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Korean J Gastroenterol Vol. 67 No. 4, 168-177 http://dx.doi.org/10.4166/kjg.2016.67.4.168 pISSN 1598-9992 eISSN 2233-6869

REVIEW ARTICLE

Type 2 Diabetes Mellitus and Its Association with the Risk of Pancreatic Carcinogenesis: A Review Belete Biadgo and Molla Abebe Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases. (Korean J Gastroenterol 2016;67:168-177) Key Words: Type 2 diabetes mellitus; Pancreatic neoplasms

insulin secretion, and excessive or inappropriate glucagon

INTRODUCTION

secretion. It comprises over 90% of all DM cases and is usuDiabetes mellitus (DM) is a group of metabolic disorders

ally diagnosed after 40 years of age, although recently much

of multiple etiologies characterized by chronic hyperglycemia

younger cases are being reported. Poorly controlled T2DM is

with disturbances of carbohydrate, fat and protein metabo-

associated with an array of microvascular and macro-

lism resulting from defects in insulin secretion, action, or

vascular complications.

2,3

1 both. Several pathogenic processes are involved in the de-

Longitudinal and cross-sectional studies have demon-

velopment of DM. These range from autoimmune destruction

strated that the earliest detectable abnormality in T2DM is

of the cells of the pancreas with consequent insulin deficiency

an impairment of the body’s ability to respond to insulin.

to abnormalities that result in resistance to insulin action.

Genetic susceptibility and environmental factors are the

Deficient insulin action results from inadequate insulin secre-

most likely triggers of T2DM.

tion and diminished tissue responses to insulin at one or more 1

points in the complex pathways of hormone action.

4,5

The main function of the pancreas is to produce endocrine hormones and digestive enzymes that help break down car-

Type 2 diabetes mellitus (T2DM) consists of an array of dys-

bohydrates, fats and proteins. The link between diabetes and

functions characterized by hyperglycemia and resulting from

cancer exists because T2DM is associated with increased in-

the combination of resistance to insulin action, inadequate

sulin production; insulin causes the growth of cells and the

CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2016. Korean Society of Gastroenterology.

Correspondence to: Belete Biadgo, Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P.O.Box 196, Gondar, Ethiopia. Tel: +251-581117678, Fax: +251-918295071, E-mail: [email protected] Financial support: None. Conflict of interest: None.

Korean J Gastroenterol, Vol. 67 No. 4, April 2016 www.kjg.or.kr

Biadgo B and Abebe M. Association between Type 2 DM and Pancreatic Carcinogenesis

proliferation of blood vessels in the pancreas that generates 6

a hospitable environment for tumor formation.

169

A helpful perspective can be obtained by examining research focusing on T2DM in the setting of PC to gain further

Pancreatic cancer (PC) is a malignant tumor of the pan-

understanding of the link between T2DM and PC. In develop-

creas, and one of the most tragic and least understood of can-

ing countries, especially in Ethiopia, T2DM patients are not

6

cers, affecting the cells that produce insulin and glucagon.

screened for PC, although glycemic control is used for man-

The majority of PC originates from the ductal epithelial cells

agement of DM to control micro and macro vascular compli-

of the exocrine portion of the pancreas. There is extensive in-

cation. Therefore, this review examines the metabolic link

teraction between the endocrine and exocrine portions of the

and association between T2DM and the risk of pancreatic

6

pancreas during pancreatic carcinogenesis. It is charac-

carcinogenesis, and provides the most reliable information

terized by an increased incidence in Western industrialized

on the magnitude of association.

countries, an extremely poor median survival of four to six months after diagnosis and with an overall five-year survival of less than 4%.

