Original Study

Human Insulin Does Not Increase Prostate

Cancer Risk in Taiwanese
Chin-Hsiao Tseng1,2,3
Abstract
To evaluate the association between human insulin use and prostate cancer risk, 498,407 Taiwanese men with
type 2 diabetes were followed for 6 years. Results showed that human insulin use was not associated with
prostate cancer after multivariable adjustment. Therefore, there is no concern for an increased risk of prostate
cancer in insulin-treated patients with type 2 diabetes.
Background: Whether human insulin can increase the risk of prostate cancer is rarely studied. Patients and
Methods: The reimbursement databases of all Taiwanese patients with diabetes from 1996 to 2009 were retrieved
from the National Health Insurance databases of Taiwan. An entry date was set at January 1, 2004 and a total of
498,407 men with type 2 diabetes were followed for prostate cancer incidence until the end of 2009. Incidence for
ever-users, never-users, and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin,
cumulative dose, and cumulative duration of insulin) were calculated, and the age-adjusted and multivariable-adjusted
hazard ratios were estimated using Cox regression. Results: There were 72,948 ever-users and 425,459 never-users,
with respective numbers of incident prostate cancer of 768 (1.05%) and 6282 (1.48%), and respective incidence of
236.87 and 276.88 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) indicated a sig-
nificant negative association with insulin in the age-adjusted model (0.910; 0.843-0.981), but lack of association in the
full model adjusted for multivariables (0.989; 0.912-1.072). The hazard ratios for the different categories of the dose-
responsive parameters might show significantly lower risk with insulin use in the age-adjusted models, but none of the
hazard ratios were significant in the full models. Conclusion: This study suggests a lack of association between the
use of human insulin and prostatic cancer risk in patients with type 2 diabetes after multivariable adjustment.

Clinical Genitourinary Cancer, Vol. 12, No. 1, e7-12 ª 2014 Elsevier Inc. All rights reserved.
Keywords: Epidemiology, Incidence, National health insurance, Type 2 diabetes mellitus, Taiwan

Introduction insulin might promote the growth of the prostate by mechanisms

Long-term insulin treatment has been shown to increase the risk
of overall cancer mortality and incidence.1,2 However, whether in-
sulin use might increase the risk of prostate cancer is still a subject of
debate.
Theoretically, hyperinsulinemia as a result of insulin resistance in
patients with type 2 diabetes mellitus might increase the risk of
prostate cancer via the insulin-like growth factor pathway3-5; and
1
Department of Internal Medicine, National Taiwan University College of Medicine,
Taipei, Taiwan
2
Division of Endocrinology and Metabolism, Department of Internal Medicine,
National Taiwan University Hospital, Taipei, Taiwan
3
Division of Environmental Health and Occupational Medicine of the National Health
Research Institutes, Taipei, Taiwan
Submitted: May 29, 2013; Revised: Aug 8, 2013; Accepted: Aug 27, 2013; Epub:
Oct 11, 2013
Address for correspondence: Chin-Hsiao Tseng, MD, PhD, Department of Internal
Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road,
Taipei (100), Taiwan
Fax: 886-2-23883578; e-mail contact: ccktsh@ms6.hinet.net
that upregulate the production of aromatase.4
Some in vitro and human studies provide evidence for a potential
risk of prostate cancer associated with insulin use. For example,
insulin and the serum of diet-induced hyperinsulinemic rats might
promote the growth of a prostate cancer cell line.6 The promotion
of in vitro growth of prostate cancer cells might be induced by
insulin through its enhancement on steroidogenesis,7 or its abro-
gation of the leptin inhibitory effect on prostate cancer cell growth.8
In human observational studies, insulin level is significantly
associated with prostate size9; and a recent Swedish prospective
cohort study showed that higher insulin level might predict the
incidence of prostate cancer in men with a benign prostatic disor-
der.10 Another recent retrospective nested case-control study from
the United States showed that in contrary to patients with diabetes
using metformin and thiazolidinediones, those who used sulfonyl-
ureas or high-dose insulin tended to develop high-grade prostate
cancer.11 Furthermore, a recent human interventional study con-
ducted in men with prostate cancer suggested that a diet rich in fiber

