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Diabetes mellitus and cancer
European Journal of Internal Medicine 11 (2000) 245–252 www.elsevier.com / locate / ejim
Review article
Diabetes mellitus and cancer ~ *, Zdzisl«awa Szczepanik Artur Czyzyk Department of Gastroenterology and Metabolic Diseases, Central Clinical Hospital, University Medical School of Warsaw, ul. Banacha 1 A, PL-02 -097 Warsaw, Poland Received 11 November 1999; received in revised form 27 March 2000; accepted 3 April 2000
Abstract Although an association between diabetes and cancer was found over 100 years ago, the issue underwent different interpretations over the subsequent decades, and only modern, prospective, epidemiological cohort and case-control studies conducted in several countries have provided reliable evidence of an increased cancer risk in diabetic patients, mainly in those with type 2 diabetes. This risk varies according to the tumor site: it is the greatest for primary liver cancer, moderately elevated for pancreatic cancer, and relatively low for colorectal, endometrial, breast, and renal cancers. The cause of the association is not clear and remains the subject of different hypotheses. The most frequently cited reason is the potential effect of insulin. Found in high concentrations, due to insulin resistance in most patients with type 2 diabetes, this hormone is believed to express a mitogenic effect. This hypothesis needs to be confirmed in appropriately programmed prospective studies, but it may already be helpful in choosing an adequate treatment for type 2 diabetes to achieve optimal metabolic control with a simultaneous reduction in hyperinsulinemia, such as diet, physical exercise, metformin, and acarbose. 2000 Elsevier Science B.V. All rights reserved. Keywords: Diabetes; Cancer; Hyperinsulinism
1. Introduction Studies of the relationship between diabetes mellitus and cancer have a long history, with the first reports already published at the end of the 19th century [1,2]. More adequately directed studies were initiated after the introduction of insulin treatment which, while prolonging the patients’ life span, resulted in an increased cancer prevalence in those same patients [3]. Three stages can be distinguished in the research. In the second and third decades of the ‘insulin era’, the first substantial reports, based on postmortem examinations, suggested an increased incidence of different cancers in diabetic patients. However, the reliability of the studies was limited because it was difficult to establish the actual morbidity and to select matched control groups [4–6]. The second stage of the research (4th and 5th decades) focused *Corresponding author. Tel.: 148-22-659-7563; fax: 148-22-6597563.
on analyzing the association using more specific epidemiological methods. However, it provided only partial confirmation of the previous reports. An analysis of 21 447 deaths among diabetic patients over a period of 26 years (1930–1956) conducted at the Joslin Clinic in Boston showed that the ratio of the observed number of cases of pancreatic cancer to that which was expected was 30:20 in men and 48:23 in women. In 90% of those cases, the diagnosis of diabetes had preceded the diagnosis of cancer [7]. Also, a 25-year-long prospective study (1945–1969) of 1135 residents of Rochester with diabetes mellitus showed that the relative risk for pancreatic cancer was only slightly higher in that group than in the general population, namely, 4.3 (95% CI52.0–8.1). After excluding the first year following the diagnosis of diabetes, the risk was 2.6 (95% CI50.9–6.1) [8]. Other cancers diagnosed more frequently at that time were endometrial and breast neoplasia. The third stage of epidemiological research, carried out in the 6th and 7th decades of the ‘insulin era’, consisted of
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well-prepared and well-documented studies based on a prospective analysis of cancer incidence and mortality among diabetic patients and included both populationbased cohort and case-control studies. Conducted mainly in the Scandinavian countries, the US, Great Britain, Germany, and Switzerland, they provided reliable evidence of an increased risk of different cancers in the diabetic population, particularly in patients with type 2 (non-insulin-dependent) diabetes (Table 1).
primary role of pancreatic cancer in its association with diabetes. Diabetes due to pancreatic cancer is characterized by a short course, a negative family history, the absence of obesity, and a rapid progression to insulin dependence. The onset of such atypical diabetes at a later age seems to suggest cancer of the pancreas and requires an adequate diagnostic protocol.
3. Primary liver cancer 2. Pancreatic cancer The association of pancreatic cancer with diabetes mellitus has been reported most frequently. In the Everhardt and Wright meta-analysis of 20 case-control and cohort studies, which included cases of diabetes diagnosed at least 1 year prior to the diagnosis or death from pancreatic cancer, the pooled relative cancer risk for the diabetic patients was 2.1 (95% CI51.6–2.8); it was somewhat higher in nine cohort studies (2.6; 95% CI5 1.6–4.1) than in 11 case-control studies (1.8; 95% CI5 1.1–2.7) [27]. An increased incidence of pancreatic cancer among diabetic patients was also found in nationwide, population-based cohort studies carried out in Denmark and Sweden [10,11]. However, the most frequent caveat concerned the place of diabetes in the association (‘the hen or the egg?’). A convincing answer appears to be provided by the studies proving that diabetes most often precedes the onset of the symptoms and signs of pancreatic cancer. In the Whitehall Study, after excluding earlier cases of pancreatic cancer, in the period of more than 10 years after the diagnosis of impaired glucose tolerance (IGT), the relative risk of developing pancreatic cancer was 3.3 (95% CI51.4–7.9), and after the diagnosis of diabetes mellitus it was 5.7 (95% CI51.4–24.0) [9]. In the Swedish population-based cohort study, after 10 or more years following the first hospital admission for diabetes mellitus, the standardized incidence ratio (SIR) for pancreatic cancer was 1.7 (95% CI51.4–2.1) and did not differ significantly from values after 5–9 years of follow-up [10]. In the Everhardt–Wright meta-analysis, patients with a 5-year or longer history of diabetes showed a relative risk for pancreatic cancer of 2.0 (95% CI51.2–3.2) [27]. Recently published results of a population-based, case-control study of pancreatic cancer conducted in three areas of the US also demonstrated an increased risk for this cancer, by 70% in patients with diabetes of 5–9 years’ duration and by 50% in patients with at least a 10-year history of diabetes [12]. Interestingly, an Italian multicenter study of the medical history of a large group of patients (n5720) with pancreatic cancer showed that a diabetes-associated increase in the risk for the tumor was limited only to the first 1–10 years of diabetes (type 2) duration; no increased risk was found among patients with a longer history of the disease [28]. Clinical evidence also raises doubts about the
