Sabtu, 31 Januari 2009

Janus Face of Glucose and Glucose-Regulating Hormones

An average person on a normal western diet consumes 0.5 kg of sugar-related carbohydrates each week, consisting of highly refined sugars in the forms of sucrose
(table sugar), dextrose (corn sugar), and high-fructose corn syrup, which comes from
many processed foods such as bread, breakfast cereals, pastries, candies, ketchup, and a plethora of soft drinks.

Since the 1850s, sugar consumption in Germany has risen 10-fold to 34 kg per person
per year. Even more dramatic findings can be made in the USA, with an explosion
in the average consumption of pure sugar from 5 lb per person per year
(1887–1890) to 135 lb of sugar per person per year in the late 1990s! This goes hand
in hand with the consequence that cardiovascular diseases and cancer was virtually
unknown in the early 1900s, but today are leading causes of death and the main reason
for an increasing mortality in the industrialized world. Therefore, it is necessary
to provide a deeper insight into the role of glucose and possible changes in the glucose metabolism in oncogenesis, especially with respect to proliferation, cell signaling and cell survival.

Metabolic Syndrome The latest statistical studies have revealed that patients with type 2 diabetes bear a higher risk for various kinds of cancer (e.g. breast, colon, kidney, liver, and pancreas) [1–3]. Type 2 diabetes can be seen as an extreme state of glucose intolerance, and is associated with elevated plasma levels of glucose as well as insulin, but also other glucose- regulating hormones are influenced by this disease. More important, this misbalanced glucose metabolism appears both a long time before and after its diagnosis, and is associated with multiple risk factors, such as increased triglyceride levels and reduced HDL cholesterol. Since most of the patients are obese, the complications mentioned are not solely specific for type 2 diabetes, but also indicators for hypertension and other cardiac diseases. All these metabolic disorders can be summarized and are best described as metabolic syndrome [4, 5].

The causes of the metabolic syndrome are still not completely understood, and up
to now there is no conclusive definition (no ICD-10 code). The actual definition for
Germany is adapted from the International Diabetes Foundation IDF [http://www.]. A common premise
is adiposity or generally a visceral obesity. Therefore, the diagnosis of the metabolic syndrome is existent when a visceral obesity is associated with at least two additional risk factors, such as increased triglyceride levels, diabetes, and reduced HDL cholesterol (or increased LDL and cholesterol).

Excess body weight is the sixth most important risk factor contributing to the
overall burden of disease worldwide. In the UK, 12 million adults and 10% of children
are now classified as overweight or obese. Average life expectancy is already diminishing;the main adverse consequences are cardiovascular disease, type 2 diabetes andseveral cancers. Obesity with its array of comorbidities requires careful clinicalassessment to identify underlying factors and to allow coherent management. The epidemic reflects progressive secular and age-related decreases in physical activity,along with substantial dietary changes combined with passive overconsumption of energy, despite the neurobiological processes controlling food intake. Effective long-term
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Incretin-Based Therapies for the Treatment of Type 2 Diabetes – DPP-4 Inhibitors and Incretin Mimetics

Current Therapies in Type 2 Diabetes
The prevalence of type 2 diabetes is rising dramatically consecutively leading to an
increase of complications of the disease. It is predicted that the total number of people with diabetes may be 370 million worldwide by the year 2030, along with a substantial rise in prediabetic conditions [1]. Since type 2 diabetes is increasing and
most patients do not reach their therapeutic goals, novel treatment options are

While insulin resistance is constant in the course of type 2 diabetes, islet function
continuously declines over time. Disease progression of type 2 diabetes is characterized by the loss of islet function. Hyperglycemia, free fatty acids, cytokines, adipokines and toxic metabolic products may lead to a loss of -cell function and -cell mass in the islets. The  cells in the islet additionally develop a disturbance of glucagon secretion. In healthy subjects, glucagon secretion is suppressed under hyperglycemic conditions,
whereas in type 2 diabetes glucagon secretion is elevated, leading to excessive
glucose production by the liver [2].
The therapeutic options currently available do not address the problem of islet-cell
dysfunction. Sulfonylureas and glinides both exclusively stimulate insulin secretion
from the  cells; metformin and glitazones act on insulin resistance, and -glucosidase delays the breakdown of complex carbohydrates. Exogenous insulin replaces the endogenous secretory insulin deficit, although it potentially causes weight gain and hypoglycemia. The progressive loss of islet function observed in type 2 diabetes is not ameliorated by any of the current therapeutic options [3].
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Altered Sex Hormone Regulation as a Possible Link between Diabetes and Breast Cancer

