.
Conclusions: A optimal glycemic control level for colon cancer patients with diabetes should
be recommended as an HbA1c of 7.8% or below.
Ó 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction of studies have been recently conducted on the impact of type

Diabetes mellitus (DM) is one of the most common chronic
diseases worldwide and constitutes a major health burden in
terms of mortality and impaired quality of life [1]. Diabetes
mellitus (DM) is associated with a risk of cancer and its asso-
ciated mortality. Epidemiologic evidence has suggested that
people with DM are at a significantly higher risk of developing
various types of cancer, such as colorectal, pancreatic, lung,
breast, bladder, gastric, prostate, and kidney. Mortality in DM
patients with these cancers is also increased [2,3]. A number
2 diabetes on the clinical outcomes of patients with various
cancers types, including gynecologic cancers. These studies
have demonstrated that type 2 diabetes has a negative impact
on the outcome of these cancers [4]. In a study of 202 women
with breast cancer, an increased risk of recurrence was noted
to correlate with increased serum glucose levels [5]. A meta-
analysis found that cancer patients with DM had a signifi-
cantly increased risk of mortality compared to cancer patients
without DM [5]. Although the biological mechanisms associ-
ated with the relationship between DM and cancer are not

* Corresponding author. Fax: +82 51 990 3065.

E-mail address: 79kyung@hanmail.net (B.K. Kim).
http://dx.doi.org/10.1016/j.diabres.2016.12.009
0168-8227/Ó 2016 The Authors. Published by Elsevier Ireland Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 diabetes research and clinical practice
fully understood, we speculate that controlling one’s current
diabetic state can affect the risk of cancer.
Colorectal cancer (CRC) is one of the most common can-
cers in patients with type 2 diabetes. Furthermore, type 2 dia-
betes increases the lifetime risk of colon cancer by up to three
times when compared to the general population [6]. CRC is
also the second leading cause of cancer death in the world,
and it has been shown that preexisting diabetes mellitus
(pre DM) increases the risk of CRC-specific mortality [7]. One
study on CRC patients demonstrated that poorly controlled
DM, as determined by HbA1c levels, independently predicted
more advanced disease and a poorer five-year survival.
Among non-diabetic patients and those who had well-
controlled type 2 diabetes (HbA1c <7.5%(58 mmol/mol)), the
calculated five-year cancer-specific survival (64% and 74%,
respectively) was significantly higher than in patients with
poorly controlled type 2 diabetes (HbA1c P7.5%(58 mmol/
mol)) (52%, P < 0.05) [8]. However, until now, no additional
research on the relationship between glycemic control status
and mortality in colon cancer patients with DM has been
reported.
In this study, we aimed to explore differences in mortality
among colon cancer patients with DM compared to patients
without DM. A specific aim was to examine the association
between glycemic control status and mortality in colon can-
cer patients with DM.
2. Research design and methods
2.1. Study population
Data from patients with colon cancer who were diagnosed
between April 1999 and December 2010 at Kosin University
Gospel Hospital were reviewed retrospectively. Patients were
eligible for inclusion in this study if they had the following
criteria: 1. a histologically confirmed diagnosis of colon can-
cer, 2. no evidence of any other malignancies, 3. fasting
plasma glucose level measured at the time of diagnosed colon
cancer. Among a total of 2048 patients with colon cancer, only
741 patients had initial fasting plasma glucose levels. Finally,
741 patients were enrolled in the present study. The stage of
colon cancer was classified by AJCC stage and TNM staging
system [9]. All patients received tailored therapy depending
on the stage of colon cancer.
2.2. Data collection
Patients were divided into two groups according to fasting
plasma glucose levels. Group I (n = 634) included non-DM
patients with a fasting plasma glucose <126 mg/dL, while
group II (n = 107) included DM patients with a fasting plasma
glucose P126 mg/dL.
Patients with DM were divided into two subgroups accord-
ing to their glycemic control. Subgroup I (n = 23) was the
uncontrolled group consisting of patients with an HbA1c
P8%(64 mmol/mol), and subgroup II (n = 38) was the well-
controlled group consisting of patients with an HbA1c <8%
(64 mmol/mol). We compared differences in mortality accord-
ing to the DM status and glycemic control.
1 2 4 ( 2 0 1 7 ) 6 6 –7 1 67
2.3. Statistical analysis
Data were analyzed by SPSS version 18.0 (SPSS Inc., Chicago,
IL, USA). The student‘s t-test and chi square test were used
for analysis of baseline characteristics. Kaplan–Meier analysis
was used to assess factors affecting mortality and overall and
median survival. A log-rank test was used to compare sur-
vival rates between the two groups. Overall survival was
defined as the length of time from either the date of diagnosis
or the start of treatment for colon cancer. We analyzed the
relative risk of mortality based on the status of DM and glyce-
mic control by using logistic regression. ROC curve analysis
was performed to determine the cut off value of HbA1c that
is indicative of proper glycemic control in colon cancer
patients with DM. In all cases, a p-value <0.05 was considered
statistically significant.
3. Results
3.1. Baseline characteristics
Of all the study patients, 107 patients were categorized as DM,
and 634 patients were categorized as non-DM. The mean age
was 64.72 ± 11.60 in non-DM patients and 68.05 ± 9.95 in DM
patients.
There were no significant differences in cancer staging,
total cholesterol, triglyceride, HDL(high-density lipoproteins),
LDL(low-density lipoproteins), neutrophil lymphocyte ratio,
or CRP(C-reactive protein) levels. Patients with DM were more
likely to have a higher WBC count than patients without DM.
The baseline characteristics of both DM and non-DM patients
are given in Table 1.
Of all DM patients, 39 patients were categorized as con-
trolled DM, and 22 patients were categorized as uncontrolled
DM. The mean age was 67.72 ± 9.91 in controlled DM patients
and 67.86 ± 8.65 in uncontrolled DM patients.
There were no significant differences in cancer staging,
total cholesterol, triglyceride, HDL, LDL, neutrophil lympho-
cyte ratio, CRP, WBC levels. The baseline characteristics of
both controlled DM and uncontrolled DM patients are given
in Table 2.
3.2. Mortality of colon cancer patients
A Kaplan–Meier analysis showed a significant difference in
mortality based on the presence of DM and HbA1c levels
(Fig. 1). Patients with DM had significantly shorter OS and MS
than non-DM patients (14.0 vs 22.8 mo., p = 0.003 and 11.4 vs
17.7 mo., p = 0.003, respectively) (Fig. 1A). Among patients with
DM, uncontrolled DM patients had a significantly shorter OS
and MS than well-controlled DM patients (11.4 vs 17.6 mo.,
p = 0.003 and 8.0 vs 10.7 mo., p = 0.003, respectively) (Fig. 1B).
3.3. Relative risk of mortality
The relative risk of mortality is higher for DM patients than
for non-DM patients (RR 1.17, 95% CI 0.76–1.80); however, this
difference was not significant. After adjusting for age, sex,
CRP, WBC, and cholesterol, it was still not significant. The
68 diabetes research and clinical practice 1 2 4 ( 2 0 1 7 ) 6 6 –7 1