A study of the causes of mortality in 32 222 diabetic patients in the Osaka district of Japan in the period 1960– 1989 showed a significant increase in the number of deaths due to primary liver cancer. Although the standardized mortality ratio (SMR) for malignant neoplasms at all sites remained unchanged for the entire study period, the ratio for liver cancer doubled [29]. Three recent studies yielded convincing evidence of an increased incidence of primary liver cancer in diabetic patients: population-based cohort studies conducted in Denmark and in Sweden, and a case-control study carried out in northern Italy. The Danish study showed that the incidence of primary liver cancer in the diabetic cohort was four-fold in men, two-fold in women, and slightly increased in patients who were under 50 years of age when they entered the study [11]. In the Swedish study, the incidence of primary liver cancer in diabetic patients was four-fold in men and more than three-fold in women as compared to the figures for the general population. After exclusion of patients with diseases predisposing to liver cancer (hepatitis, hepatic cirrhosis, hemochromatosis, alcoholism), the risk still remained three times higher. Completion of the follow-up or the duration of diabetes prior to the diagnosis of primary liver cancer had no significant effect on SIR, which was almost the same in men and women regardless of the duration of diabetes: for 1–4 years or 15–24 years in men it was 4.8 (95% CI54.1–5.7) and 4.8 (95% CI52.7–7.8), and in women its value was 3.6 (95% CI52.9–4.5) and 3.0 (95% CI51.2–6.1), respectively. In fact, these data refer to type 2 diabetes; a small number of younger patients (born after 1940) was not sufficient to determine whether the increased risk for primary liver cancer also included patients with type 1 diabetes [13]. In the Italian study, the relative risk for primary liver cancer was twice as high for diabetic patients as it was for controls; it was higher for men than for women, and it was similar for diabetic patients under and over 45 years of age. The risk was also unrelated to the duration of diabetes prior to the diagnosis of liver cancer. It is noteworthy that the relative risk for primary liver cancer was almost twice as high in diabetic patients with a body mass index (BMI) above 25 as it was in subjects with a BMI below 25; OR was 3.3 (95% CI51.8–6.1) and 1.4 (95% CI50.8–2.5), respectively [14]. Diabetic patients show a markedly lower increase in the
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Table 1 Excess risk of cancer in diabetes mellitus [9–25] Authors/reference
Location
Description of the study
No of subjects who entered the study
Years of the study
Risk excess (95% confidence interval, CI)a
Pancreatic cancer Smith et al., 1992 [9]
United Kingdom
Prospective mortality study Population-based cohort study Population-based cohort study Case-control study
18 274 (males) IGT: 998, DM: 224 134 096 (diabetic patients) 109 581 (diabetic patients) 484 cases; 2099 controls
1967/69–1987
RR (IGT) 2.3 (1.1–4.7) (DM) 5.3 (1.9–14.6) SIR (M) 1.9 (1.7–2.1) (F) 2.0 (1.8–2.2) SIR (M) 1.7 (1.5–2.0) (F) 1.6 (1.4–1.9) OR DM: 5–9 years 1.7 (1.0–2.9) DM: .10 years 1.5 (1.0–2.2)
Population-based cohort study Population-based cohort study Case-control study
153 852 (diabetic patients) 109 581 (diabetic patients) 428 cases; 1502 controls
Denmark
Population-based cohort study
109 581 (diabetic patients)
1977–1989
Weiderpass et al., 1997 [15]
Sweden Italy
Le Marchand et al., 1997 [17]
United States (Hawaii)
Case-control study
153 852 (diabetic patients) 1993 cases; 4154 controls 1192 cases; 1192 controls
1965–1983
La Vecchia et al., 1997 [16]
Population-based cohort study Case-control study
Will et al., 1998 [18]
United States
Cohort study
Hu et al., 1999 [19]
United States
Cohort study
Endometrial cancer O’Mara et al., 1985 [20]
United States
Case-control study
Brinton et al., 1992 [21]
United States
Case-control study
La Vecchia et al., 1994 [22]
Northern Italy
Case-control study
Maatela et al., 1994 [23]
Finland
Case-control study
Wideroff et al., 1997 [11]
Denmark
Weiderpass et al., 1997 [24]
Sweden
Population-based cohort study Population-based cohort study
Chow et al., 1995 [10]
Sweden
Wideroff et al., 1997 [11]
Denmark
Silverman et al., 1999 [12]
United States
Primary liver cancer Adami et al., 1996 [13]
Sweden
Wideroff et al., 1997 [11]
Denmark
La Vecchia et al., 1997 [14]
Northern Italy
Colorectal cancer Wideroff et al., 1997 [11]
1965–1983 1977–1980 1986–1989
1965–1983 1977–1989 1984–1996
1992–1996 1987–1991
15 487 diabetic patients 863 699 non-diabetic subjects 7069 diabetic females 111 003 non-diabetic females
1959–1972
14 910 cases; 4838 controls 405 cases; 297 controls 9991 cases; 7834 controls 1715 cases; 1715 controls 55 010 (diabetic females)
1957–1965
1976–1992
SIR (M) 4.7 (4.2–5.2) (F) 3.4 (2.9–3.9) SIR (M) 4.0 (3.5–4.6) (F) 2.1 (1.6–2.7) OR (M) 2.4 (1.5–3.8) (F) 2.0 (1.0–4.2) SIR colon: (M) 1.3 (1.1–1.4) (F) 1.1 (1.0–1.2) SIR rectum: (M) 1.1 (0.9–1,2) (F) 1.0 (0.9–1.2) SIR colon: (M) 1.4 (1.2–1.5) (F) 1.4 (1.3–1.6) OR colon: 1.2 (0.8–1.6) OR rectum: 1.5 (1.1–2.2) OR left colon: (M) 1.9 (1.1–3.5) (F) 3.0 (1.2–7.1) OR rectum: (M) 0.7 (0.3–1.6) (F) 1.8 (0.7–4.4) IDR colon and rectum: (M) 0.7 (0.3–1.6) (F) 1.8 (0.7–4.4) RR colon and rectum: 1.43 (1.1–1.9) DM: ,10 years 1.29 (0.0–1.9) DM: 11–15 years 2.30 (1.4–3.7) DM: .15 years 1.08 (0.6–2.0)
1987–1990
RR endometrium 2.0 (P,0.01) vagina and vulva 1.5 RR 2.0 (1.1–3.6)
1983–1992
RR 3.4 (2.7–4.3)
1970–1974
RR 4.1 (2.7–6.9)
1997–1989
SIR 1.4 (1.2–1.6)
88 005 (diabetic females)
1975–1983
SIR 1.8 (1.6–2.0)
Population-based cohort study Population-based cohort study
55 010 54 571 80 005 73 847
1977–1983
SIR (M) 1.1 (0.4–2.2) (F) 1.1 (1.1–1.2) SIR (M) 2.0 (1.0–3.4) (F) 1.3 (1.2–1.4)
Unites States
Case-control study
Wideroff et al., 1997 [11]
Denmark
1977–1989
Lindblad et al., 1999 [25]
Sweden
Population-based cohort study Population-based cohort study
14 910 cases; 4838 controls 109 581 (diabetic patients) 153 852 (diabetic patients)
1965–1983
Breast cancer Wideroff et al., 1997 [11] Weiderpass et al., 1997 [24] Renal cancer O’Mara et al., 1985 [20]
a
Denmark Sweden
(diabetic (diabetic (diabetic (diabetic
females) males) females) males)
1965–1983
1957–1965
RR (M) 0.7 (F) 3.0 (P,0.05) SIR (M) 1.4 (1.2–1.6) (F) 1.7 (1.4–1.9) SIR (M) 1.4 (1.2–1.6) (F) 1.7 (1.5–2.0)
RR, relative risk; OR, odds ratio; SIR, standardized incidence ratio; IDR, incidence density ratio [26]; M, males; F, females.