High endogenous plasma levels of estrogens and androgens and low plasma levels of
sex hormone binding globulin (SHBG) are strongly associated with breast cancer risk
in postmenopausal women. Obesity, a breast cancer risk factor, is characterized by
increased production of sex hormones in the adipose tissue and decreased liver production of SHBG levels [6]. A meta-analysis of 43 prospective and cross-sectional
studies, comprising 6,974 women, indicated lower levels of SHBG and higher levels of
estrogen and testosterone among patients with type 2 diabetes, compared to controls,
even after adjustment for obesity [19]. Thus, deregulation
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The IGF Pathway as a Possible Link between Diabetes and Breast Cancer

The IGF system comprises a network of ligands (IGF-1 and IGF-2), which are highly
homologous to insulin; IGF-1 receptor (IGF-1R), which shares 55% homology with
the IR; and IGF-binding proteins (IGF-BPs) [16]. The IR and the IGF-IR are capable
of forming a hybrid receptor, which, like the IGF-IR, show high affinity to IGF-1 and
lower affinity to insulin. Activation of the IGF-IR by its ligand results in activation of the same proteins and pathways activated by the insulin and IR, i.e. the IRS, SHC adaptor proteins, PI3K and MAPK. Thus, the specificity of the IGF pathway depends mainly on the ligand and its receptor, and not on the downstream parts of the cascade.
The IGF system is considered to be a key regulatory pathway in breast cancer
and is an attractive target for the development of novel breast cancer therapies. High circulating levels of IGF-1 and IGF-BP3 are associated with increased risk of premenopausal breast cancer, and increased IGF-1 is considered to be a link between
obesity to increased risk of breast cancer [17]. However, type 2 diabetes usually affects postmenopausal women and, controlled for obesity, blood concentrations of IGF-1,IGF-2, and their binding proteins are usually not raised and may actually be reduced in both type 2 diabetes mellitus and the metabolic syndrome [18]. These findings suggest that the IGFs and the IGF-BPs may not play a major role in the association between diabetes and breast cancer. A high concentration of insulin could stimulate the IGF pathway in type 2 diabetes through the non-specific activation of the IGF-1R and the IGF-1R/IR hybrid receptor. However, the importance of this mechanism in the pathogenesis of breast cancer remains to be defined.
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Diabetes Mellitus and Breast Cancer: Possible Associating Mechanisms

Four major mechanisms may contribute to the association between type 2 diabetes
mellitus and breast cancer (fig. 2): activation of the insulin pathway, activation of theinsulin-like growth factor (IGF)-1 pathway, altered regulation of endogenous sex hormones,altered regulation of adipocytokines.The Insulin Pathway and Breast CancerInsulin is a polypeptide hormone secreted from pancreatic -cells in response to elevationin glucose levels [7]. The first step in activation of the insulin pathway is bindingof insulin to the insulin receptor (IR). The primary targets for insulin are skeletalmuscle, adipose tissue and the liver, however many other tissues, including normalbreast tissue and breast cancer, express the IR. The IR is a tyrosine kinase receptor,composed of two extracellular -subunits and two transmembrane -subunits. Insulinbinding leads to autophosphorylation of tyrosine residues in the intracellular subunitsand thus activates the tyrosine kinase. Once activated, the IR phosphorylates a numberof intracellular proteins, including members of the insulin receptor substrate family(IRS) and SHC adaptor protein. Binding of IRS to the IR leads to activation the phosphatidylinositol3-kinase (PI3K), which turns on the Akt pathway. Binding of Shc tothe IR leads to activation of the extracellular signal-regulated kinase (ERK) cascade,one of the mitogen-activating protein kinase (MAPK) pathways [8]. Although themajor role of insulin is metabolic, both the Akt and the MAPK pathways also have
important roles in tumorigenesis. Indeed, insulin was found to stimulate cell cycle progression in MCF-7 breast cancer cells either by itself or synergistically with estradiol[9]. IRS-1 may also interact directly and activate the estrogen receptor (ER). Thus,activation of the insulin pathway may also affect the ER pathway [10].
The IR has a major role in the activation of the insulin pathway in breast cancer.
The IR is expressed and can be stimulated by insulin in breast cancer cell lines, and
overexpression of it can induce malignant transformation in breast epithelial cell lines.Stimulation by progestins, inactivation of p53 or activity of oncogenes such as Wnt-1, Neu and Ret can lead to overexpression of the IR in breast cancer [11].
Several clinical studies have investigated the role of the insulin pathway, and
mainly the part played by the IR, in breast cancer. Papa et al. [12] measured IR content in 159 breast cancer specimens and found it to be sixfold higher than in 33 samples of normal breast tissues, and also higher than in other normal tissues, including the liver. High IR content correlated positively with tumor size, grade and ER content. Mathieu et al. [13] found detectable IR levels in 444 of 584 (76%) breast cancer specimens and found it to be a strong predictor of disease-free survival. Similarly, analysis of IR expression in a cohort of 191 early breast cancer patients revealed an association between high IR expression and favorable prognostic factors and improved diseasefree
and overall survival [14].
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Diabetes Mellitus and Breast Cancer