1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.clgc.2013.08.004 Clinical Genitourinary Cancer February 2014 - e7
 Human Insulin and Prostate Cancer
from rye whole grain and bran might inhibit prostate cancer pro-
gression by reducing the exposure to insulin as indicated by plasma
insulin level and urinary C-peptide.12
The purpose of the present study was to evaluate whether human
insulin use would increase the risk of prostate cancer in patients
with type 2 diabetes mellitus, by using the National Health In-
surance (NHI) databases of Taiwan.
Patients and Methods
This is a retrospective cohort analysis using the NHI databases
including all patients with a diagnosis of diabetes mellitus during the
period from 1996 to 2009 in Taiwan. The study was approved by
an ethics review board of the National Health Research Institutes
with registered approval number 99274.
Since March 1995, a compulsory and universal system of health
insurance (the so-called NHI) was implemented in Taiwan. All
contracted medical institutes must submit computerized and stan-
dard claim documents for reimbursement. More than 99% of cit-
izens are enrolled in the NHI, and > 98% of the hospitals
nationwide are under contract with the NHI.
The National Health Research Institutes is the only organization
approved, as per local regulations, for handling the NHI reim-
bursement databases for academic research. The databases contain
detailed records on every visit for each patient, including outpatient
visits, emergency department visits, and hospital admission. The
databases also include principal and secondary diagnostic codes,
prescription orders, and claimed expenses.
The identification information of the individuals was scrambled
for the protection of privacy. Diabetes was coded 250.1-250.9 and
prostate cancer 185, based on the International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
The databases of all patients who had been diagnosed as having
diabetes and being treated with either oral antidiabetic agents or
insulin during the period 1996 to 2009 and who remained enrolled
in the insurance program after a selected entry date of January 1,
2004 were first retrieved from the whole nation (n ¼ 1,554,800).
The entry date was selected based on the following reasons. First,
the first insulin analogue (ie, insulin glargine) was marketed in
Taiwan in February 2004. Therefore, all of the patients recruited at
baseline at this entry date would not have taken any form of insulin
analogues, which might show a different risk association with cancer
from human insulin.13-15 Second, this entry date allowed a follow-
up of 6 years such that a large enough sample size of incident cases
of prostate cancer could be collected. Third, insulin glargine or
other insulin analogues would have been used in many patients who
had been previously treated with human insulin before the intro-
duction of insulin analogues in Taiwan. If these users of insulin
glargine or other insulin analogues were excluded from analyses,
many of the previous users of human insulin might have been
excluded from the analyses.
After excluding women (n ¼ 746,843), patients who had a
diagnosis of diabetes after the year 2004 (n ¼ 533,525), patients
who held a Severe Morbidity Card as having type 1 diabetes (n ¼
5521 (in Taiwan, patients with type 1 diabetes were issued a so-
called “Severe Morbidity Card” after a certified diagnosis and they
were waived for much of the copayments)), patients having a
diagnosis of prostate cancer before 2004 (n ¼ 6916), duplicated
e8 - Clinical Genitourinary Cancer February 2014
identification number (n ¼ 64), and unclear information on date of
birth or sex (n ¼ 2100), a total of 498,407 male patients with a
diagnosis of type 2 diabetes mellitus were recruited.
Those who had ever been prescribed with insulin (human insu-
lin) before entry date were defined as ever-users (n ¼ 72,948;
14.6%); and never-users (n ¼ 425,459; 85.4%) were defined as
those who had never been prescribed any insulin before the entry
date. To evaluate whether a dose-response relationship could be
observed between insulin and prostate cancer, tertile cutoffs for the
following 3 variables were used: time since starting insulin in
months, duration of therapy in months, and cumulative dose in
units, were calculated from the databases and used for analyses.
All comorbidities and covariates were determined as a status/
diagnosis before the entry date. The ICD-9-CM codes for the
comorbidities were16-18: benign prostatic hyperplasia, 600; ne-
phropathy, 580-589; urinary tract disease, 590-599; hypertension,
401-405; chronic obstructive pulmonary disease (a surrogate for
smoking), 490-496; stroke, 430-438; ischemic heart disease, 410-
414; peripheral arterial disease, 250.7, 785.4, 443.81, and 440-448;
eye disease, 250.5, 362.0, 369, 366.41, and 365.44; dyslipidemia,
272.0-272.4; congestive heart failure, 398.91, 402.11, 402.91,
404.11, 404.13, 404.91, 404.93, and 428; and cancer other than
prostate cancer, 140-208 (excluding 185). Medications included
insulin, pioglitazone, rosiglitazone, sulfonylurea, meglitinide, met-
formin, acarbose, statin, fibrate, angiotensin-converting enzyme
inhibitor and/or angiotensin receptor blocker, calcium channel
blocker, aspirin, other nonsteroidal antiinflammatory drug, alpha
blocker, clopidogrel, ticlopidine, and 5-alpha reductase inhibitor.
Baseline characteristics between ever-users and never-users were
compared using the c2 test.
The incidence density of prostate cancer was calculated for ever-
users and never-users and for different subgroups of exposure. The
numerator for the incidence was the number of patients with
incident prostate cancer during the 6-year follow-up (from January
1, 2004 to December 31, 2009), and the denominator was the
person-years of follow-up. For ever-users, the follow-up duration
was either censored at the date of initiation of insulin glargine or
other insulin analogues, or prostate cancer diagnosis or at the date of
the last record of the available reimbursement databases in in-
dividuals without incident prostate cancer. For never-users, the
follow-up was censored at the date of insulin initiation (including
human insulin or insulin analogues) or prostate cancer diagnosis or
the last reimbursement record, depending on whichever occurred
first. This ensured no exposure to insulin of any form throughout
the whole follow-up period until censor in the referent group of
never-users; and no exposure to insulin glargine or other insulin
analogues in the group of ever-users of human insulin.
Cox proportional hazards regression was performed to estimate
the hazard ratios for prostate cancer for ever-users vs. never-users,
and for the various subgroups of dose-responsive parameters based
on the tertile cutoffs. The following 2 models were created: (1)
adjusted for age (age-adjusted model); and (2) adjusted for all var-
iables compared previously as baseline characteristics between ever-
users and never-users (full model).
Analyses were conducted using SAS statistical software, version
9.3 (SAS Institute, Cary, NC). P < .05 was considered statistically
significant.
 Chin-Hsiao Tseng
Table 1 Baseline Characteristics Between Ever- and Never-Users of Human Insulin (n [ 498,407)