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incidence of biliary tract cancer. In the Scandinavian population-based cohort studies, it accounted for 30–40%; only the Swedish study showed a twofold increase in the incidence of cancer of the ampulla of Vater in women [11,13]. In the Italian study, the relative risk for biliary tract cancer in diabetic patients was increased by 20% (1.2; 95% CI50.5–2.9) [14].
4. Colorectal cancer The increased incidence of colon cancer in diabetic patients has recently been supported by four prospective, population-based cohort studies in Denmark, Sweden, and the US. In the Danish study, the incidence of colon cancer in diabetic patients was higher by 30% in men and only by 10% in women in comparison with that in the general population, and without a significant difference among patients who were under or over 50 years of age when they entered the study [11]. In the Swedish study, the relevant increase in incidence was 39% and was not related to the patients’ age when they entered the study, the gender, or the duration of diabetes prior to the diagnosis of colon cancer: SIR was 1.5 (95% CI51.4–1.7) for 1–4 years of follow-up and 1.3 (95% CI51.1–1.5) for 10–24 years of follow-up. The overall standardized mortality ratio (SMR) calculated in the study was 1.6 (95% CI51.5–1.8) in men and 1.5 (95% CI51.4–1.6) in women. An increased incidence of colon cancer was also found in a small group of diabetic patients who were under 40 years of age when they entered the study and who might have represented type 1 diabetes. There was no difference in the diabetesassociated increased incidence of colon and rectal cancer in men; however, the increase was lower for rectal cancer in women (SIR: 1.1; 95% CI51.0–1.3) than it was for colon cancer (SIR: 1.4; 95% CI51.3–1.6) [15]. The first Cancer Prevention Study of the American Cancer Association was the greatest prospective epidemiological study of the colorectal cancer incidence in diabetic patients. The questionnaire analysis, carried out from 1959 to 1960, covered over 1 million people over 30 years of age, and 15 487 diabetic patients were selected from the cohort for a further follow-up. The development of colorectal cancer in those patients within the subsequent 13 years (until 1972) was compared with that of a group of 863 699 non-diabetic subjects. After adjusting for known cancer risk factors, it was noted that in diabetic patients the increased risk of developing colorectal cancer (incidence density ratio, IDR) accounted for 30% in men and 16% in women [18]. A greater risk for colon cancer in women with type 2 diabetes was found in another prospective cohort study conducted in the years 1976–1992 within the Nurses Health Study in Boston. After excluding such confounding factors as age, BMI, smoking, alcohol use, menopause and estrogen therapy, and a family history of colorectal cancer, the relative risk for colorectal cancer was
found to be 43% higher in diabetic women than in nondiabetic ones. It is worth noting that this risk substantially decreased in women having diabetes for more than 15 years [19]. An increased incidence of colorectal cancer was also reported in recently published case-control studies. The Italian authors found that diabetic patients had a higher relative risk for rectal cancer than for colon cancer, i.e. 1.5 (95% CI51.1–2.2) and 1.2 (95% CI50.8–1.6), respectively [16]. Another study conducted among the multiethnic population of the Oahu Island (Hawaii) showed that an increased risk of developing a left-sided colon cancer and rectal cancer was greater in diabetic women than in diabetic men [17].
5. Endometrial cancer The association between diabetes and endometrial cancer has been widely discussed in literature since diabetes, moderate hyperglycemia, and increased HbAl values have been found to be two to three times more frequent in women with an intravital and postmortem diagnosis of cancer [30–33]. The findings were confirmed in both case-control and cohort studies. In a case-control study conducted at the Roswell Park Memorial Institute (1957– 1990) on white women admitted for cancer, previously diagnosed diabetes produced a double risk for endometrial cancer and one and a half times greater risk for cancer of the vagina and vulva [20]. Similarly, another case-control study carried out in five American centers (1987–1990) showed that diabetes doubled the relative risk for this type of cancer also after adjusting for age, body weight, number of childbirths, the use of contraceptives, and menopausal estrogens. The increased relative risk was also noted when diabetes preceded the onset of cancer by more than 5 years. In patients with type 2 diabetes, who accounted for 70% of the cohort, the relative risk was slightly higher (2.1; 95% CI51.0–4.2) than in patients with type 1 diabetes (1.7; 95% CI50.6–4.6) [21]. In the case-control study in northern Italy, the relative risk for endometrial cancer was almost three times higher in diabetic patients than in controls (after allowing for obesity, education, and age), slightly decreasing to 2.0 (95% CI51.4–2.9) in the course of diabetes with a history longer than 10 years prior to the diagnosis of endometrial cancer [22]. In Finland, in a nationwide screening for endometrial cancer, 1715 women with the disease were selected and compared with individually matched controls. The study provided evidence of a relative risk for endometrial cancer that was four times higher in diabetic females than in non-diabetic controls [23]. The Danish and Swedish population-based cohort studies showed that SIRs for endometrial cancer were higher than those in the general population by 40% and 80%, respectively [11,24]. In spite of the evidence suggesting that diabetes in-
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creases the incidence of endometrial cancer, this issue is still under discussion because of a large number of other contributing risk factors accompanying diabetes in postmenopausal women, particularly obesity. The Wisconsin case-control study carried out from 1991 through 1994, which included 745 cases of endometrial cancer and 2408 controls, showed a twofold increase in the relative risk for endometrial cancer in all of the cases (1.9; 95% CI51.4– 2.5). However, the OR value displayed a substantial correlation with body weight and was the greatest in the group of obese females (3.0; 95% CI51.6–5.5), moderately increased in overweight women (1.6; 95% CI50.8–3.1), and only slightly higher in non-overweight women (1.1; 95% CI50.7–1.9). In this study, a long duration of diabetes ($ 14 years) was also not associated with the risk for the cancer [34]. Another case-control study assessing risk factors for endometrial cancer in non-diabetic women demonstrated that a high relative risk (2.2; 95% CI51.3– 3.7) associated with an elevated serum C-peptide concentration (.2.2 mg / l) decreased to 1.2 (95% CI50.6– 2.1) after adjusting for BMI [35].