Breast cancer is the most common malignant neoplasm in women, affecting 1 of every
8 women. The estimated new breast cancer cases and deaths among women in the
USA in 2007 are 178,000 and 40,000 respectively [1]. Type 2 diabetes is another major
health problem in developed countries, and affects about 7% of adults and about 15%
of people older than 60 years [2]. The main risk factors for type 2 diabetes are old age obesity, and genetic predisposition. Similarly to type 2 diabetes, the incidence of breast cancer rises with age, and the cumulative incidence in Western Europe and the USA is about 2.7% by age 55, about 5.0% by age 65, and about 7.7% by age 75. Breast cancer is associated with multiple risk factors, which are commonly divided into modifiable and non-modifiable. Non-modifiable risk factors include family history of breast cancer, germline mutations in breast cancer susceptibility genes including BRCA1, BRCA2,

P53, PTEN, and ATM, hormonal factors such as younger age at menarche and older
age menopause, and the presence of benign breast disease [3]. Modifiable risk factors
include low parity, use of oral contraceptives and hormone replacement therapy, alcohol
consumption, obesity, and lack of physical activity [3].
Breast cancer and diabetes commonly occur together, and up to 16% of older
breast cancer patients may suffer from diabetes [4]. An association between diabetes
and various types of cancer was first reported more than 100 years ago and diabetes is now recognized as a risk factor for several types of cancer, including endometrial and pancreatic carcinoma [5]. In recent years, a growing number of data, both laboratory and clinical, suggest complex associations between type 2 diabetes mellitus and breast cancer (fig. 1). Diabetes may have direct biologic effects on breast cancer risk, clinical and pathological characteristics, and outcome. Moreover, certain antidiabetic therapies may have direct activity against breast cancer. Diabetes may also affect breast cancer outcome indirectly, and have been shown to influence medical decision-making regarding screening and management of breast cancer. Obesity, which affects more than 20% of the population in developed countries, is a major risk factor for the development of type 2 diabetes. It is also a well-established risk factor for breast cancer and is associated with increased risk for the development

of postmenopausal breast cancer, but with reduced breast cancer risk among premenopausal women [6]. Obesity is also a poor prognostic factor and is associated
with adverse outcomes in both pre- and postmenopausal women with breast cancer.
Mechanisms connecting obesity to postmenopausal breast cancer include altered regulation of estrogen and adipocytokines levels, and increased insulin synthesis. Thus, obesity is a major confounding factor in many studies regarding the association
between diabetes and breast cancer.

Ido Wolf Tamar Rubinek
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Diabetes Mellitus and Cancer – A Conclusion

Many studies have suggested that diabetes mellitus type 2 may alter the risk of developing a variety of cancers, and the associations are biologically plausible. One of largest prospective studies worldwide, enrolling 467,922 men and 588,321 women
who had no reported history of cancer at the time of enrollment, revealed after 16
years of follow-up that diabetes was significantly associated with fatal colon cancer in men and women, and with PC in men, and significantly associated with liver cancer and bladder cancer. In addition, diabetes was significantly associated with breast cancer in women [61]. These findings strongly suggest that diabetes is an independent predictor of mortality from these cancer entities.
When treating cancer patients who have diabetes, clinicians must consider the cardiac, renal, and neurologic complications commonly associated with diabetes; continued improvement of cancer outcomes may also depend upon improved diabetes control [62].
Diabetes rates continue to skyrocket – nearly 21 million people in the USA are
afflicted by diabetes and roughly 250 million worldwide. Health analysts project that
by 2025, 50 million Americans and up to 380 million globally will have diabetes. The
International Diabetes Federation, which tracks global diabetes, says the disease will cause 3.8 million deaths worldwide in 2007, about equal to HIV/AIDS and malaria
combined. In the USA, the Centers for Disease Control and Prevention state that diabetes is the sixth leading cause of death, contributing to nearly 225,000 deaths in 2002, up from 213,064 in 2000 – there is a ‘growing tsunami of diabetes’.
Considering the numerous results of epidemiologic and clinical studies involving
diabetes mellitus and malignancies, clinicians must also consider the increased risk of new-onset and longstanding diabetics for some tumor entities by regularly screening diabetic patients for early development of tumors.
The association between diabetes and cancer is complex and warrants further and
differentiating types of clinical studies – from molecular epidemiology to clinical
interventions. The general population ages and the magnitude of both health problems
continues to grow. As one consequence, scientists, clinicians and politicians
have to develop national policies for early diagnosis and prevention of diabetes mellitus and cancer more effectively, otherwise both diseases and their biologic and sociologic relationships could likely overwhelm health systems.
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Diabetes and Its Relationship to Pancreatic Carcinoma