MAIN SUBJECTS

7

The incidence and number of deaths caused by PC have been gradually rising, although incidence and mortality of 8

1. Mechanism of T2DM-associated pancreatic carcinogenesis

other common cancers have been declining. Inability to de-

Carcinogenesis is a multifaceted process whereby normal

tect PC at an early stage, its aggressiveness, and the lack of

cells go through multiple genetic hits before the full neoplastic

effective systemic therapy are responsible for the rapid death

phenotype of growth, invasion, and metastasis occurs. This

9 of PC patients. The poor outcome is a strong motivation for

process of malignant transformation can be divided into mul-

epidemiological research designed at identifying and re-

tiple steps: initiation, promotion and progression.

ducing risk factors for PC. Besides age and genetic risk fac-

that affect one or more steps of this pathway could be asso-

tors, several lifestyle and environmental factors, such as

ciated with cancer incidence or mortality. The mechanism of

smoking, obesity, low physical activity and alcohol con-

the association between DM and PC is mysterious but most

10

20

Factors

hypothesized mechanisms underlying the association be-

sumption are associated with PC.

T2DM is associated with PC, but it is unclear whether DM

tween T2DM and PC include hyperinsulinemia, insulin resist-

11

is a causal factor or the result of subclinical malignancy.

ance (IR), elevated levels of circulating insulin-like growth fac-

T2DM may directly promote the progression of PC by pancre-

tors (IGFs), hyperglycemia and chronic inflammation that in-

atic duct enlargement and hypertension, as well as increased

fluences tumor growth.

20

tumor size. Up to 80% of PC patients are either hyperglycemic

The pancreas is exposed to high concentrations of endoge-

or diabetic, both of which can be detected in the pre-sympto-

nously produced insulin. The causal nature of the association

matic phase. Hyperglycemia and glucose tolerance aberrations

with PC risk is complicated by the fact that abnormal glucose

12

metabolism may be a consequence of PC. However, a positive

At question is whether coincidence of diabetes and the risk

association between T2DM and PC risk has been found when

of certain cancers is largely due to shared risk factors, or

restricted to T2DM that precedes the diagnosis of PC by at

whether diabetes itself, and the specific metabolic disorders

least five years.

may be the first easily testable clinical manifestation of DM.

13

typical of diabetes, increase the risk of some types of cancer.

21

1) Hyperinsulinemia and insulin resistance

The development of DM within a few years of a PC diagnosis

Recent epidemiological and clinical evidence points to a

suggests an effect of the tumor, whereas DM of longer dura-

link between IR and PC. Increased risk of cancer among IR pa-

tion is more likely to contribute to the development of cancer.

14

tients is explained in part by overproduction of reactive oxy-

T2DM and PC are linked, but researchers have found it diffi-

gen species (ROS) that can damage DNA, contributing to mu-

15

cult to determine which influences the other. Based on the

tagenesis and carcinogenesis. On the other hand, it is possi-

findings from several retrospective and prospective ob-

ble that the abundance of inflammatory cells in adipose tis-

servational studies, T2DM and glucose intolerance are fairly

sue of obese and T2DM promotes systemic inflammation.

16-19

Such adiposity is common with hyperinsulinemia and IR,

reliable, albeit somewhat debatable, risk factors for PC.

Vol. 67 No. 4, April 2016

170


Both insulin and

in all stages of mammalian growth.29 IGFBP-1 is suppressed

IGF-1 have affinity for both the insulin receptor and IGF-1 re-

by insulin; this raises the levels of bioavailable IGF-1. Further-

ceptor (IGF-1R) because of similar structural homology.

more, insulin up-regulates the bioavailability of IGFs by re-

However, it is important to recognize that insulin’s affinity for

ducing hepatic production of IGFBP.

leading to a tumorigenic environment.

22

30

23

The mitogenic and anti-apoptotic activities of IGF-1 are

Both IGF-1 and IGF-1R tend to have stronger mitogenic and

more potent than those of insulin and may act as growth stim-

anti-apoptotic effects, and the hyperinsulinemia that occurs

uli in cells expressing insulin and the IGF-1R. IGF-1 and

the insulin receptor is 1,000 fold greater than for IGF-1R.

in IR individuals may enhance this effect.

