Type 2 diabetes mellitus and cancer: carcinogenesis and protective effect of antidiabetic drugs

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REVISTA

UNIMONTES CIENTÍFICA

(ISSN 2236-5257)

I Congresso Nacional de Oncologia da Associação Presente - Agosto de 2017.

TYPE 2 DIABETES MELLITUS AND CANCER: CARCINOGENESIS AND

PROTECTIVE EFFECT OF ANTIDIABETIC DRUGS

Diabetes Mellitus tipo 2 e câncer: Carcinogênese e efeito protetor dos fármacos antidiabéticos

Hadison Santos Nogueira Curzio1

Gabriel Ataíde Monção1 Higor Rabelo Guedes1 Rafael Durães Leite1 Mauro Aparecido de Sousa Xavier1 Alessandra Rejane Ericsson de Oliveira Xavier1

Abstract: Recent epidemiological evidence suggests that the type 2 diabetes mellitus, which accounts for

90% of all diabetics in the world, is closely linked to the increased incidence of certain types of cancer

such as pancreas, breast, ovarian, endometrial, liver, colon, stomach and skin. Furthermore, it determines

unfavorable evolution in these cases, increasing the mortality of patients simultaneously affected by such

diseases, when compared to non-diabetic patients with some type of cancer. Well-designed studies also

demonstrate the existence of a protective relationship, as much for the development as for progression of

these cancers, provided by Metformin, the main drug used nowadays in the treatment of type 2 diabetes, in

relation to the other antidiabetic therapies or the lack of treatment. This review aims to present and analyze

some of the most recent published studies results about the relationship between type 2 diabetes mellitus

and the incidence/mortality of several types of cancers, the carcinogenesis phenomena involved in this

process, and the performance of metformin as a protective factor for the development of cancer in this

population.

Keywords: Type 2 diabetes mellitus; Cancer; Metformin.

________________

Corresponding author: Hadison Santos Nogueira Curzio. E-mail: [email protected]

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REVISTA UNIMONTES CIENTÍFICA

Montes Claros, I Congresso Nacional de Oncologia da Associação Presente - Agosto de 2017.

193 Resumo: Evidências epidemiológicas recentes apontam que o quadro de Diabetes mellitus tipo 2, tipo

que representa 90% de todos diabéticos no mundo, está intimamente ligado ao aumento da incidência de

determinados tipos de câncer, como pâncreas, mama, ovário, endométrio, fígado, cólon, estômago e pele,

além de determinar evolução desfavorável nestes casos, aumentando a mortalidade dos pacientes acometidos

simultaneamente por tais doenças, quando comparado a pacientes não-diabéticos que apresentam algum

tipo de câncer. Estudos bem delineados demonstram, ainda, a existência de uma relação protetora, tanto

para desenvolvimento quanto para progressão destes cânceres, proporcionada pela Metformina, principal

droga utilizada no tratamento do diabetes tipo 2 atualmente, em relação a outras terapias antibiabéticas ou

à ausência de tratamento. Esta revisão de literatura tem como objetivos apresentar e analisar resultados de

alguns dos estudos mais recentes publicados acerca da relação entre Diabetes mellitus tipo 2 e a incidência/

mortalidade de diversos tipos de cânceres, os fenômenos de carcinogênese envolvidos neste processo, e a

atuação da metformina como fator protetor do desenvolvimento de câncer nesta população.

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Type 2 diabetes mellitus and cancer: carcinogenesis and protective effect of antidiabetic drugs CURZIO, H. S. N.; MONÇÃO, G. A.; GUEDES, H. R.; LEITE , R. D.;

XAVIER, M. A. S.; XAVIER, A. R. E. O. ISSN 2236-5257

194 INTRODUCTION

Diabetes Mellitus (DM) represents a

heterogeneous set of organic dysfunctions that

have as their central point the inefficiency in the

maintenance of glycemic control due to the inability

of synthesis or proper use of insulin.

1,2

This dysfunction is framed by the World

Health Organization (WHO) in the group of chronic

non-communicable diseases, which currently

represents more than 70% of deaths around the

world.

1-3

_{In addition to the resulting impact of}

its severity, epidemiological studies indicate its

significant global prevalence, affecting 9.2% of

all men and 9.8% of women in the world in 2008.