The link between pancreatic cancer (PC) and diabetes mellitus is recognized, however
controversy still exists because no criteria have been established for the efficient
selection of a high-risk group among patients with diabetes mellitus. Regulation of
endocrine cell mass is thought to have a central role in the pathogenesis of both diseases.
The processes that operate during pancreatic adaptation to a changing hormonal
milieu are important in pancreatic carcinogenesis. There is evidence that
somatostatin and its receptors are fundamental regulators of endocrine cell mass and
are involved in islet tumorigenesis [57].
A hospital-based case-control study revealed that cigarette smoking, family history
of PC, heavy alcohol consumption (60 ml ethanol/day) and diabetes mellitus
are significant risk factors for PC. The significant synergy between these risk factors
suggests a common pathway for carcinogenesis of the pancreas [58].
Because of the poorly understood temporal association between diabetes mellitus
and PC, a research group at the Mayo Clinic College of Medicine, Rochester,
Minn., USA [59] compared temporal patterns in diabetes prevalence in PC and
controls. Diabetes has a high prevalence in PC and frequently is now onset.
Longstanding type 2 diabetes increases the risk of PC by approximately 50%.
Furthermore, there seems to be a positive association between obesity and PC [60].
However, as the mechanisms for these associations remain speculative, further
studies are deserved. Above all, there is an urgent need for the identification of
specific biomarkers for PC-induced diabetes, which may allow screening for PC in
new-onset diabetes.
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The Metabolic Syndrome, Diabetes and Steatosis and Incidence of Hepatocellular

Carcinoma The incidence of hepatocellular carcinoma (HCC) is increasing, but the temporal changes of risk factors remain unclear. A significant proportion of HCC develops in cryptogenic cirrhosis, and may present the most worrisome complication of non-alcoholic

steatohepatitis. Non-alcoholic steatohepatitis is tightly linked to insulin resistance and several features of the MeS, e.g. obesity, diabetes and dyslipidemia.
A systemic review and meta-analysis of a total of 26 studies revealed that diabetes
is associated with an increased risk for HCC [50]. A population-based case-control
study in the USA documented that diabetes increases the risk of HCC two- to threefold, regardless of the presence of other major HCC risk factors. Findings from this study suggest that diabetes is an independent risk factor for HCC [51]. Databases from the Surveillance & Risk Assessment Division of Health Canada & Statistics Canada were analyzed for trends in both age-adjusted incidence of and mortality due to HCC from 1984 to 2001 [52]. The incidence of HCC in Canada has increased in the past 20 years and is associated with a rise in the incidence of hepatitis C, obesity and diabetes. Similar results are reported by two studies from Taiwan [53] and Japan [54].

It is likely that the association of HCC with obesity and diabetes represents the
progression of underlying non-alcoholic fatty liver disease to cirrhosis. The mechanisms most likely involve replicative senescence of steatotic mature hepatocytes and compensatory hyperplasia of progenitor cells as a reaction to chronic injury due to ongoing non-alcoholic steatohepatitis [55] and inflammation [56].
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Hyperinsulinemia and Insulin Resistance Linked to Colorectal Cancer

Non-insulin-dependent diabetes mellitus (NIDDM) seems to be one risk factor for
colorectal cancer. Usually, in the pre-NIDDM state, hyperinsulinemia is seen for several years. Insulin is a growth factor of epithelial and cancer cells of colon and rectum. At the Department of General Surgical Science, Gumma University, Gumma, Japan [46], patients suffering from colorectal cancer but never diagnosed for diabetes, were tested for glucose tolerance. Serum glucose and insulin levels were found to be higher in cancer patients than in controls. The authors concluded that hyperinsulinemia may be one of the causes of colorectal cancer and should be controlled to prevent recurrence of colorectal cancer even after curative resection. Mechanistically, hyperinsulinemia has been associated with insulin resistance, increased levels of growth factors, including IGF-1, and alterations in NF-B and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. The insulin resistance colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasized the potential for this cancer to become a modifiable disease [47]. This hypothesis is supported by results from a prospective study including anthropometric and clinical measurements associated with insulin resistance syndrome and colorectal cancer in malesmokers [48].