20,23

IGF-1R are highly expressed in PC cells. IGF-1-mediated sig-

IR status, characterized by hyperinsulinemia, is asso-

naling transduction increases proliferation, invasion, and ex-

ciated with an increased risk for a number of malignancies,

pression of angiogenesis mediators and decreases apopto-

including carcinomas of the breast, prostate, colon, pan-

sis in PC cells. IGF-1R mediated initiation of signal trans-

18

creas and kidney. The insulin cancer hypothesis proposes

duction activates important intracellular signal pathways, in-

that chronic hyperinsulinemia reduces concentrations of

cluding the Ras/Raf/mitogen-activated protein kinase

IGF binding protein (IGFBP-1 and -2), leading to increased

(MAPK) and phosphoinositide-3 kinase/Akt/(PI3K) mam-

tissue levels of IGF-1, crucial in the development and pro-

malian target of rapamycin (mTOR) pathways.

24

18 gression of cancers. Hyperinsulinemia may also accelerate

Furthermore, in IR states, T2DM causes impairment of

tumor growth indirectly through its effects on IGF-1. Cancer

downstream glucose transporter 4 (GLUT4) translocation by

cells over-express insulin and IGF-1 receptors, and insulin re-

disruption of insulin receptor substrate-1 (IRS-1)-associated

duces the hepatic production of IGFBP-1 and -2. This leads

31 PI3K signaling in the metabolic pathway of insulin. Insulin,

to increased levels of free circulating physiologically active

to a lesser degree than IGF-1, motivates cellular growth and

24

IGF-1. This could act as a growth stimulus in cancer cells 24

protein synthesis through the protein kinase B (PKB) system 32

that express such receptors. Hyperinsulinemia stemming

and activation of mTOR.

from IR may happen for many years before diabetes diag-

from over activation of mTOR creates a negative feedback

nosis, with widespread effects. Normally, when insulin binds

loop that attenuates the metabolic pathway in hyperinsuli-

to its receptors, it activates two pathways: the metabolic

24 nemia. IRS-2 expression by insulin phosphorylation leads

25

Abnormal IRS-1 phosphorylation

to increased extracellular signal regulated kinase (ERK) acti-

pathway and the mitogenic pathway.

Insulin resistance hinders the metabolic pathway, which is

vation; MAPK because the mitogen pathways mediated by 32

This drive towards the mi-

the pathway that increases transport of glucose into cells,

mTOR and Ras remain intact.

stimulates glycogen synthesis, and suppresses liver gluco-

togen pathway with hyperinsulinemia leads to enhanced cell

neogenesis. In the absence of insulin’s normal postprandial

growth and survival. Therefore, the leading hypothesis for the

inhibition activity lipolysis, circulating free fatty acid levels im-

relationship between T2DM and PC is that IR and con-

portant to the pathogenesis of IR and liver triglyceride pro-

sequently hyperinsulinemia may promote tumor cell growth

duction rise, which contributes to atherogenic dyslipidemia.

33 34 directly via insulin receptors or indirectly via the IGF-1R.

In contrast, IR does not inhibit activation of the mitogenic

The shared metabolic factors underlying both T2DM and

pathway that promotes proliferation of normal and cancer-

cancer, including visceral adiposity, inflammation, hyper-

26

Chronic hyperinsulinemia results, leading to a

glycemia, and hyperinsulinemia, lead to increased IRS, stim-

chain of metabolic responses, including changes in IGFBP

ulating the phosphorylation of Ras signaling proteins, and po-

that result in increased tissue availability of both IGF-1 and

tentially increasing tumor cell growth and proliferation.