6. Breast cancer In a 3-year prospective study (1971–1973) of breast ¨ tumors conducted in Nurnberg among women diagnosed as having breast cancer, manifest diabetes was recognized in 22.3% of the cases and subclinical diabetes (IGT) in 6.7% of the women. However, in the group of patients with benign breast tumors, the relevant percentage was much lower, accounting for 3.2 and 2.5%, respectively. Also, after matching both groups for age, weight, and height, the frequency of manifest and subclinical diabetes among women with breast cancer was twice as high as that among patients with benign tumors [36]. Similarly, a retrospective ¨ study in Zurich during the years 1971–1988 showed that the incidence of diabetes in a group of 992 patients with breast cancer was twice as high as that among 482 controls matched for age and year of hospitalization. A significant difference was, however, found only for type 2 diabetes (6.2 and 3.5%, respectively; P50.04) [37]. In the population-based cohort study in Rochester (1945–1969), the relative risk for breast cancer in diabetic women was 1.4 (95% CI50.7–2.4), but the overall number of cases with the malignancy was very small [8]. However, also in much larger population-based cohort studies, the SIRs for breast cancer were moderately elevated. In Denmark, the SIR for diabetic women over 50 years of age when they entered the cohort study (697 cases) was 1.2 (95% CI51.1–1.2) [11], whereas in the Swedish study of women over 40 years of age when they entered the cohort study (1145 cases) SIR was 1.3 (95% CI51.2–1.4) and was not increased in a group of younger patients [24]. It is of interest that the Swedish study
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demonstrated a twofold increase in the incidence of breast cancer in men with diabetes. Evidence has also been found of a deleterious effect of diabetes on the course of breast cancer. A retrospective study carried out in Germany (1984–1985) demonstrated that, in diabetic women, the course of the malignancy was twice as rapid as that in non-diabetic patients with the same primary tumor status and lymph node involvement: the metastatic frequency in the follow-up was 40.3 and 22.5% (P,0.0001), respectively [38]. A prospective cohort study in Iowa (41 837 women) showed that the relative risk for breast cancer in patients with a positive family history was 1.4 (95% CI51.1–1.7) and that it increased to 1.9 (95% CI50.91–3.8) when the patients had diabetes [39]. However, the assessment of family histories did not show any consistent association between breast cancer and diabetes in the families, with the exception of siblings (sisters) [40]. In a case-control study carried out in the Netherlands (1986–1987), which included 223 nondiabetic women with an early-stage breast cancer and 441 non-diabetic women without the malignancy, the cancer patients had higher serum C-peptide concentrations in contrast to the controls. The former had an increased relative risk simultaneous to an increased serum C-peptide concentration which, at a serum C-peptide level of 1.3 mg / l, was 1.0, but at a concentration of 3.0 mg / l, it reached the value of 2.9 (95% CI51.7–5.1) [41].
7. Renal cancer In the abovementioned Danish nationwide, populationbased cohort study, the SIR for renal cancer was increased by 40 and 70% among men and women, respectively. The calculated incidence ratios did not differ for patients under or over 50 years of age when they entered the cohort study [11]. The Swedish study showed a similar SIR increase, by 40% in men and by 70% in women. The increase in SIR remained steady for the entire follow-up period, and in men it even rose to 2.0 (95% CI51.0–3.7) after 15–25 years of follow-up. An analysis of birth dates showed that the increased incidence of renal cancer affected mainly patients with type 2 diabetes. In obese patients, the relative risk for renal cancer was also the greatest (3.2; 95% CI51.9–5.1) [25]. It is of interest that in both studies the increase in incidence for renal cancer proved to be higher for women than for men. The gender-related difference was particularly significant in a large case-control study conducted at the Roswell Park Memorial Institute, in which a prior history of diabetes was associated with a three-fold increase in the relative risk for renal cancer in women, but without any effect on the incidence of malignancy in men [20]. However, this gender-related difference was not found in the retrospective International Renal Cell Cancer Study, which showed that a 5- to
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10-year history of diabetes increased the relative risk for renal cancer by 40%, both in men and women [42].
8. Discussion The results of recent epidemiological studies seem to confirm the view that diabetes mellitus does increase the risk of cancer incidence. The increase in the risk varies according to the cancer site: it is the greatest for primary liver cancer, moderately high for pancreatic cancer, and relatively small for the remaining cancers mentioned above. The very reason for this association, however, has not been explained and remains the subject of different hypotheses. First, a question arises, namely, whether the diabetes itself is a factor increasing the risk of cancer incidence or whether it is a vehicle of associated effective causes. The linkage of the genetic background of both conditions appears not to be valid [12,40]. Autosomal recessive hemochromatosis (both homozygous and heterozygous) also appears to have limited significance in the association of diabetes mellitus with primary liver cancer or colon cancer [43,44]. However, there are many arguments supporting the role of environmental factors in this association: a high energy intake, a high-fat and low-fiber diet, and physical inactivity (all components of the western lifestyle) with resulting obesity which, on the one hand, is a risk factor for type 2 diabetes due to an increased insulin resistance and, on the other hand, is a risk factor for some of the cancers mentioned above [45,46]. This is particularly true for hormone-related malignancies: endometrial cancer and postmenopausal breast cancer due to extragonadal estrogen overproduction, resulting from aromatization of androstenedione in adipose tissue as well as to an increased release of ‘free’ and loosely albuminbound estrogens from sex hormone binding globulin (SHBG) [47,48]. Apart from this, the influence of obesity on the incidence of pancreatic, liver, and renal cancers has also been found in diabetic patients [12,14,25]. However, allowing for BMI showed a moderate reduction in the increased risk for these cancers, which suggests that other factors associated with diabetes may also be responsible. Among the causes of an increased incidence of primary liver cancer in patients with diabetes, attention has been drawn to the fatty liver commonly occurring in type 2 diabetes and a high incidence of hepatitis B and C virus infections [49]. With respect to colorectal cancer, interest has been focused on diabetes-related digestive disorders: a slower bowel transit, frequent constipation, increased production of cancerogenic bile acids and hydroxy-fatty acids and, regarding cancer of the biliary tract, decreased gallbladder emptying followed by gallstone formation [18,50]. However, in the extensive Swedish epidemiological study, no evidence was found to support the view that complications of diabetes may have any effect on the degree of the cancer risk [13].