A cohort study on the impact of diabetes within a large randomized adjuvant
chemotherapy trial of 3,759 patients with high-risk stage II and stage III colon cancer was carried out in 2003 at the Dana-Farber Cancer Institute, Eastern Cooperative Oncology Group Statistical Center, and Channing Laboratory, Department of
Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston,
Mass., USA [49]. Patients with diabetes and high-risk stage II and stage III colon cancer experienced a significantly higher rate of overall mortality and cancer recurrence. Median survival was 6.0 and 11.3 years for diabetics and non-diabetics, respectively. In various animal models, it could be shown that insulin and insulin-like growth factor axes and insulin resistance are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. Clinical conditions associated with hyperinsulinemia and increased IGF-1 levels are related to an increased risk of colon cancer. Global nutrition studies [39] indicate that dietary patterns that stimulate insulin secretion and resistance, including a high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated w ith a higher r isk of c olon c ancer. E fforts to c ounter t hese p atterns are likely to have the most potential to reduce colon cancer incidence and tumor recurrence.
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Metabolic Syndrome and Risk of Colorectal Adenoma Development

Two Asian-Pacific Epidemiologic Studies showed an increased risk of colorectal adenoma
development associated with MeS: (1) the Self-Defense Forces Health Study, carried
out between 1995 and 2002 at two Self Defense Forces hospitals in Japan [44] and
(2) one study carried out at the Center for Health Promotion, Samsung Medical Center,
Seoul, Korea, between March 2004 and December 2005 [45]. Both studies included
subjects who underwent colonoscopy as a s creening examination for polyps. Apart
from the association of MeS with colorectal adenoma, an increased risk for MeS was
more evident for proximal than distal colon, for multiple (3), and for advanced adenoma.
Abdominal obesity of the individual components of MeS was an important risk
factor for colorectal adenoma. Thus, the MeS appears to be a crucial entity with regard
to the prevention of colorectal adenoma and consequently colorectal cancer.
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Metabolic Syndrome and Risk of Prostate Cancer

Currently, there is a debate whether MeS predicts the incidence of prostate cancer.
The hypothesis was tested using the 27-year follow-up of the prospective cohort of
the Oslo Study in 1972–1973. MeS was found to predict prostate cancer during 27
years of follow-up, indicating an association between insulin resistance and the incidence
of prostate cancer [33]. Features of the MeS, specifically abdominal obesity and
hypertension, are also associated with prostate cancer in African-American men [34],
a population which is more prone to developing MeS symptoms.
A conducted nested case-control study within the Northern Sweden Health and
Disease Cohort Study found an increased risk of prostate cancer in men with elevated
IGF-1, suggesting that circulating IGF-1 may be specifically involved in the early
pathogenesis of prostate cancer [35]. An extension of this study by measuring levels
of IGF-1 and IGFBP-3 in prediagnostic blood samples from a total of 281 men who
were subsequently diagnosed with prostate cancer supported that IGF-1 is an etiologic
factor in prostate cancer. The circulating IGF-1 levels measured at a comparatively
young age may be most strongly associated with prostate cancer risk [36].
Despite a growing amount of epidemiologic literature suggesting an association
between MeS and prostate cancer risk, there is also growing evidence of an inverse association
between history of diabetes – one feature of MeS – and risk of incident prostate
cancer. The CaPSURE Study, a community-based prostate cancer registry study,
revealed that a history of diabetes was not associated with any diagnostic clinical parameter
or with treatment-specific recurrence rates for prostate cancer. Only among men
with a low prognostic risk or who were younger at prostate cancer diagnosis, being diabetic
(versus not being diabetic), was there a tendency of association in a multivariate
analysis with an elevated risk of recurrence after radiation therapy [37]. The NIH-AARP
Diet and Health Study disclosed an inverse association between diabetes and prostate
cancer which was particularly strong among men in the highest category of routine
physical activity at work or at home [38]. This relationship strengthens the importance
of high levels of routine physical activity, either for the prevention of prostate cancer
and/or cancer in general [39] and MeS. Gonzalez-Perez and Garcia Rodriguez [9] used
the General Practitioner Research Database in the UK and found that diabetic patients
had a decreased risk of prostate cancer. Interestingly, this association was observed
among treated diabetics but not among untreated diabetics. They discussed the possibility
that the observed risk could be restricted to users of insulin or sulfonylureas, a very
provocative hypothesis considering the mode of action of these therapeutics.
Werny et al. [40] investigated the association between diabetes and prostate-specific
antigen levels, controlling for potential confounders, in a nationally representative
cross-sectional survey of the US population (National Health and Nutrition Examination
Survey, 2001–2002). The reported results are consistent with the hypothesis that
long-term diabetes is associated with a lower risk of prostate cancer.
Diabetes seems to be associated with a reduced risk of prostate cancer, but whether
the MeS is also associated with prostate cancer is marginally established. Therefore,
Tande et al. [41] assessed this association in the Atherosclerosis Risk in Communities
(ARIC) Study. When diabetic participants were excluded, the inverse association
between MeS and prostate cancer incidence was slightly strengthened.
Diabetes may be a protective factor for prostate cancer since both were found to be
negatively associated. Based on the same genetic background, parents of diabetic
patients might show similar risks concerning cancers. Meyer et al. [42] investigated
family history in as far as genetic factors may play an important role in the negative
association between diabetes and prostate cancer. Mothers of diabetic patients
showed an increased history of cancers of the liver and biliary tract. Fathers of
patients suffering from type 2 diabetes were diagnosed less frequently with prostate
cancer compared to fathers of non-diabetic controls. The first genome-wide association
scan to search for sequence variants conferring risk of prostate cancer was performed
within a population of 1,501 Icelandic men with prostate cancer and 11,290
controls. It was found that two variants on chromosome 17 confer prostate cancer
risk; one of the variants is in TCF2 (HNF1), a gene known to be mutated in individuals
with maturity-onset diabetes of the young type 5. However, results from eight
case-control groups, including one West African and one Chinese, demonstrate that
this wild-type confers protections against type 2 diabetes [43].
Prostate cancer is an example of the complexity of carcinogenesis associated with
MeS and/or diabetes. On the one hand, an association between diabetes, IGF-1,
hyperinsulinemia and insulin resistance appears plausible, but on the other, these features
can be somewhat counterbalanced as well and reduce hereby the risk for the
development of one of the leading cancer entities worldwide.
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Risk of Endometrial Cancer and Diabetes Mellitus Type 2