27 -2. Insulin itself is a growth promoting hormone with mito-

IRS-associated PI3K signaling is compromised by IR states,

genic (but not mutagenic) effects and diabetes associated

such as in T2DM, and downstream GLUT4 translocation is

cancer cells express insulin and IGF-1 receptors which play

disrupted. This disruption drives PI3K signaling towards

ous cells.

27,28

a key role in cell growth and differentiation.

Experimental evidence on animal studies complemented by case studies in humans demonstrate the critical role of IGF

AKT/mTOR. AKT and mTOR can affect both the metabolic and mitogenic pathway, but because of the signaling dysfunction, 35

AKT and mTOR are driven towards the mitogenic pathway.

The Korean Journal of Gastroenterology


(1) Insulin-insulin like growth factor axis: Insulin and

171 43

tion end products (AGEs) that can increase inflammation.

the IGF axis have a number of effects on cancer cells. When

These studies also report the link between elevated hemo-

both the insulin and IGF receptors interact with their ligands,

globin A1C and other measures of hyperglycemia with an in-

multiple signaling pathways are activated, leading to phos-

creased risk of colorectal, pancreatic, endometrial, and oth-

phorylation of adaptor proteins such as the IRS family. These

er cancers.

signaling pathways may promote proliferation and may affect

metabolic pathways like polyol pathway, auto oxidation of glu-

36

cose, lipid peroxidation and Maillard’s reaction, appear to be

Insulin and IGF receptors form a complex network of cell

linked to PC, suggested to be mitogenic and capable of stim-

invasion, metastasis, and protection from apoptotic stimuli.

10,43

ROS, produced due to activation of various

44

Moreover, hyperglycemia IR, hy-

surface receptors; homodimers and heterodimers have

ulating cell proliferation.

been described, and all function to mediate insulin and IGF

perinsulinemia and inflammation can cause DNA damage,

24 responses. The majority of cancer cells express insulin and

boost the invasive and migratory activity of PC cells via hydro-

IGF-1Rs; the A isoform of the insulin receptor is frequently

gen peroxide and the increased expression of urokinase plas-

expressed. The ‘A’ receptor isoform can encourage in-

45 minogen activator (uPA). Hyperglycemia can attenuate an-

sulin-mediated mitogenesis, even in cells deficient in

tioxidant enzyme activity and in turn create a state of oxida-

37 IGF-1Rs. In addition to its metabolic functions, the insulin

tive stress.

receptor is accomplished in stimulating cancer cell pro-

3) Chronic inflammation

46

liferation and metastasis. Because most glucose uptake in

Inflammatory cytokines, ROS, and mediators of inflam-

cancer cells is constitutively high and independent of insulin

matory pathways, such as cyclooxygenase-2 (COX-2) and nu-

binding to its receptor, the effects of insulin receptor activa-

clear factor kappa B (NFκB) are associated with oncogene ex-

tion on neoplastic cells may relate more to cell survival and

pression, silencing of tumor suppressor genes, and affect the

38

cell cycle, all of which may facilitate pancreatic carcino-

mitogenesis than to enhanced glucose uptake.

Multiple signaling pathways are activated after IGF-1Rs in-

genesis.

46,47

Chronic, low-grade inflammation can result

teract with their ligands by phosphorylating adaptor proteins,

from DNA damage and create an environment in which more

most notably the IRS family. The initial kinase event is linked

damage occurs.

36

48

Once activated these

Adipose tissue is an active endocrine organ recognized as

signaling pathways may stimulate multiple cancer pheno-

a low-grade inflammatory state in which overproduction of

types including proliferation, protection from apoptotic stim-

certain molecules, such as free fatty acids, interleukin-6,

uli, invasion, and metastasis, potentially enhancing the pro-

monocyte chemo attractant protein, plasminogen activator

to downstream signaling pathways.

36,39

motion and progression of many types of cancer cells.