Human Insulin
Never-Users, n [ 425,459 Ever-Users, n [ 72,948
Variable n % n % P
Age (Years) <.0001
<40 23,230 5.46 4684 6.42
40-49 75,703 17.79 10,857 14.88
50-59 115,302 27.10 17,472 23.95
60-69 103,530 24.33 19,191 26.31
70 107,694 25.31 20,744 28.44
Diabetes Duration (Years) <.0001
<1 44,268 10.40 2677 3.67
1-3 86,160 20.25 6833 9.37
3.1-5 83,806 19.70 9386 12.87
>5 211,225 49.65 54,052 74.10
Benign Prostatic Hyperplasia 47,209 11.10 15,246 20.90 <.0001
Nephropathy 40,486 9.52 21,037 28.84 <.0001
Urinary Tract Disease 51,663 12.14 20,139 27.61 <.0001
Hypertension 207,094 48.68 48,164 66.03 <.0001
Chronic Obstructive Pulmonary Disease 54,330 12.77 19,110 26.20 <.0001
Stroke 50,162 11.79 18,712 25.65 <.0001
Ischemic Heart Disease 79,968 18.80 24,837 34.05 <.0001
Peripheral Arterial Disease 39,808 9.36 17,616 24.15 <.0001
Eye Disease 22,982 5.40 15,244 20.90 <.0001
Dyslipidemia 169,553 39.85 34,543 47.35 <.0001
Congestive Heart Failure 19,139 4.50 8929 12.24 <.0001
Other Cancer Before Baseline 35,897 8.44 8809 12.08 <.0001
Pioglitazone 8409 1.98 3310 4.54 <.0001
Rosiglitazone 35,439 8.33 15,681 21.50 <.0001
Sulfonylurea 320,019 75.22 65,839 90.25 <.0001
Meglitinide 27,024 6.35 11,951 16.38 <.0001
Metformin 263,528 61.94 62,602 85.82 <.0001
Acarbose 31,711 7.45 14,194 19.46 <.0001
Statin 77,990 18.33 19,335 26.51 <.0001
Fibrate 79,121 18.60 18,442 25.28 <.0001
Angiotensin-Converting Enzyme Inhibitor/Angiotensin 158,925 37.35 42,472 58.22 <.0001
Receptor Blocker
Calcium Channel Blocker 109,985 25.85 31,522 43.21 <.0001
Aspirin 105,874 24.88 31,181 42.74 <.0001
Nonsteroidal Antiinflammatory Drug (Excluding Aspirin) 229,657 53.98 60,222 82.55 <.0001
a-Blocker 72,788 17.11 23,696 32.48 <.0001
Clopidogrel 6706 1.58 2648 3.63 <.0001
Ticlopidine 10,660 2.51 4243 5.82 <.0001
5-a Reductase Inhibitor 2295 0.54 754 1.03 <.0001