A meta-analysis based on 16 studies (3 cohort and 13 case-cohort studies) showed for
12 studies a statistically significantly increased risk and for 4 studies a non-significant increased risk of endometrial cancer [24]. The association between diabetes and incidence of endometrial cancer and the potential effect of modification by obesity and physical activity was prospectively examined in the Swedish Mammography Cohort

Study. Diabetes was associated with a twofold increased risk, and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer [25]. Therefore, interventions to reduce body weight and increase physical activity may have important implications in terms of endometrial cancer and future management of diabetic subjects.
In 1986, Folsam et al. [26] obtained risk factor information on 41,836 women aged
55–66 years living in Iowa. They followed those initially free of cancer through to 2000 and identified incident endometrial cancers via linkage to a cancer registry. Diabetes was associated with poorer survival after incident endometrial cancer, independent of tumor stage and grade. The findings support the possibility of a diabetes-related condition, such as hyperglycemia or hyperinsulinemia, contributing to poorer endometrial cancer survival. A case-control study, which was nested within three cohorts in New York (USA), Umeå (Sweden) and Milan (Italy), investigated for the first time prospectively
the association of prediagnostic blood concentrations of C-peptide, a marker of
pancreatic insulin production, IGF-1, (insulin-like growth factor binding protein,
IGFBP) IGFBP-1, -2 and -3 with endometrial cancer risk. Chronic hyperinsulinemia, as
reflected by increased circulating C-peptide, was associated with increased endometrial cancer risk. Risk was unrelated to levels of IGF-1, IGFBP-2 and IGFBP-3 [27].
A German study (charts abstracted from patients with endometrial cancer from
1985 to 1995) investigating the influence of diabetes mellitus type 2 and nodal distribution in endometrial cancer showed a univariate correlation between lymph node
involvement and diabetes [28]. The extension of this study to the year 2003 revealed
by multivariate analysis that diabetes mellitus type 2, FIGO stage and depth of
myometrial invasion were significantly associated with overall survival [29].
A case-control study performed in Italy and Switzerland found a supramultiplicative
effect for obese diabetic women and risk of endometrial cancer [30]. Obesity is a
well-known risk factor for the development of endometrial cancer, however weight
alone does not account for all cases. Insulin resistance also contributes to an increased risk for endometrial cancer. Adiponectin is a protein secreted by adipose cells and has been shown to be a surrogate marker for insulin resistance, with low levels of adiponectin correlated with hyperinsulinemia and a degree of insulin resistance.