It is also worth mentioning the research that has provided evidence of the effect of fatty acids and their metabolites (eikosanoids) stimulating the DNA transcription factor, peroxysome proliferator activated receptor g (PPAR g), whose increased expression has been found in rat and human colon cancer cell lines [51]. As many neoplasmatic cells express on the transcriptional and protein level several growth factors, the question arises as to whether diabetes exerts its cancerogenic effect in this way [52–55]. However, in studies of rats with streptozotocin-induced diabetes, the expression of these factors (insulin growth factor 1, platelet-derived growth factor, epidermal growth factor) in renal cells was differentiated, as was the modification of their expression by metabolic control of the disease [56]. It is still an open question whether the increased expression of the growth factors in tumors is a cause or rather a manifestation of neoplasia. A hypothesis was also made that a factor predisposing to cancerogenesis in diabetes may be oxidative stress, leading to DNA damage and limiting its repair [57]. Undoubtedly, further studies are needed to establish the role of the abovementioned mechanisms underlying the increased association of diabetes with cancer. Similarly, a report on an elevated plasma amylin concentration in patients with diabetes and pancreatic cancer requires further investigations to establish its epidemiological significance for the association between diabetes and cancer [58]. At present, the most frequent hypothesis proposed to explain the mechanism by which diabetes mellitus contributes to the increased tumor incidence, is that of a potential effect of insulin [12,19,41,50–62]. This hormone arises from the same precursor as insulin-like growth factor 1 (IGF-1) and, although it has a weaker affinity for the IGF-1 receptor, in high concentrations it may demonstrate its effects as a mitogenic factor. It is also possible that impaired insulin signalling, characteristic of type 2 diabetes, through upregulation of insulin receptor substrate 1, may lead to increased IGF-1 signalling and subsequent cell growth [63]. The ‘insulin’ hypothesis is supported by the following arguments: 1. Present epidemiological studies show mainly the association between an increased cancer risk and type 2 diabetes which, in the majority of cases, is primarily conditioned by insulin resistance, leading to secondary hyperinsulinemia. The numbers of patients with type 1 diabetes in these studies were small and selected mainly on the grounds of birth year or year of entry into the cohort, which had its impact on a more thorough classification. However, the large populationbased cohort studies showed that, in these subgroups, the increase in the incidence of cancer was lower than in the patient populations with type 2 diabetes [21,25,38]. It is also significant that the greatest risk for cancer in diabetic patients is to the organs in which
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concentrations of endogenous insulin reach particularly high values (liver, pancreas). In type 1 diabetes, these organs are exposed to much lower levels of exogenously administered insulin. The decrease observed in some studies in the cancer risk in longlasting type 2 diabetes may reflect the inverse relationship between the duration of this type of diabetes and insulin secretion [12,19,22,28,34]. 2. In animals with decompensated streptozotocin-induced diabetes, the induction of pancreatic cancer with an appropriate carcinogen or with implantation of cancer cells was less effective than in animals in which the effect of streptozotocin is compensated with insulin or nicotinamide [64,65]. 3. The present studies support the view that signals released, due to the binding of insulin with its receptor, pass parallel along the metabolic pathway and along the pathway stimulating mitogenesis and growth [66]. Interestingly, in the obese (fa / fa) Zucker rat, which is an animal model of human type 2 diabetes, it was found that the defect of insulin signaling, leading to insulin resistance, relates only to the former pathway and does not, or on a significantly smaller scale, refer to the latter pathway [67]. In insulin resistance (also prior to manifest diabetes), the pancreas compensates for the defect with an increased secretion of insulin sufficient (at least at the early stage) to control the disturbed glucose metabolism, but probably excessive for the pathway of protein synthesis and cell proliferation, which may be manifested by the progression of atherogenesis [68] and expression of cancerogenic activity. Hyperinsulinemia-dependent adipose tissue proliferation, through secondary extragonadal hyperestrogenism (and possibly other effects), may also contribute to an increased incidence of endometrial and breast cancers in postmenopausal women with diabetes. It is obvious that the ‘insulin hypothesis’ should be reexamined in appropriately programmed prospective studies employing modern biochemical, hormonal, and molecular techniques that should consider not only the relevant significance of insulin, but also a likely role of insulin precursors and particular growth factors and cytokines. However, the hypothesis may already be helpful in choosing an adequate treatment for type 2 diabetes that may make it possible to achieve optimal metabolic control of the disease with a simultaneous reduction in frequently present hyperinsulinemia, i.e. via diet, physical exercise, metformin, and acarbose.
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Review article
Diabetes mellitus and cancer ~ *, Zdzisl«awa Szczepanik Artur Czyzyk Department of Gastroenterology and Metabolic Diseases, Central Clinical Hospital, University Medical School of Warsaw, ul. Banacha 1 A, PL-02 -097 Warsaw, Poland Received 11 November 1999; received in revised form 27 March 2000; accepted 3 April 2000
Abstract Although an association between diabetes and cancer was found over 100 years ago, the issue underwent different interpretations over the subsequent decades, and only modern, prospective, epidemiological cohort and case-control studies conducted in several countries have provided reliable evidence of an increased cancer risk in diabetic patients, mainly in those with type 2 diabetes. This risk varies according to the tumor site: it is the greatest for primary liver cancer, moderately elevated for pancreatic cancer, and relatively low for colorectal, endometrial, breast, and renal cancers. The cause of the association is not clear and remains the subject of different hypotheses. The most frequently cited reason is the potential effect of insulin. Found in high concentrations, due to insulin resistance in most patients with type 2 diabetes, this hormone is believed to express a mitogenic effect. This hypothesis needs to be confirmed in appropriately programmed prospective studies, but it may already be helpful in choosing an adequate treatment for type 2 diabetes to achieve optimal metabolic control with a simultaneous reduction in hyperinsulinemia, such as diet, physical exercise, metformin, and acarbose. 2000 Elsevier Science B.V. All rights reserved. Keywords: Diabetes; Cancer; Hyperinsulinism
1. Introduction Studies of the relationship between diabetes mellitus and cancer have a long history, with the first reports already published at the end of the 19th century [1,2]. More adequately directed studies were initiated after the introduction of insulin treatment which, while prolonging the patients’ life span, resulted in an increased cancer prevalence in those same patients [3]. Three stages can be distinguished in the research. In the second and third decades of the ‘insulin era’, the first substantial reports, based on postmortem examinations, suggested an increased incidence of different cancers in diabetic patients. However, the reliability of the studies was limited because it was difficult to establish the actual morbidity and to select matched control groups [4–6]. The second stage of the research (4th and 5th decades) focused *Corresponding author. Tel.: 148-22-659-7563; fax: 148-22-6597563.