This repercussion led WHO to classify the DM as a

worldwide epidemic.

1-3

Because of the wide variety of etiologies

of diabetes, the American Diabetes Association

(ADA) in 1997, divided its clinical presentation

in four general subclasses, different from the

classification previously adopted, based on the

type of treatment. With this, the terms insulin

dependant DM and non-insulin dependant DM

became obsolete.

4,5

_{The classification of ADA}

was reaffirmed and adopted in 2006 by the World

Health Organization and recommended, from

then on, by international guidelines, including the

Brazilian Society of Diabetes, and maintained since

then.

6

_{The four general classes are: Type 1 diabetes}

mellitus (DM1), diabetes mellitus type 2 (DM2),

other types of diabetes and gestational diabetes, as

presented in table 1.

1,2,4-6

Table 1. Etiologic Classification of Diabetes Mellitus. Adapted from American Diabetes Association,

2009.

9

I. Diabetes type 1 (destruction of β cells, giving origin commonly to an absolute deficiency of insulin. 5 to 10% of all cases of diabetes)

a. Of Immune Mediation b. Idiopathyc

II. Type 2 Diabetes (there can be from the predominance of insulin resistance associated with the relative deficiency of insulin, until a defect predominantly secretory of insulin with insulin resistance. 5 to 90% of all cases of diabetes) III. Other specific types of diabetes

a. Genetic defects in function of β cells, characterized by mutations in:

1- Factor of nuclear transcription of hepatocytes (UFH) 4α (MODY 1); 2- Glicoquinase (MODY 2); 3- HNF-1α (MODY 3); 4- Factor promoter of insulin 1 (IPF-1; MODY 4); 5- HNF-1β (MODY 5); 6- NeuroD1 (MODY 6); 7- mitochondrial DNA; 8- subunits of the potassium channel sensitive to ATP; 9- Proinsulin or insulin

b. Genetic deffects in insulin action

1- insulin resistance type A; 2- Leprechaunism; 3- Syndrome of Rabson-Mendenhall; 4- lipodistrophic syndromes

c. Diseases of exocrine pancreas

Example: Pancreatitis, Pancreatectomy, neoplasia, cystic fibrosis, Hemochromatosis, fibrocalculous pancreatitis, mutations of the carboxyl ester lipase

d. Endocrine disease

Example: Acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, Somatostatin, aldosteroma

e. Induced by drugs of chemical substances

Example: Glucocorticoids, vacor (a rodenticide), pentamidine, nicotinic acid diazoxide, agonists β-adrenergic agonist, thiazides, Hydantoins, asparaginase, α-interferon, protease inhibitors, antipsychotics (atypical and others), epinephrine

(4)

195 DM2 is the most common form of disease,

representing 90% of all DM cases. Of multifactorial

origin, resulting from a complex interaction of

genetic, immunological and environmental factors,

its pathophysiology is based in dysfunction of

insulin due to the emergence of resistance to its

action, associated to a gradual secretory deficit of

this hormone by pancreatic beta cells.

1,2

Once established, the DM progresses

with involvement of intermediate metabolism,

leading to hyperglycemia, which generates serious

systemic repercussions such as neuropathy,

diabetic retinopathy and nephropathy, in addition

to significantly increasing the risk of vascular

diseases and predisposing to acute ketoacidosis

and hyperosmolar hyperglycemic state , of great

morbidity and mortality.

1,2

_{In addition to these}

clinical signs, the metabolic instability resulting

from DM, associated to the effects on the endocrine

and immune systems, is related to an increased risk

of developing various types of cancers.

7

The relationship between DM and

carcinogenesis is a very current point of discussion

in the medical literature. In some well-designed

studies a statistically significant increase was

reported in the incidence or mortality of cancers

of some organs, such as the pancreas, breast,

ovary and endometrium, liver, colon, stomach

and skin in diabetic patients. Other studies that

followed a similar line of approach also indicated

that metformin, an oral anti-diabetic of first line,

currently considered the basis for the treatment

of DM2, has been shown to be effective in the

prevention of cancer and reduce mortality due

to cancer among diabetic patients. However, in

spite of the significant epidemiological impact of

these studies, there is a need for further research

to consolidate this relationship in the scientific

literature.