Indeed, women with endometrial cancer were more likely to have low adiponectin
levels than controls, even after adjusting for body mass index. This suggests that
insulin resistance is independently associated with endometrial cancer [31] and
insulin resistance/hyperinsulinemia is associated with poorly differentiated endometrial adenocarcinomas and a more aggressive course of the disease [32].
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Breast Cancer Risk and Diabetes Mellitus Type 2

Upper body obesity and the related metabolic disorder type 2 diabetes have been
identified as risk factors for breast cancer, and associated with late-stage disease and poor prognosis. Components of the MeS, including visceral adiposity, insulin resistance,hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus type 2, low serum HDL cholesterol and hypertension have all been
related to an increased risk of breast cancer [10]. One of the hallmarks of aggressive cancer cells is a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA. The breast cancer gene 1 (BRCA-1) stabilizes the inactive (phosphorylated) form of the acetyl coenzyme A carboxylase , the rate-limiting enzyme catalyzing de novo fatty acid biogenesis. Therefore, one mode of action of BRCA-1 is a tumor suppressor activity which depends on its ability to mimicry a cellular low-energy status, which is also known to block tumor cell anabolism and suppress the malignant phenotype. It is interesting to see that physical activity and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA-1 gene mutations [11].
The adipocytes, forming the belly fat, are now in the focus of metabolic research in
oncology. Adipocytes produce adipocytokines, which are biologically active polypeptides and act by endocrine, paracrine, and autocrine mechanisms; most have been associated with MeS. Six adipocytokines – vascular endothelial growth factor, hepatocyte growth factor, leptin, tumor necrosis factor-, heparin-binding epidermal
growth factor-like growth factor, and interleukin-6 – promote angiogenesis. Obesity
and insulin resistance, again, have been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis [12]. However, the picture is not as clear as to be expected because a case-control study in Chile did not show any association between obesity and breast cancer at any age, although the same study revealed that insulin resistance was independently associated with breast cancer in postmenopausal women, but not in premenopausal women [13].
Insulin growth factors (IGFs) are important mediators of growth, development,
differentiation and survival of normal and transformed cells. Recent studies confirmed the association between serum levels of IGF-1 and diverse malignant diseases, while some relationships with other pathologies since diabetes mellitus type 2 have been described. Currently, IGFs are considered important targets for the study of new therapeutic drugs and strategies for cancer treatment [14].
A meta-analysis of case-control (n  5) and cohort studies (n  15) to assess the
evidence regarding the association between diabetes and risk of breast cancer yielded
a summary RR of 1.24 for women with (versus without) diabetes. Findings from this
The Epidemiologic Relationship between Diabetes and Cancer 87
meta-analysis indicate that diabetes is associated with an increased risk of breast cancer
[15]. However, it is important to know for diagnostic purposes that, although the
breast cancer risk is increased among women with type 2 diabetes, type 2 diabetes
does not significantly influence mammographic breast density [16].
The role of diabetes in the etiology of breast cancer in Asian-Americans is of special
interest because of their consumption of soy. A population-based case-control
study in Los Angeles County that included 1,248 Asian-American women with incident,
histologically confirmed breast cancer and 1,148 control women, who were frequency
matched to cases on age, Asian ethnicity and neighborhood of residence,
showed that the diabetes-breast cancer association was observed only in low/intermediate
soy consumers but not among high soy consumers [17].
Another question is becoming increasingly common: How does gestational diabetes
relate to future risk of disease? The Jerusalem Perinatal Study, including 37,926 women,
suggests that gestational diabetes may be an important early marker of breast cancer risk
among postmenopausal women; however, the authors clearly state that these results
need to be confirmed in future studies [18]. Another study in Israel revealed after adjustment
for body mass index that breast cancer among diabetic patients was more often
hormone receptor negative [19]. Population-based health databases from Ontario,
Canada, used for retrospective cohort studies showed that diabetes was associated with
a close to 40% increase in mortality within the first 5 years following breast cancer,
which means that early survival following breast cancer is reduced in women with diabetes
[20]. Results from the same databases indicate that women with diabetes were less
likely to have a mammogram during a 2-year period than were women without diabetes,
despite more healthcare visits. These findings highlight the need for better organization
of primary care for patients with chronic diseases, like diabetes and/or cancer [21].
It has been recently shown that activation of the AMP kinase pathway is necessary
for metformin to inhibit gluconeogenesis in hepatocytes. This pathway is also
involved in metformin-induced growth inhibition of epithelial cells. Breast cancer
cells escape metformin-induced growth inhibition by small interfering RNA against
AMP kinase. These results provide evidence for a mechanism that may contribute to
the antineoplastic effects of metformin suggested by some population studies and
stress the potential role for activators of AMP kinases in (breast) cancer prevention
and treatment [22, 23].
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The Epidemiologic Relationship