on analyzing the association using more specific epidemiological methods. However, it provided only partial confirmation of the previous reports. An analysis of 21 447 deaths among diabetic patients over a period of 26 years (1930–1956) conducted at the Joslin Clinic in Boston showed that the ratio of the observed number of cases of pancreatic cancer to that which was expected was 30:20 in men and 48:23 in women. In 90% of those cases, the diagnosis of diabetes had preceded the diagnosis of cancer [7]. Also, a 25-year-long prospective study (1945–1969) of 1135 residents of Rochester with diabetes mellitus showed that the relative risk for pancreatic cancer was only slightly higher in that group than in the general population, namely, 4.3 (95% CI52.0–8.1). After excluding the first year following the diagnosis of diabetes, the risk was 2.6 (95% CI50.9–6.1) [8]. Other cancers diagnosed more frequently at that time were endometrial and breast neoplasia. The third stage of epidemiological research, carried out in the 6th and 7th decades of the ‘insulin era’, consisted of
0953-6205 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0953-6205( 00 )00106-0
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well-prepared and well-documented studies based on a prospective analysis of cancer incidence and mortality among diabetic patients and included both populationbased cohort and case-control studies. Conducted mainly in the Scandinavian countries, the US, Great Britain, Germany, and Switzerland, they provided reliable evidence of an increased risk of different cancers in the diabetic population, particularly in patients with type 2 (non-insulin-dependent) diabetes (Table 1).
primary role of pancreatic cancer in its association with diabetes. Diabetes due to pancreatic cancer is characterized by a short course, a negative family history, the absence of obesity, and a rapid progression to insulin dependence. The onset of such atypical diabetes at a later age seems to suggest cancer of the pancreas and requires an adequate diagnostic protocol.
3. Primary liver cancer 2. Pancreatic cancer The association of pancreatic cancer with diabetes mellitus has been reported most frequently. In the Everhardt and Wright meta-analysis of 20 case-control and cohort studies, which included cases of diabetes diagnosed at least 1 year prior to the diagnosis or death from pancreatic cancer, the pooled relative cancer risk for the diabetic patients was 2.1 (95% CI51.6–2.8); it was somewhat higher in nine cohort studies (2.6; 95% CI5 1.6–4.1) than in 11 case-control studies (1.8; 95% CI5 1.1–2.7) [27]. An increased incidence of pancreatic cancer among diabetic patients was also found in nationwide, population-based cohort studies carried out in Denmark and Sweden [10,11]. However, the most frequent caveat concerned the place of diabetes in the association (‘the hen or the egg?’). A convincing answer appears to be provided by the studies proving that diabetes most often precedes the onset of the symptoms and signs of pancreatic cancer. In the Whitehall Study, after excluding earlier cases of pancreatic cancer, in the period of more than 10 years after the diagnosis of impaired glucose tolerance (IGT), the relative risk of developing pancreatic cancer was 3.3 (95% CI51.4–7.9), and after the diagnosis of diabetes mellitus it was 5.7 (95% CI51.4–24.0) [9]. In the Swedish population-based cohort study, after 10 or more years following the first hospital admission for diabetes mellitus, the standardized incidence ratio (SIR) for pancreatic cancer was 1.7 (95% CI51.4–2.1) and did not differ significantly from values after 5–9 years of follow-up [10]. In the Everhardt–Wright meta-analysis, patients with a 5-year or longer history of diabetes showed a relative risk for pancreatic cancer of 2.0 (95% CI51.2–3.2) [27]. Recently published results of a population-based, case-control study of pancreatic cancer conducted in three areas of the US also demonstrated an increased risk for this cancer, by 70% in patients with diabetes of 5–9 years’ duration and by 50% in patients with at least a 10-year history of diabetes [12]. Interestingly, an Italian multicenter study of the medical history of a large group of patients (n5720) with pancreatic cancer showed that a diabetes-associated increase in the risk for the tumor was limited only to the first 1–10 years of diabetes (type 2) duration; no increased risk was found among patients with a longer history of the disease [28]. Clinical evidence also raises doubts about the
A study of the causes of mortality in 32 222 diabetic patients in the Osaka district of Japan in the period 1960– 1989 showed a significant increase in the number of deaths due to primary liver cancer. Although the standardized mortality ratio (SMR) for malignant neoplasms at all sites remained unchanged for the entire study period, the ratio for liver cancer doubled [29]. Three recent studies yielded convincing evidence of an increased incidence of primary liver cancer in diabetic patients: population-based cohort studies conducted in Denmark and in Sweden, and a case-control study carried out in northern Italy. The Danish study showed that the incidence of primary liver cancer in the diabetic cohort was four-fold in men, two-fold in women, and slightly increased in patients who were under 50 years of age when they entered the study [11]. In the Swedish study, the incidence of primary liver cancer in diabetic patients was four-fold in men and more than three-fold in women as compared to the figures for the general population. After exclusion of patients with diseases predisposing to liver cancer (hepatitis, hepatic cirrhosis, hemochromatosis, alcoholism), the risk still remained three times