It

inhibitor 1 (PAI-1), adiponectin, leptin, and tumor necrosis

is also clear that during hyperglycemia, IGF may stimulate

factor alpha (TNF-) that might play an etiologic role in regu-

normal cells that are involved in cancer progression that al-

lating malignant transformation or cancer progression.

lows IGF-1 to stimulate vascular smooth muscle cell pro39

49-51

Adiponectin increases fatty acids oxidation, which lowers

Although this process has been

circulating free fatty acids and prevents IR, and it exerts an

linked to the pathophysiology of atherosclerosis, abnormal

anti-atherosclerotic effect, while augmenting endothelial ni-

liferation and migration.

40,23

vascular growth is also a hallmark of cancer.

trous oxide production and protecting the vasculature by re-

2) Hyperglycemia

ducing platelet aggregation and vasodilation.

Laboratory studies suggest that higher circulating glucose may support malignant cell growth.

42

Biologically based

mass spectrometry techniques document that proliferating tumor cells preferably use glucose to synthesize the ribose 43

52

Apart from

causing metabolic dysfunction, adiponectin deficiency may also contribute to cardiovascular disease, IR, and a wide ar52

ray of cancers.

The decrement of adiponectin precedes the development of IR and myocardial infarction in humans; low levels of adipo-

5-phosphate required for nucleic acid synthesis.

Prospective cohort and case-control studies show that hy-

nectin are likely to be a causal component of those 53

A study in Pima Indians shows individuals with

perglycemia is associated with increased free radical for-

disorders.

mation and may lead to the development of advanced glyca-

high levels of adiponectin were less likely to develop T2DM,

Vol. 67 No. 4, April 2016

172


69

suggesting that high adiponectin concentration has anti-in-

diagnosed.

flammatory, anti-apoptotic and pro-angiogenic activities,

those of the lung, breast, and colorectal, whereas the most

54,55

protective factor against development of T2DM.

The most commonly diagnosed cancers were

common causes of cancer deaths were lung, stomach, pan69

creas and liver cancer. It has long been known that PC is as2. Epidemiological evidences for type 2 diabetes mel-

sociated with DM, and recent studies have revealed that

litus and pancreatic cancer

about 85% of patients diagnosed with PC have impaired glu-

The prevalence of DM has increased dramatically around

cose tolerance.

70

the globe and is rapidly becoming an overwhelming public 56 health problem in developing countries. An estimated 366

3. The association between type 2 diabetes mellitus

million people were living with DM in 2011. The number is ex-

and the risk of developing pancreatic cancer

pected to grow to 552 million by 2030, and the largest age

Assessing the relationship between DM and the risk of PC

group currently affected by DM is between 40-59 years. The

poses challenges. Some epidemiological studies observe a

African continent is expected to experience the highest in-

relationship between the presence of T2DM and the develop-

crease in the coming years with estimated increase in preva-

ment of PC. There are a number of potentially plausible ex-

lence rates of 98% for sub-Saharan Africa, and 94% for North

planations for the observed association between T2DM and

Africa and the Middle East and 20% increase in developed

PC, including shared risk factors, and metabolic derange-

57,58

ments such as the metabolic syndrome. IR and hyper-

countries.

A 2010 consensus report from a panel of experts chosen

insulinemia are hallmarks of cancers associated with these 51,71

Although there are proposed mechanisms of

jointly by the American Diabetes Association and American

conditions.

Cancer Society suggested that people with T2DM are at an

diabetes related pancreatic carcinogenesis, epidemiological

16,50,59-61

increased risk for many types of cancer.

Evidence

from observational studies suggests that some medications used to treat hyperglycemia are associated with changed risk 50

studies clearly indicate that DM is positively associated with an increased risk of PC.