10,13-33

This review aims to present and analyze

some of the most recent published studies results

about the relationship between type 2 diabetes

mellitus and the incidence/mortality of several types

of cancers, the carcinogenesis phenomena involved

in this process, and the performance of metformin

as a protective factor for the development of cancer

in this population. .

LITERATURE REVIEW

DM, along with its complications, is

considered the fifth leading cause of deaths,

accounting for over 5% of all deaths each year,

according to WHO estimates at the beginning of

the 21st century.

1-3

To worsen the statistics, epidemiological

studies point to a trend of increase of almost 100

million diabetics in the next 20 years, in relation

to the current prevalence of approximately 387

million individuals affected.

1

_{This increase is due}

to factors such as growth and population aging,

Continuação da tabela 1.

f. Infections

Example: Congenital rubella, cytomegalovirus, virus Coxsackie

g. Uncommon forms of diabetes of immune mediation

Example: “Stiff person” Syndrome, antibodies antirreceptor of insulin

h. Other genetic syndromes occasionally associated with diabetes

Example: Wolfram Syndrome, Down syndrome, Klinefelter syndrome, Turner syndrome, ataxia of Friedreich, Korea Huntington, syndrome of Laurence-Moon-Biedl, myotonic dystrophy, porphyria, Prader-Willi

syndrome

IV. Gestational Diabetes Mellitus (arises or is diagnosed during pregnancy, usually after the 22nd week, occurring in approximately 7% of pregnancies)

(5)

196 share non-modifying risk factors (such as age, sex,

race/ethnicity) and modifying ones (such as diet,

physical activity, smoking, alcohol, obesity and

weight change). In addition, some bodies of research

suggest that cancer and diabetes can be triggered by

similar molecular genetic mechanisms, as well as

possess biological relationships (described below)

that approach them even more.

10

The complex events that involve the

carcinogenesis, obey certain steps that modify the

physiological process of cell division and promote

malignant transformation followed by tissue

invasion and possible metastasis. These steps are

represented by initiation (first step in irreversibility

of cancer, from mutation of specific genes that

regulate the cell cycle), promotion (stimulation of

the growth of the cells affected) and progression

(appearance of the most aggressive character

of the promoted cells). The factors that interact

synergistically with these steps may be associated

with cancer incidence or mortality. The mechanisms

by which diabetes may influence the neoplastic

progression involve mainly the hyperinsulinemia

(of endogenous cause, such as the mechanism

to attempt to overcome the resistance provided

in DM2, or exogenous, by means of treatment

using insulin or other medicines that increase its

synthesis or secretion), hyperglycemia or chronic

inflammation.

10

The insulin, mean anabolic hormone in the

metabolism of carbohydrates, exerts proliferative

effects directly via the insulin receptor (IR), and

indirect effects by increasing the circulating levels

of insulin-like growth factor 1 (IGF-1). The insulin

receptor is tyrosine-kinase type, similar to other

growth factors and, as such, it has as a final result

of delayed pathway of intracellular signals the

activation of kinases with mitogen purpose , from

the gene transcription.

11

_{The majority of cancerous}

cells express this type of receptor on their surface.

associated with obesity and a sedentary life style,

which represents another major health problem

worldwide, in addition to the increased survival of

the diabetic patients themselves , with advances in

monitoring and treatment of the disease.

1,2

In Brazil, data from the Ministry of Health

reveal a growth of 61.8% in the number of patients

diagnosed with DM2 between 2006 and 2016. In

2006, the amount of Brazilians diabetics accounted

for 6.9% of the population, while in 2016, the

statistics of this same body already pointed to a total

of 8.9%. Such data also revealed that the prevalence

is lower among men (7.8%) than among women

(9.9%).

8

_{It is estimated that due to the chronicity}

of the disease and the severity of its complications,

Brazil spends about 3.9 billion dollars per year with

the management of diabetic patients. Therefore,

DM represents a great impact not only for affected

individuals and their families, but also for the

health care system, bringing economic costs and

intangible quality of life.