higher. Completion of the follow-up or the duration of diabetes prior to the diagnosis of primary liver cancer had no significant effect on SIR, which was almost the same in men and women regardless of the duration of diabetes: for 1–4 years or 15–24 years in men it was 4.8 (95% CI54.1–5.7) and 4.8 (95% CI52.7–7.8), and in women its value was 3.6 (95% CI52.9–4.5) and 3.0 (95% CI51.2–6.1), respectively. In fact, these data refer to type 2 diabetes; a small number of younger patients (born after 1940) was not sufficient to determine whether the increased risk for primary liver cancer also included patients with type 1 diabetes [13]. In the Italian study, the relative risk for primary liver cancer was twice as high for diabetic patients as it was for controls; it was higher for men than for women, and it was similar for diabetic patients under and over 45 years of age. The risk was also unrelated to the duration of diabetes prior to the diagnosis of liver cancer. It is noteworthy that the relative risk for primary liver cancer was almost twice as high in diabetic patients with a body mass index (BMI) above 25 as it was in subjects with a BMI below 25; OR was 3.3 (95% CI51.8–6.1) and 1.4 (95% CI50.8–2.5), respectively [14]. Diabetic patients show a markedly lower increase in the
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Table 1 Excess risk of cancer in diabetes mellitus [9–25] Authors/reference
Location
Description of the study
No of subjects who entered the study
Years of the study
Risk excess (95% confidence interval, CI)a
Pancreatic cancer Smith et al., 1992 [9]
United Kingdom
Prospective mortality study Population-based cohort study Population-based cohort study Case-control study
18 274 (males) IGT: 998, DM: 224 134 096 (diabetic patients) 109 581 (diabetic patients) 484 cases; 2099 controls
1967/69–1987
RR (IGT) 2.3 (1.1–4.7) (DM) 5.3 (1.9–14.6) SIR (M) 1.9 (1.7–2.1) (F) 2.0 (1.8–2.2) SIR (M) 1.7 (1.5–2.0) (F) 1.6 (1.4–1.9) OR DM: 5–9 years 1.7 (1.0–2.9) DM: .10 years 1.5 (1.0–2.2)
Population-based cohort study Population-based cohort study Case-control study
153 852 (diabetic patients) 109 581 (diabetic patients) 428 cases; 1502 controls
Denmark
Population-based cohort study
109 581 (diabetic patients)
1977–1989
Weiderpass et al., 1997 [15]
Sweden Italy
Le Marchand et al., 1997 [17]
United States (Hawaii)
Case-control study
153 852 (diabetic patients) 1993 cases; 4154 controls 1192 cases; 1192 controls
1965–1983
La Vecchia et al., 1997 [16]
Population-based cohort study Case-control study
Will et al., 1998 [18]
United States
Cohort study
Hu et al., 1999 [19]
United States
Cohort study
Endometrial cancer O’Mara et al., 1985 [20]
United States
Case-control study
Brinton et al., 1992 [21]
United States
Case-control study
La Vecchia et al., 1994 [22]
Northern Italy
Case-control study
Maatela et al., 1994 [23]
Finland
Case-control study
Wideroff et al., 1997 [11]
Denmark
Weiderpass et al., 1997 [24]
Sweden
Population-based cohort study Population-based cohort study
Chow et al., 1995 [10]
Sweden
Wideroff et al., 1997 [11]
Denmark
Silverman et al., 1999 [12]
United States
Primary liver cancer Adami et al., 1996 [13]
Sweden
Wideroff et al., 1997 [11]
Denmark
La Vecchia et al., 1997 [14]
Northern Italy
Colorectal cancer Wideroff et al., 1997 [11]
1965–1983 1977–1980 1986–1989
1965–1983 1977–1989 1984–1996
1992–1996 1987–1991
15 487 diabetic patients 863 699 non-diabetic subjects 7069 diabetic females 111 003 non-diabetic females
1959–1972
14 910 cases; 4838 controls 405 cases; 297 controls 9991 cases; 7834 controls 1715 cases; 1715 controls 55 010 (diabetic females)
1957–1965
1976–1992
SIR (M) 4.7 (4.2–5.2) (F) 3.4 (2.9–3.9) SIR (M) 4.0 (3.5–4.6) (F) 2.1 (1.6–2.7) OR (M) 2.4 (1.5–3.8) (F) 2.0 (1.0–4.2) SIR colon: (M) 1.3 (1.1–1.4) (F) 1.1 (1.0–1.2) SIR rectum: (M) 1.1 (0.9–1,2) (F) 1.0 (0.9–1.2) SIR colon: (M) 1.4 (1.2–1.5) (F) 1.4 (1.3–1.6) OR colon: 1.2 (0.8–1.6) OR rectum: 1.5 (1.1–2.2) OR left colon: (M) 1.9 (1.1–3.5) (F) 3.0 (1.2–7.1) OR rectum: (M) 0.7 (0.3–1.6) (F) 1.8 (0.7–4.4) IDR colon and rectum: (M) 0.7 (0.3–1.6) (F) 1.8 (0.7–4.4) RR colon and rectum: 1.43 (1.1–1.9) DM: ,10 years 1.29 (0.0–1.9) DM: 11–15 years 2.30 (1.4–3.7) DM: .15 years 1.08 (0.6–2.0)
1987–1990
RR endometrium 2.0 (P,0.01) vagina and vulva 1.5 RR 2.0 (1.1–3.6)
1983–1992
RR 3.4 (2.7–4.3)
1970–1974
RR 4.1 (2.7–6.9)
1997–1989
SIR 1.4 (1.2–1.6)
88 005 (diabetic females)
1975–1983
SIR 1.8 (1.6–2.0)
Population-based cohort study Population-based cohort study
55 010 54 571 80 005 73 847
1977–1983
SIR (M) 1.1 (0.4–2.2) (F) 1.1 (1.1–1.2) SIR (M) 2.0 (1.0–3.4) (F) 1.3 (1.2–1.4)
Unites States
Case-control study
Wideroff et al., 1997 [11]
Denmark
1977–1989
Lindblad et al., 1999 [25]
Sweden
Population-based cohort study Population-based cohort study
14 910 cases; 4838 controls 109 581 (diabetic patients) 153 852 (diabetic patients)
1965–1983
Breast cancer Wideroff et al., 1997 [11] Weiderpass et al., 1997 [24] Renal cancer O’Mara et al., 1985 [20]
a
Denmark Sweden
(diabetic (diabetic (diabetic (diabetic
females) males) females) males)
1965–1983
1957–1965
RR (M) 0.7 (F) 3.0 (P,0.05) SIR (M) 1.4 (1.2–1.6) (F) 1.7 (1.4–1.9) SIR (M) 1.4 (1.2–1.6) (F) 1.7 (1.5–2.0)
RR, relative risk; OR, odds ratio; SIR, standardized incidence ratio; IDR, incidence density ratio [26]; M, males; F, females.
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incidence of biliary tract cancer. In the Scandinavian population-based cohort studies, it accounted for 30–40%; only the Swedish study showed a twofold increase in the incidence of cancer of the ampulla of Vater in women [11,13]. In the Italian study, the relative risk for biliary tract cancer in diabetic patients was increased by 20% (1.2; 95% CI50.5–2.9) [14].