Results
In Table 1, baseline characteristics between ever-users (n ¼
72,948) and never-users (n ¼ 425,459) of human insulin are
compared. All of the variables differed significantly between the 2
groups. Ever-users are characterized by older age distribution, higher
proportion with a diabetes duration  5 years, higher proportions of
all comorbidities and other cancer, and higher proportions of using
other medications.
Table 2 shows the incidence of prostate cancer between ever-
users and never-users of human insulin, and among the different
tertiles of the dose-responsive parameters for human insulin expo-
sure. In the models evaluating the overall hazard ratios for ever-users

Clinical Genitourinary Cancer February 2014 - e9

e10
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Human Insulin and Prostate Cancer

Clinical Genitourinary Cancer February 2014

Table 2 Exposure to Human Insulin, Incidence of Prostate Cancer, and Hazard Ratios Comparing Exposed to Unexposed

Exposure to Incident Prostate Cancer Incidence Rate Age-Adjusted Model Full Modela
Human (Per 100,000
Insulin Cases, n n % Person-Years Person-Years) HR 95% CI P HR 95% CI P
Never-Users 425,459 6282 1.48 2,268,887.92 276.88 1.000 1.000
Ever-Users 72,948 768 1.05 324,224.92 236.87 0.910 (0.843-0.981) .0142 0.989 (0.912-1.072) .7917
Tertile Cutoffs
Time Since Starting Insulin (Months)
Never-users 425,459 6282 1.48 2,268,887.92 276.88 1.000 1.000
<23 23,691 234 0.99 106,609.67 219.49 0.903 (0.792-1.029) .1257 1.013 (0.886-1.158) .8491
23-55 24,277 258 1.06 108,672.92 237.41 0.931 (0.822-1.055) .2613 1.033 (0.909-1.174) .6204
>55 24,980 276 1.10 108,942.33 253.35 0.896 (0.794-1.012) .0766 0.932 (0.821-1.057) .2712
Cumulative Dosage of Insulin Exposure (Units)
Never-users 425,459 6282 1.48 2,268,887.92 276.88 1.000 1.000
<200 23,589 250 1.06 110,251.25 226.75 0.870 (0.766-0.988) .0315 0.977 (0.859-1.111) .7218
200-15,000 24,336 237 0.97 105,713.33 224.19 0.892 (0.783-1.016) .0849 0.995 (0.870-1.137) .9377
>15,000 25,023 281 1.12 108,260.33 259.56 0.965 (0.856-1.088) .5611 0.996 (0.879-1.130) .9562
Cumulative Duration of Insulin Exposure (Months)
Never-users 425,459 6282 1.48 2,268,887.92 276.88 1.000 1.000
<0.5 24,148 280 1.16 109,719.42 255.20 0.977 (0.867-1.102) .7057 1.086 (0.961-1.227) .1875
0.5-7.8 24,001 221 0.92 107,640.00 205.31 0.819 (0.716-0.937) .0037 0.924 (0.805-1.060) .2601
>7.8 24,799 267 1.08 106,865.50 249.85 0.927 (0.820-1.049) .2300 0.950 (0.835-1.081) .4379