Table 1 – Baseline characteristics.

Variables Non-DM (n = 634) DM (n = 107) P-value

Age (yrs) 64.72 ± 11.60 68.05 ± 9.95 0.002

Sex 0.112
Male 369 (58.2%) 71 (66.4%)
Female 265 (41.8%) 36 (33.6%)
Stage 0.931
0 11 (1.9%) 1 (1.1%)
I 84 (14.4%) 14 (15.1%)
II 206 (35.3%) 35 (37.6%)
III 177 (30.4%) 29 (31.2%)
IV 105 (18.0%) 14 (15.1%)
FPG (mg/dL) 95.59 ± 11.11 163.17 ± 39.03 0.000
HbA1c (%) 5.45 ± 0.19 7.97 ± 1.86 0.000
Total Chol (mg/dL) 182.36 ± 46.19 172.71 ± 45.42 0.067
HDL (mg/dL) 42.06 ± 13.50 39.07 ± 10.33 0.052
LDL (mg/dL) 115.15 ± 35.88 110.88 ± 38.09 0.479
TG (mg/dL) 118.25 ± 87.80 134.45 ± 93.97 0.112
Hb (g/dL) 12.02 ± 2.26 12.32 ± 2.23 0.193
Plt (103/lL) 289 ± 102 290 ± 103 0.913
WBC (103/lL) 7.89 ± 2.71 8.43 ± 2.49 0.041
NLR 2.97 ± 3.27 3.30 ± 3.90 0.356
CRP (mg/dL) 0.99 ± 2.48 1.91 ± 3.85 0.084
FPG: fasting plasma glucose; TG: triglyceride; WBC: white blood cell; Plt: platelet; NLR: neutrophil lymphocyte ratio; CRP: C-reactive protein; Hb:
hemoglobin; HbA1c: hemoglobin A1c.