72,73

A large prospective study in the United States (US) followed

of PC. For more than 50 years, clinicians have reported the

a cohort of 467,922 men and 588,321 women for 16 years

62

occurrence of patients with concurrent DM and PC.

who had no reported history of cancer. The results showed

However, research as early as 1959 stated that although

that independent of a high body mass, T2DM acts as a pre-

studies examining the association between DM and cancer

dictor of mortality from cancer of the colon, pancreas, female

were conducted over several years, there was no conclusive

74 breast, male liver and bladder. Even though there is a strong

evidence of a positive association. Subsequently, an associa-

association between PC and DM, the temporal sequence is

tion between the diseases was identified in the 1960s in pop-

unclear. However, 1% of newly diagnosed DM patients great-

63

75

er than 50 years of age will contract PC within three years.

ulation based studies.

PC is the fourth or fifth most common cause of cancer 64-66

A population based retrospective cohort study in China

In the Euro-

showed that increased risk of developing cancer was found

pean Union, 29,600 deaths in men and 29,900 deaths in

in both male and female T2DM patients with a standardized

deaths in economically developed countries.

65

The bilateral

incidence ratio (SIR) of 1.331 (95% CI, 1.143-1.518) and

causality between the diseases has been widely docu-

1.737 (1.478-1.997), respectively. As for different cancer

women due to PC were estimated for 2004. mented.

13,67

subtypes, both male and female T2DM patients had a sig-

Epidemiological studies clearly indicate that the risk of PC

nificantly increased risk of PC with the SIRs of 2.973

is increased in DM patients, but most studies focus on T2DM.

(1.73-4.21) and 2.687 (1.445-3.928), respectively. These

The recent increase in the prevalence of T2DM is thought to

findings indicated that patients with T2DM have an in-

68

have contributed to a parallel rise in the incidence of PC.

76

creased risk of developing PC.

Worldwide, the prevalence of cancer is difficult to establish

A systematic review of the association between DM and PC

because many areas do not have cancer registries, but in

was undertaken by searching electronic databases and jour-

2008 there were an estimated 12.4 million new cancer cases

nal references from 1973 to 2013 in Australia. A total of 88

The Korean Journal of Gastroenterology


independent studies, including 50 cohort and 39 case con-

173

protective effect on the development of PC.15

trol studies, were examined. The overall summary RR was

A hospital-based case-control study at University of Texas

1.97 (95% CI, 1.78-2.18) with marked heterogeneity that

M. D. Anderson Cancer Center, USA was conducted from

could not be clearly attributed to any subgroup analyses. The

2004 to 2008 enrolling 973 patients with pancreatic ad-

risk of PC was greatest early after the diagnosis of DM and

enocarcinoma, including 259 DM and 863 controls, 109 of

remained elevated long after the diagnosis. The individual

whom were diabetics. DM patients who had taken metformin

level RR ranged from 6.69 at less than 1 year to 1.36 at 10

had a significantly lower risk of PC compared to those who

years.

77,78

had not taken metformin, with adjustments for potential con-

A prospective study found an association between a his-

founders. This difference remained statistically significant

tory of DM and subsequent risk of cancer in Japan. In men,

when the analysis was restricted to patients with a duration

a 27% increase in the risk of total cancer incidence (hazard

of diabetes over two years or those who never used insulin.

ratio [HR] 1.27, 95% CI 1.14-1.42; and HR 1.85, 95% CI

In contrast, diabetic patients who had taken insulin or insulin

1.07-3.20)

78

was seen for PC alone with a history of DM. A

study done by the Alpha-Tocopherol Beta-Carotene Cancer

secretagogues had a significantly higher risk of PC compared 12

to DM patients who had not taken these drugs.

prevention study shows smoking had significant (two-fold)

A meta-analysis of 9,220 individuals with PC in 36 studies

contribution, increasing the risk of PC carcinogenesis among

published between 1966 to 2005 included 17 case-control

79

and 19 cohort studies. The combined summary OR was 1.82,

male DM patients male smokers.

Recent meta-analyses revealed an association between

95% CI 1.66-1.89, with evidence of heterogeneity across the

T2DM and cancer in Austria. The strongest relationship was

studies (p