Abbreviation: HR ¼ hazard ratio.

a
Adjusted for all variables in Table 1.

vs. never-users, a significantly lower risk of prostate cancer was
observed in the age-adjusted model, which became insignificant
after multivariable adjustment (full model). In the models used to
evaluate the dose-responsive exposure to human insulin, although
some categories in the age-adjusted models might show a signifi-
cantly lower risk associated with insulin use, none of the categories
showed a significant association in the full models.
Discussion
The findings of this large population-based study suggest that
exposure to human insulin might not increase or decrease the risk of
prostate cancer (Table 2). However, in models that considered only
the adjustment for age, a false negative association might be
observed (Table 2).
In a previous 12-year prospective follow-up of a large cohort of
patients with diabetes, use of human insulin at baseline (from 1995
to 1998, before the marketing date of insulin analogues in Taiwan)
is not significantly associated with the risk of prostate cancer mor-
tality.19 Taken together with the findings of the present study, it is
almost safe to conclude that use of human insulin might not affect
the risk of prostate cancer in terms of either mortality or incidence.
Insulin users had a higher probability of receiving other oral
antidiabetic agents (Table 1). Among them, metformin and sulfo-
nylureas were the 2 most commonly used (Table 1). Metformin and
thiazolidinediones might reduce the risk of prostate cancer incidence
and mortality, and patients using sulfonylureas might have a higher
risk.11,20,21 This might have caused a more complicated condition
and probably a biased estimate if these concomitant medications
were not considered simultaneously during the analysis of the as-
sociation between prostate cancer and insulin use. The higher
proportions of the use of metformin and thiazolidinediones among
insulin users might have attenuated the hazard ratios toward a
significantly lower risk in these patients if the only adjustment was
for age (age-adjusted model in Table 2).
Dyslipidemia is a significant risk factor associated with the
growth of the prostate.9 It is also an independent risk factor for
prostate cancer in our previous study.18 Additionally, we also
identified several comorbidities as risk factors for prostate cancer,
such as nephropathy and ischemic heart disease.18 Therefore, a lack
of adjustment for many potential confounders might also have led
to biased estimates in the age-adjusted models (Table 2).
Insulin is always used at a late stage of type 2 diabetes when
pancreatic b cells are exhausted and most oral antidiabetic agents fail
to adequately control blood glucose. Furthermore, insulin might be
indicated for those with nephropathy and ischemic heart disease
when most oral antidiabetic agents might be relatively contra-
indicated. Therefore, indication bias associated with insulin use
might have existed if these comorbidities were not included as po-
tential confounders in the models.
A recently published study from Denmark indicated that insulin
users might have a lower risk of prostate cancer.22 This finding is
somewhat similar to the age-adjusted model in the present study
(Table 2). It is worth mentioning that the Danish study fell short of
a lack of information on the cumulative duration and dose of
exposure, and was unable to differentiate the use of human insulin
and insulin analogues, and lack of adjustment for many potential
confounders.
Chin-Hsiao Tseng
An important clinical implication of the present study is that,
while evaluating the potential risk of prostate cancer associated with
a certain medication, adjustment for age only might not be suffi-
cient to infer a cause-effect relationship. The comorbidities such as
dyslipidemia, nephropathy, and ischemic heart disease, and
concomitant medications such as metformin, thiazolidinediones,
and sulfonylureas should always be considered for adjustment,
because these are important factors for prostate cancer and are
commonly used in patients with diabetes who might have a long
duration of diabetes and happen to use insulin.
Hyperinsulinemia as a result of insulin resistance might poten-
tially increase the risk of prostate cancer.3-5 It should be pointed out
that an association with endogenous insulin hypersecretion should
not be readily translated into a scenario of the use of exogenous
insulin for the control of blood glucose in patients with diabetes.