Table 2 – Baseline characteristics according to the status of glycemic control.

Variables Controlled DM (n = 39) Uncontrolled DM (n = 22) P-value

Age (yrs) 67.72 ± 9.91 67.86 ± 8.65 0.954

Sex 0.027
Male 23 (59.0%) 19 (86.4%)
Female 16 (41.0%) 3 (13.6%)
Stage 0.418
0 0 (0.0%) 1 (5.6%)
I 7 (20.6%) 1 (5.6%)
II 12 (35.3%) 8 (44.4%)
III 10 (29.4%) 5 (27.8%)
IV 5 (14.7%) 3 (16.7%)
FPG (mg/dL) 150.38 ± 24.95 192.27 ± 55.48 0.002
HbA1c (%) 6.83 ± 0.60 9.99 ± 1.61 0.000
Total Chol (mg/dL) 176.03 ± 44.34 176.22 ± 30.26 0.985
HDL (mg/dL) 39.69 ± 8.91 38.37 ± 10.02 0.628
LDL (mg/dL) 120.89 ± 37.89 113.83 ± 23.25 0.674
TG (mg/dL) 141.21 ± 72.11 142.00 ± 147.84 0.979
Hb (g/dL) 12.21 ± 2.39 12.02 ± 2.07 0.762
Plt (103/lL) 296 ± 99 326 ± 121 0.295
WBC (103/lL) 8.34 ± 2.23 8.97 ± 2.33 0.303
NLR 2.55 ± 1.78 2.70 ± 1.51 0.747
CRP (mg/dL) 1.68 ± 2.85 1.15 ± 2.07 0.570

relative risk of mortality (model 1) was significantly higher for
uncontrolled DM patients than for well-controlled DM
patients (RR 4.58, 95% CI 1.37–15.35). After adjusting for age
and sex (Model 2), the relative risk was even higher than
before adjusting (RR 5.84, 95% CI 1.52–22.49). The association
between risk of mortality and poor glycemic control disap-
peared after adjusting for CRP, WBC (model 3), and cholesterol
(model 4) (Table 3).
3.4. Receiver-Operating characteristic curve and optimal
HbA1c level
The area under the curve of the ROC curve to analyze the rela-
tionship between mortality and HbA1c level was 0.73 (Fig. 2).
The cut off HbA1c value that was indicative of optimal glu-
cose control in colon cancer patients was 7.75% (61 mmol/-
mol) (sensitivity 62.5%, specificity 71.4%).
 diabetes research and clinical practice 1 2 4 ( 2 0 1 7 ) 6 6 –7 1 69

Fig. 1 – Kaplan-Meier curve for OS probability according to: (A) the history of DM; (B) HbA1c levels. DM = diabetes mellitus;
HbA1c = hemoglobin A1c; MS = median survival; OS = overall survival.

Table 3 – The relative risk of mortality in DM patients compared to non-DM patients and in uncontrolled DM patients
compared to well-controlled DM patients.
Non-DM DM (95% CI) P-value Well-controlled DM Uncontrolled DM (95% CI) P-value

Model 1 1 1.17 (0.76–1.80) 0.48 1 4.58 (1.37–15.35) 0.01

Model 2 1 1.09 (0.70–1.68) 0.71 1 5.84 (1.52–22.49) 0.01
Model 3 1 0.86 (0.44–1.68) 0.66 1 1.26 (0.17–9.60) 0.82
Model 4 1 0.57 (0.22–1.47) 0.24 1 0.00 0.98
Model 1. non-adjusted group; Model 2. adjusted for age and sex; Model 3. adjusted for WBC, CRP, plus all variables in Model 2; Model 4. adjusted
for total cholesterol, HDL, LDL, triglycerides, plus all variables in Model 3.