1,2

DM2, the most common type of disease,

has as its pathophysiological basis the peripheral

resistance to insulin action, which is related to

several environmental factors and lifestyle that

contribute effectively to its genesis. Among

these factors the following stand out: obesity, a

sedentary lifestyle and the diets rich in fat, typical

of developed countries, countries which comprise

80% of the global prevalence of this disease.

1,2

_In

addition to the environmental factors, the genetic

influence is without doubt a great impact, since the

concordance between univitelline twins approaches

100%. However, despite the clear association of

genetic factors in the development of the disease,

the heritability has not been fully elucidated,

possibly due to its polygenic nature.

1,2,9

Just as the genetic influence, the mechanisms

of carcinogenesis related to DM2 require further

studies. It is known currently that both diseases

(6)

197 Due to peripheral insulin resistance, the developing

cancer cells receive more of this hormone and

develop a phenomenon of up-regulation of the IRs.

However, due to the fact that the cancerous cells

have independent means of insulin for acquisition

of glucose, the activity of insulin becomes less

metabolic and more related to the mitotic capacity,

leading to increasingly induction of kinase

activating of mitotic and growth genes, thus

increasing the multiplication and cell survival.

10,12

In turn, their indirect effect is through the

reduction of hepatic production of protein 1 ligand

of IGF, thus increasing the levels of IGF-1. This

hormone, in addition to the anabolic effects related

to an increase in blood glucose, protein synthesis

and lipid degradation, has stimulating growth,

increasing the rate of cell division and predisposing

to the development of cancers

2,10-12

The hypothesis that hyperglycemia (one

of the main findings in diabetes mellitus) can

have significant carcinogenic action, serving as

a substrate for the process of carcinogenesis,

emerged in the mid 1950s, since the studies of Otto

Warburg. Normally, cancer cells produce ATP by

anaerobic glycolysis. Under these conditions, the

production of cytoplasmic ATP via glycolysis

by tumor cells is less efficient than the synthesis

via oxidative phosphorylation in mitochondria of

normal cells. In addition to this mechanism, the

high cellular activity, related to the proliferation

induced by mutations, requires great synthesis

activity of various products necessary for the

progression. Cancer cells, therefore, need more

glucose than normal cells, taking advantage of

the hyperglycemia of Diabetes. Various types of

cancers have been detected by positron-emission

tomography based on this theory. In addition, the

effects of high rates of glucose in stimulating the

vasculogenesis and transformation were proved.

However, hyperglycemia is considered by some

authors as subordinate to the hyperinsulinemia as

carcinogenic factor.

10

Whereas the chronic inflammation is

related to central obesity, which is often associated

to diabetes mellitus type 2 and can be a trigger

for the carcinogenesis through pro-inflammatory

cytokines secreted by adipose visceral tissues.

These cytokines, such as adipokines, interleukin-6

(IL-6) and inhibitor of plasminogen activation 1

(PAI-1), are produced when there is excess of fat

visceral compartment and give result to chronic

inflammation of low degree in peripheral tissues,

which provides an optimal microenvironment for

tumor installation, with stimulus to blood supply

to tumors, activation of transcription factors that

increase the proliferation, survival and invasion,

and inhibition of the immune pathways of tumor

suppression.

10

The set of factors that relate the DM2 and

the carcinogenesis are summarized in the following

figure (Figure 1).

In spite of having possible common

pathways of carcinogenesis, the strong association

between cancer and diabetes depends on the type

of cancer. The current studies reveal relation of

statistically significant increase in the incidence or

in aggressiveness of cancer of some organs such

as breast, ovary and endometrium, pancreas, liver,

colon, stomach and skin in diabetic patients.

10,13-28

The increase in risk of carcinogenesis

for malignant tumors of the breast, ovary

and endometrium in diabetic patients has the

relationship between this disease and the increase

of serum levels of estrogen. This hormone has an

important function as a growth factor and has its

primary synthesis in high peripheral fat due to

metabolic disorders caused by DM, especially

when it is associated with obesity.

12-16

(7)

198 The importance of this mechanism was also

emphasized in studies that studied the relationship

of gestational diabetes (GDM) as a triggering factor

of cancer. A population study of case-control study

carried o ut in Washington with an odds ratio of

1.73 and a confidence interval of 95%, showed

that women with a history of GDM had a higher

risk of developing cancer of the endometrium

(EC) or endometrial hyperplasia (its predecessor),

especially when these arise in women under 50 years

of age and obese. Among the cases of HE/EC with

a history of GDM, 40.4% had a diagnosis of DM2.