The Epidemiologic Relationship
between Diabetes and Cancer
Kurt S. Zänker

Institute of Immunology and Experimental Oncology, University of Witten/Herdecke,
Witten, Germany Abstract There is a growing amount of epidemiologic literature suggesting an association between history of metabolic syndrome/diabetes and risk of developing a variety of cancers. Data of populations from different hospital- and community-based case-control studies, from cancer registries and a health survey suggest that metabolic syndrome/diabetes mellitus type 2 are associated with an increased risk of cancer or are even independent predictors of mortality from cancer of the colon, pancreas, hepatocellular carcinoma, femalebreast and endometrium, and in men of liver and bladder. However, the association is still complex because
some studies show controversial results of even a lower risk of cancer, e.g. for prostate cancer, in diabetic than in non-diabetic subjects. An association between diabetes, hyperinsulinemia, insulin resistance, insulin-like growth factors, lipotoxicity, obesity, adipokines, Western-style dietary habits and carcinogenesis appears plausible, yet clusters of increased or reduced risk factors need to be confirmed in future studies. Evidence from the intensive care literature indicates that achieving glucose control leads to a better outcome in clinical
oncology. If so, continued improvement of cancer outcomes may also depend upon improved diabetes control. As the general population ages, the magnitude of both health problems continues to grow and could overwhelm health systems. It is prime time to break the growing tsunami of both diseases by community-based prevention programs. Copyright © 2008 S. Karger AG, Basel The metabolic syndrome (MeS) encompasses a constellation of metabolic disorders that places patients at high risk for the development of cardiovascular diseases and diabetes mellitus type 2, and possibly cancer. The MeS is the concurrence of hypertension, abdominal obesity, impaired fasting blood glucose, dyslipidemia, e.g. low levels of high-density lipoproteins (HDL) cholesterol, and insulin resistance. The diagnostic concept of MeS is still controversially discussed, which is illustrated on the basis of
recent primary-care data from Germany and the Centers for Disease Control and
Prevention. In Germany, the prevalence ranges from 19 to 31% [1] and in the USA
about 22% of the adults have MeS according to the currently existing definitions. The
book on MeS as a clinically valuable indicator for estimating the risk of diabetes
The Epidemiologic Relationship between Diabetes and Cancer 85 mellitus type 2, cardiovascular morbidity and mortality is not yet closed. However,
many people afflicted by MeS will develop type 2 diabetes. By 2010 it is suggested that 30 million people in Europe will suffer from diabetes, creating a huge burden on the health service and the economy, not to forget the individuals themselves; to close thiscircuit of syndromes, many of these people will have features of the MeS.
Although the pathogenesis of MeS is under debate, it is now realized that insulin
resistance plays a principle role in initiating and perpetuating the pathological manifestations of the MeS [2]. Studies have shown that MeS and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis and clinical study protocols are designed to understand in more detail the role of insulin and insulin resistance in cancer-struck subjects [3]. Therefore, basic and clinical science will face a twofold problem in the future, timely summarized by the following questions: (1) how does a clinically manifested diabetes or prediabetes (comorbidity) influence the outcome of a cancer disease (mortality), and (2) how is type 2 diabetes associated with cancer incidence?
A recently published study on the glucose tolerance status and 20-year cancer incidence within a sample of a Jewish Israeli population (n  2,780) showed an increased long-term cancer risk for individuals with impaired fasting glucose or diabetes [4].

The Vasterbotten Intervention Project of Northern Sweden showed an association of
hyperglycemia with total cancer risk in women and in women and men combined for
several cancer sites, independently of obesity [5]. A case-control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort supports the view that the presence of obesity, hypertension and hyperglycemia increase the risk of colorectal cancer [6].
A cross-sectional study investigated the question of comorbidity and reduced
health-related quality of life (HRQL) in patients that have either diabetes or cancer.

The data from the Public Use File of the Canadian Community Health Survey
revealed that individuals with diabetes and cancer had a clinically important and significantly lower HRQL than those with either conditions alone [7].
An association between diabetes mellitus type 2 and cancerogenesis appears
plausible, considering the complexity of the mode of action of insulin (pro- and
pre-insulin), insulin-like growth factor and the appropriate receptors, including the
type of oral antidiabetic drugs. It was found that patients with type 2 diabetes
exposed to sulfonylureas and exogenous insulin had a significantly increased risk of
cancer-related mortality compared with patients exposed to metformin; the cause
of this in-/decreased risk-related effect remains speculative [8]. Interestingly, an
evaluation of the General Practitioner Research Data in the UK suggests that
patients with diabetes have a reduced risk for prostate cancer when using insulin or
sulfonylureas [9].

All the epidemiological studies involving diabetes mellitus type 2 and malignancies
do have limitations, e.g. differences in treatment modalities, lifestyle and nutrition behavior, race and genetics of participants. A promising way to give some
86 Zänker answers is to focus on specific tumor entities in order to develop tumor-specific and individualized management strategies.
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