The present study did not support that the use of human insulin in
clinical practice would increase the risk of prostate cancer.
Although misclassification of prostate cancer might occur, such
a probability was low because labeled diagnoses should be printed
out for all prescriptions handed to the patients. Because the da-
tabases were derived from the whole population, there was no
concern of potential selection bias related to sampling error. It is
also worth mentioning that the sensitivity and specificity of using
the “Severe Morbidity Card” as a surrogate for the diagnosis of
type 1 diabetes in the study are not known. However, both were
believed to be good for the following reasons. Patients with type 1
diabetes would tend to request such a card because card holders
can receive a waiver for many of the copayments that patients with
type 2 diabetes would not. However, such a card would not be
issued until after a diagnosis is confirmed by the history of diabetes
onset with ketoacidosis together with laboratory examinations of
C-peptide and/or glucagon test. It should also be stressed that such
a possibility of misclassification of type 1 diabetes would not affect
the conclusions of the present study, because in secondary analyses
the hazard ratios in Table 2 were not remarkably affected even if
the patients with type 1 diabetes were included in the analyses
(data not shown).
This study has several strengths. The databases included all
claim records on outpatient visits, emergency department visits,
and hospital admission, and we used the diagnoses from all
sources. Cancer is considered a severe morbidity by the NHI and
most medical copayments can be waived. Furthermore, there is a
low drug cost-sharing required by the NHI and patients with
certain conditions such as low-income household, veterans, or
patients with prescription refills for chronic disease are exempted
from the drug cost-sharing. Therefore the detection rate of pros-
tate cancer would not tend to differ among different social classes.
The use of medical records also reduced the potential bias related
to self-reporting.
The study limitations included a lack of actual measurement data
for confounders such as obesity, smoking, alcohol drinking, family
history, lifestyle, diet, hormones, and genetic parameters. In addi-
tion, we did not have biochemical data such as levels of blood
glucose, hemoglobin A1c, insulin, C-peptide, or prostate-specific
antigen for evaluating their effect. Another limitation is the lack
of information on the pathology, grading, and staging of prostate
cancer.
Clinical Genitourinary Cancer February 2014 - e11
 Human Insulin and Prostate Cancer
Conclusion
This retrospective cohort study suggests a lack of association
between the use of human insulin and prostate cancer risk in
Taiwanese patients with type 2 diabetes. Future prospective follow-
up studies are required to confirm the findings.
Clinical Practice Points
 Diabetes increases the risk of cancer mortality and incidence.
 Insulin might promote the growth of prostate cancer cells in
in vitro studies.
 Human observational studies suggest that insulin level is asso-
ciated with prostate size and might predict the incidence of
prostate cancer.
 Human insulin use in patients with type 2 diabetes does not
increase the risk of prostate cancer after multivariable adjustment.
 In models adjusted only for age, a spurious lower risk of prostate
cancer could be observed in individuals who used human insulin.
 There is no concern of an increased risk of prostate cancer when
human insulin is used for glycemic control in male patients with
type 2 diabetes.
Acknowledgments
The author thanks the Department of Health (DOH89-TD-
1035; DOH97-TD-D-113-97009) and the National Science
Council (NSC 101-2314-B-002-117, NSC102-2314-B-002-067)
of Taiwan for their continuous support on epidemiologic studies of
diabetes. The study is based in part on data from the National
Health Insurance Research Database provided by the Bureau of
National Health Insurance, Department of Health, and managed by
National Health Research Institutes (Registered number 99274).
The interpretation and conclusions contained herein do not repre-
sent those of Bureau of National Health Insurance, Department of
Health or National Health Research Institutes. The author had full
access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Disclosure
The author has stated that he has no conflicts of interest.
e12 - Clinical Genitourinary Cancer February 2014
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