Thus, it is estimated that as rates of obesity and type

2 diabetes mellitus increases in the United States

and abroad, the rates of EC may also increase.

17

Regarding breast cancer, other studies have

confirmed not only the increase of its incidence,

as well as its relationship with the increase of

serum levels of estrogen triggered by DM2. A

meta-analysis of 20 studies (5 case-control and

15 cohorts) developed in different countries in

North America, Asia and Europe, with a relative

risk of 1.20; with 95% of the confidence interval

between 1.12 and 1.28, came to the conclusion that

women with DM are 20% more likely to develop

breast cancer. However, this association was not so

well established when using population of women

already in menopause stage, which strengthens the

influence of estrogen levels in the pathogenesis of

this type of cancer.

15

As the cancer of the pancreas, in a

meta-analysis showed that the likelihood of initial ealy

DM2 to be a manifestation of pancreatic cancer,

while the DM2 for long term development was

considered a probable risk factor for this cancer.

The high mortality for patients with cancer of

(8)

199 the pancreas with DM2 is probably related to the

aggressive growth of the tumor, which may be

evidenced by markers of cancer as the CA19-9.

Furthermore, the insulin therapy seems to reduce

the incidence of cancer of the pancreas, probably

reducing the blood glucose and thus reducing

the supply of glucose to the tumor growth. Some

studies state association of up to 70% of cancers

with diabetes

18-21

Another study raised the association

between DM and cystic pancreatic lesions (PCLs),

an important precursor of cancers of the pancreas,

especially when associated with obesity. Insulin

resistance was considered as the central factor for

the development of PCL, however, there is a need for

further exploration to elucidate this association.

22-24

A cohort based on the population of Uppsala,

Sweden, has confirmed the risk significantly

increased of development of hepatocellular

carcinoma, as well as cancer of the pancreas in

diabetic patients, with a relative risk of 1.5. In the

same way, in two large cohorts performed in Sweden

and Denmark, and in one case-control study carried

out in Italy, DM was listed as an independent risk

factor for prevalence, recurrence and mortality for

the hepatocellular carcinoma.

13

As for colorectal cancer, a dutch

cross-sectional study carroed out in a university

hospital from the research of patients subjected to

colonoscopy, concluded an increase from 20 to 40%

in the risk of developing such cancer in diabetic

patients compared to non-diabetics. In addition,

It was detected higher presence of colorectal

adenomas and serrated polyps (precursor lesions of

cancer) in diabetic patients, compared to those who

did not have the disease.

25

_{Another study performed}

in Denmark noted further a statistically secure

increase of 12% of mortality from colorectal cancer

in diabetic patients.

26

In turn, it was observed in a meta-analysis

of 22 cohort studies an important divergence

between the relationship of risk and mortality of

gastric cancer in diabetic patients compared to

non-diabetics. Such contrast of results was interpreted by

the authors as a factor that does not allow to relate

such diseases, although in some of the cohorts used

in the present study, in addition to other studies not

included in this meta-analysis, such an association

was made.

27

When it comes to skin cancer, a retrospective

cohort study was performed involving the whole

population of Taiwan, which obtained as results

a relationship of significant increase in incidence

of skin cancers, (including melanoma and

melanoma) in diabetic patients compared to

non-diabetic patients, with ratio of the incidence rates

of 1.44 and P=0.02.

28

It is interesting to mention that not only the

condition of full diabetes, but also the pre-diabetic

state was associated with increased incidence

of cancers. A meta-analysis of 16 studies of

prospective cohort developed in different countries

in North America, Asia, Europe and Africa, came

to the conclusion that there is an increased risk of

several types of cancer (mainly liver, endometrium

and stomach/colorectal/) in pre-diabetic patients,

with statistical significance (relative risk of 1.15;

with 95% of the confidence interval between 1.06,

1.23). The authors of this study claim 15% increase

in cancer risk among pre-diabetic patients, and of

22% in overweight diabetic patients .