Fig. 2 – Receiver-operating characteristic (ROC) curve for hemoglobin A1c (HbA1c) for predicting mortality in colon cancer
patients with type 2 diabetes (T2 DM). AUC = Area under the curve.
70 diabetes research and clinical practice
4. Conclusions
The global burden of diabetes has risen dramatically over the
past two decades and is expected to affect more than 500 mil-
lion adults by 2030 [10]. More specifically, there has been a
dramatic increase in the number of obese Koreans with dia-
betes in recent decades, which has increased its prevalence
from 8.6% in 2001 to 11.0% in 2013 [11]. Cancer is a major
cause of mortality, and its global incidence is also rapidly
increasing. Some studies showed considerable evidence indi-
cating that type 2 diabetes is associated with an increased
incidence of breast, bladder, pancreatic, liver, and colon can-
cers [13].
In addition to the incidence of cancer, its associated mor-
tality is also increased in DM patients when compared with
non-DM patients [14]. It was reported that diabetic patients
suffered from higher mortality rates from all cancers or some
types of cancers (stomach, colorectum, liver in men and liver,
pancreas in women) than the general population [12]. Patients
with diabetes had higher rates of diabetes-related death and
cancer-related death. In a Swedish study, the number of
cancer-related deaths per 1000 persons per year was 8.45 in
the diabetic group and 7.64 in the general population [10]. Sev-
eral analyses showed that baseline diabetes was associated
with increased mortality from certain types of cancers. More
specifically, the relative risk of mortality was shown to be
1.2–1.4 for colorectal cancer, 1.05–2.16 for liver cancer, 1.44–
2.47 for pancreas cancer, and 1.30–1.43 for bladder cancer [14].
There have been some studies on the impact of DM on the
prognosis of several cancers, but there are no studies that
suggest proper glycemic control in colorectal cancer patients
with DM. In our present study, we examined how the risk of
death was higher in colorectal cancer patients with DM com-
pared to those without DM, and we assessed mortality based
on glycemic control status. We can now draw conclusions
about how to better control hyperglycemia in colorectal can-
cer patients with DM from these results.
In this study, we first saw how the risk of death was
increased in colon cancer patients with DM when compared
to those without DM. OS and MS were shorter in colon cancer
patients with DM than in those without DM. The relative risk
of mortality was 1.17 times higher in patients with DM com-
pared to colon cancer patients without DM, but this was not
statistically significant. The lack of significance could be due
to various DM or cancer-related factors, such as therapeutic
modality, medications, comorbidity, glycemic control, tumor
characteristics, patient personality, and socioeconomic sta-
tus. Additionally the DM group was much smaller in size than
the non-DM group. In the previous meta analysis, all-cause
mortality and cancer-specific mortality were significantly
higher (RR = 1.17, 95% CI: 1.09–1.25 and RR = 1.12, 95% CI:
1.01–1.24, respectively) in colon cancer patients with DM than
in those without DM [15]. The other study also reported that
the colorectal cancer patients with DM had a significantly
higher risk of overall mortality (HR = 1.20, 95% CI: 1.17–1.23)
[16]. These results are very similar with the results of our
study. We can confidently state that diabetes increases the
risk of total mortality among patients with colorectal cancer.
Although the mechanism of the interplay between DM and
cancer remains unclear, several hypotheses have been
1 2 4 ( 2 0 1 7 ) 6 6 –7 1
considered. First, hyperglycemia, another characterizing fea-
ture of diabetes, may also contribute to enhanced cancer risk.
Glycolysis plays a central role in tumor development, and ele-
vated glucose levels in the circulation are highly utilized by
cancer cells. In addition to its direct metabolic role, hyper-
glycemia in a subset of tumor cells can lead to increased pro-
duction of ROS (reactive oxygen species) from mitochondrial
respiration, which can lead to DNA damage that is not severe
enough to induce apoptosis [19,20]. Second, recent evidence
suggests that persistent inflammation can promote genetic
instability and that chronic inflammation is associated with
increased cancer risk. The deregulated metabolism in poorly
controlled diabetes causes a long-term, pro-inflammatory
state characterized by increased levels of interleukin-6 (IL-6),
tumor necrosis factor-alpha (TNF-a), C-reactive protein, and
other markers of chronic inflammation [18,21]. Third, various
carcinogens may also exert their effect by generating ROS
during their metabolism. Oxidative damage to cellular DNA