20

Regarding the relationship between the

use of metformin and better prognosis of cancer

in diabetic patients, a recent meta-analysis of 19

studies involving 550,882 diabetic individuals

suggested that the use of metformin reduced the

(9)

200 proportion of liver cancer in 48% compared with

those who did not use drug.

29

The results of another meta-analysis showed

that metformin exhibited greater protection for

liver cancer compared with insulin, sulfonylureas

and non-user of any diabetic medicine (MAD).

Additionally, this study showed that the use of

insulin increased the risk of liver cancer, possibly

by its mitogen action. However, this assertion

is subject to temporal bias, since insulin is

more reserved for patients with diabetes of long

duration or in more advanced stages, which may

be associated with an increased risk of developing

liver cancer.

30

_{In line with this work, it was noticed}

in a Danish study a reduction of 15% of mortality

related to colorectal cancer patients undergoing

treatment with metformin, when compared with

patients treated with insulin.

26

Although the mechanism of action of

metformin as protector for the development and

progression of cancers is not still fully elucidated,

it is possible to develop hypotheses based on their

mechanism of action. Such mechanism comprises

the blockade of gluconeogenesis (75% of its effect)

and glycogenolysis and stimulation of hepatic

gluconeogenesis. Added to this, there is the action

of glucose control, with the sensibilization of the

action of insulin, by encouraging the uptake of serum

glucose by peripheral tissue-insulin-dependent

diabetes from the increased activity of activated

protein kinase by adenosine monophosphate

(AMPK), a specific kinase that assists in regulating

energy levels, leading to increased expression of

molecules which catch glucose dependent insulin

(GLUT4) in the cell membrane. In addition, due to

not having a direct effect on the pancreatic release of

insulin and by reducing the levels of blood glucose,

this drug, indirectly, leads to reduced synthesis

of pancreatic insulin and, consequently, of its

circulating levels, avoiding the hyperinsulinemia

and its mitogens effects.

31,32

New studies also revealed that the activation

of AMPK by this drug is capable of inhibiting cell

proliferation, reducing the formation of colonies,

causing a partial shutdown of the cell cycle in

lineages of cancer cells or, at least in part, by

inhibiting the synthesis of their proteins.

10,31,32

The following figure summarizes the

effects of metformin on its targets of action and the

relationship with the reduction of tumor progression

(Figure 2).

(10)

201 Although this relationship between

metformin and protection to cancer, according to

what has been stated above, is logical, a possible

bias that makes it difficult to calculate its real

impact in epidemiological tmers is the fact that

the treatment of DM2 involves a dynamic process

in which the MADs can be exchanged continuously

and associated with other medications. This creates

great difficulty in the analysis of the benefits of the

use of metformin as monotherapy or the effects

of synergism or antagonism in protecting against

cancer when this drug is used in combination with

other MADs.

33

CONCLUSION

Diabetes and cancer are complex diseases and

of great repercussion on public health worldwide,

implying a great impact on the quality of life of the

people affected by these diseases. The association

between them is based on the principle that they

share many risk factors and pathophysiological

relationships. In addition, the scientific bodies of

research show that both metabolic and hormonal

background of DM2 including hyperglycemia,

hyperinsulinemia, changes in estrogen levels and

deregulation of pro-inflammatory cytokines, can

increase the risk of developing or progression of

cancer. On the other hand, when one takes into

account the treatment of diabetes, studies suggest

that therapy with metformin has likely protective

effect for cancer at the expense of results obtained

with other therapies, such as the exogenous insulin.

However, even with the construction of positive

evidence that strengthen and possibly confirm

such assumptions in most exploratory analyzes, a

cautious interpretation is necessary, since there is

still a need to compare and repeat the results obtained

in the present study, in addition to eliminating some

biases of research that impede the consolidation

of factual relationship between the two diseases,

including the effects of the treatment of each other.

It is believed that once well elucidated such points,

it will be possible to use metformin as a drug

associated with the treatment of cancer in diabetic

patients, as a protective factor in the progression of

both diseases for unfavorable outcomes.

ACKNOWLEDGEMENTS

To the Institutional Program of Scientific

Scholarship (PIBIC) of Montes Claros State

University, FAPEMIG for promoting this project

which originated this review article.

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