can lead to mutations and may, therefore, play an important
role in the initiation and progression of multistage carcino-
genesis. ROS are known to damage cellular DNA and to pro-
mote cancer by reacting with proteins or lipids in cells [22].
Oxidative stress is increased when plasma glucose is poorly
controlled, and the increased oxidative stress leads to a pro-
inflammatory condition [23].
There is no literature that compares the relative risk of
mortality between well-controlled DM and poorly controlled
DM patients with colon cancer. In this study, we examined
differences in mortality according to glycemic control status
among colon cancer patients with DM. Well-controlled DM
patients (HbA1c <8% (64 mmol/mol)) had a significantly
longer OS and MS than uncontrolled DM patients. Addition-
ally, the relative risk of mortality was significantly higher
(RR 4.58, 95% CI 1.37–15.35) in uncontrolled DM patients
(HbA1c P8%(64 mmol/mol)). A previous study involving
advanced pancreatic cancer patients found an association
between glycemic control and prognosis, and determined
the relative risk of mortality to be 2.55 (p < 0.033) in the poorly
controlled DM group (HbA1c P7.0% (53 mmol/mol)) compared
to well-controlled group. (HbA1c <7.0% (53 mmol/mol)) [17].
The results of this study also showed that high blood glu-
cose could be an important risk factor for morality in colon
cancer patients with DM. After adjusting for age and sex, the
relative risk increased (RR 5.84, 95% CI 1.52–22.49), but its sig-
nificance also disappeared after adjusting for CRP, WBC, and
cholesterol. CRP and WBC represent not only the presence of
infection but also systemic inflammatory status. Therefore,
we can presume that systemic inflammation is associated
with poorer glycemic control and higher mortality risk.
We have suggested a target value for glycemic control in
cancer patients with DM for the first time. ROC results
showed that the cut off HbA1C value was 7.8% (62 mmol/mol).
An average blood glucose of this value is 180 mg/dL. Although
research on glycemic control targets in cancer patients has
not been found, there have been some studies on glycemic
control and mortality of inpatients, critical illness patients,
infected patients, and ICU patients [24,25]. The results of ran-
domized trials of intensive insulin therapy in ICU patients
have been inconsistent. Most of the data do not support the
hypothesis of a survival benefit, and some data have
 diabetes research and clinical practice
suggested increased mortality. All the trials recommended a
target glycemic level of 140–180 mg/dL in ICU patients [24].
Levels lower than this target level can cause hypoglycemia, [6]
and a higher glucose level is also associated with poor out-
comes in hospitalized patients [25]. Our cut off level of glyce-
mic control was an HbA1c level of 7.8% (62 mmol/mol, [7]
average blood glucose 180 mg/dL), which was very similar
with other studies. We can also suggest that cancer
patients with diabetes have blood glucose levels lower than [8]
180 mg/dL like other hospitalized patients.
This study was a retrospective study, so many patients did
not have initial plasma fasting glucose data. At the start of [9]
this study we reviewed 2048 patients, and we finally investi-
gated 741 patients who had initial plasma fasting glucose
data, however the number of diabetic patients was relatively
small (n = 107). Additionally, the HbA1c level did not represent
the glycemic control status during colon cancer treatment.
[10]
We initially collected the HbA1c results from each patient’s
laboratory data, so unfortunately we do not know if there
were changes in the glycemic control status during treatment [11]
for each patient. Despite these limitations, this study is a
valuable reference for managing colon cancer patients. This [12]
study is the first report to show mortality according to glyce-
mic control status as well as differences in mortality accord-
[13]
ing to the presence or absence of diabetes in patients with
colorectal cancer. Additionally, we suggested a target for gly-
cemic control in cancer patients with diabetes.
In conclusion, colon cancer patients with DM had a shorter [14]
OS and MS and a higher mortality risk than patients without
DM. Furthermore, uncontrolled DM patients had a shorter OS
and MS and a higher mortality risk than well-controlled DM
[15]
patients. A target level of glycemic control for colon cancer
patients with DM should be an HbA1c level of 7.8% (62 mmol/
mol) or below. Future, large-scale, prospective studies are [16]
needed to establish guidelines for glycemic control goals in
cancer patients with DM.
[17]
Conflict of interest
The author(s) declare that they have no competing interests. [18]
[19]
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