4. Colorectal cancer The increased incidence of colon cancer in diabetic patients has recently been supported by four prospective, population-based cohort studies in Denmark, Sweden, and the US. In the Danish study, the incidence of colon cancer in diabetic patients was higher by 30% in men and only by 10% in women in comparison with that in the general population, and without a significant difference among patients who were under or over 50 years of age when they entered the study [11]. In the Swedish study, the relevant increase in incidence was 39% and was not related to the patients’ age when they entered the study, the gender, or the duration of diabetes prior to the diagnosis of colon cancer: SIR was 1.5 (95% CI51.4–1.7) for 1–4 years of follow-up and 1.3 (95% CI51.1–1.5) for 10–24 years of follow-up. The overall standardized mortality ratio (SMR) calculated in the study was 1.6 (95% CI51.5–1.8) in men and 1.5 (95% CI51.4–1.6) in women. An increased incidence of colon cancer was also found in a small group of diabetic patients who were under 40 years of age when they entered the study and who might have represented type 1 diabetes. There was no difference in the diabetesassociated increased incidence of colon and rectal cancer in men; however, the increase was lower for rectal cancer in women (SIR: 1.1; 95% CI51.0–1.3) than it was for colon cancer (SIR: 1.4; 95% CI51.3–1.6) [15]. The first Cancer Prevention Study of the American Cancer Association was the greatest prospective epidemiological study of the colorectal cancer incidence in diabetic patients. The questionnaire analysis, carried out from 1959 to 1960, covered over 1 million people over 30 years of age, and 15 487 diabetic patients were selected from the cohort for a further follow-up. The development of colorectal cancer in those patients within the subsequent 13 years (until 1972) was compared with that of a group of 863 699 non-diabetic subjects. After adjusting for known cancer risk factors, it was noted that in diabetic patients the increased risk of developing colorectal cancer (incidence density ratio, IDR) accounted for 30% in men and 16% in women [18]. A greater risk for colon cancer in women with type 2 diabetes was found in another prospective cohort study conducted in the years 1976–1992 within the Nurses Health Study in Boston. After excluding such confounding factors as age, BMI, smoking, alcohol use, menopause and estrogen therapy, and a family history of colorectal cancer, the relative risk for colorectal cancer was
found to be 43% higher in diabetic women than in nondiabetic ones. It is worth noting that this risk substantially decreased in women having diabetes for more than 15 years [19]. An increased incidence of colorectal cancer was also reported in recently published case-control studies. The Italian authors found that diabetic patients had a higher relative risk for rectal cancer than for colon cancer, i.e. 1.5 (95% CI51.1–2.2) and 1.2 (95% CI50.8–1.6), respectively [16]. Another study conducted among the multiethnic population of the Oahu Island (Hawaii) showed that an increased risk of developing a left-sided colon cancer and rectal cancer was greater in diabetic women than in diabetic men [17].
5. Endometrial cancer The association between diabetes and endometrial cancer has been widely discussed in literature since diabetes, moderate hyperglycemia, and increased HbAl values have been found to be two to three times more frequent in women with an intravital and postmortem diagnosis of cancer [30–33]. The findings were confirmed in both case-control and cohort studies. In a case-control study conducted at the Roswell Park Memorial Institute (1957– 1990) on white women admitted for cancer, previously diagnosed diabetes produced a double risk for endometrial cancer and one and a half times greater risk for cancer of the vagina and vulva [20]. Similarly, another case-control study carried out in five American centers (1987–1990) showed that diabetes doubled the relative risk for this type of cancer also after adjusting for age, body weight, number of childbirths, the use of contraceptives, and menopausal estrogens. The increased relative risk was also noted when diabetes preceded the onset of cancer by more than 5 years. In patients with type 2 diabetes, who accounted for 70% of the cohort, the relative risk was slightly higher (2.1; 95% CI51.0–4.2) than in patients with type 1 diabetes (1.7; 95% CI50.6–4.6) [21]. In the case-control study in northern Italy, the relative risk for endometrial cancer was almost three times higher in diabetic patients than in controls (after allowing for obesity, education, and age), slightly decreasing to 2.0 (95% CI51.4–2.9) in the course of diabetes with a history longer than 10 years prior to the diagnosis of endometrial cancer [22]. In Finland, in a nationwide screening for endometrial cancer, 1715 women with the disease were selected and compared with individually matched controls. The study provided evidence of a relative risk for endometrial cancer that was four times higher in diabetic females than in non-diabetic controls [23]. The Danish and Swedish population-based cohort studies showed that SIRs for endometrial cancer were higher than those in the general population by 40% and 80%, respectively [11,24]. In spite of the evidence suggesting that diabetes in-
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creases the incidence of endometrial cancer, this issue is still under discussion because of a large number of other contributing risk factors accompanying diabetes in postmenopausal women, particularly obesity. The Wisconsin case-control study carried out from 1991 through 1994, which included 745 cases of endometrial cancer and 2408 controls, showed a twofold increase in the relative risk for endometrial cancer in all of the cases (1.9; 95% CI51.4– 2.5). However, the OR value displayed a substantial correlation with body weight and was the greatest in the group of obese females (3.0; 95% CI51.6–5.5), moderately increased in overweight women (1.6; 95% CI50.8–3.1), and only slightly higher in non-overweight women (1.1; 95% CI50.7–1.9). In this study, a long duration of diabetes ($ 14 years) was also not associated with the risk for the cancer [34]. Another case-control study assessing risk factors for endometrial cancer in non-diabetic women demonstrated that a high relative risk (2.2; 95% CI51.3– 3.7) associated with an elevated serum C-peptide concentration (.2.2 mg / l) decreased to 1.2 (95% CI50.6– 2.1) after adjusting for BMI [35].
6. Breast cancer In a 3-year prospective study (1971–1973) of breast ¨ tumors conducted in Nurnberg among women diagnosed as having breast cancer, manifest diabetes was recognized in 22.3% of the cases and subclinical diabetes (IGT) in 6.7% of the women. However, in the group of patients with benign breast tumors, the relevant percentage was much lower, accounting for 3.2 and 2.5%, respectively. Also, after matching both groups for age, weight, and height, the frequency of manifest and subclinical diabetes among women with breast cancer was twice as high as that among patients with benign tumors [36]. Similarly, a retrospective ¨ study in Zurich during the years 1971–1988 showed that the incidence of diabetes in a group of 992 patients with breast cancer was twice as high as that among 482 controls matched for age and year of hospitalization. A significant difference was, however, found only for type 2 diabetes (6.2 and 3.5%, respectively; P50.04) [37]. In the population-based cohort study in Rochester (1945–1969), the relative risk for breast cancer in diabetic women was 1.4 (95% CI50.7–2.4), but the overall number of cases with the malignancy was very small [8]. However, also in much larger population-based cohort studies, the SIRs for breast cancer were moderately elevated. In Denmark, the SIR for diabetic women over 50 years of age when they entered the cohort study (697 cases) was 1.2 (95% CI51.1–1.2) [11], whereas in the Swedish study of women over 40 years of age when they entered the cohort study (1145 cases) SIR was 1.3 (95% CI51.2–1.4) and was not increased in a group of younger patients [24]. It is of interest that the Swedish study
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demonstrated a twofold increase in the incidence of breast cancer in men with diabetes. Evidence has also been found of a deleterious effect of diabetes on the course of breast cancer. A retrospective study carried out in Germany (1984–1985) demonstrated that, in diabetic women, the course of the malignancy was twice as rapid as that in non-diabetic patients with the same primary tumor status and lymph node involvement: the metastatic frequency in the follow-up was 40.3 and 22.5% (P,0.0001), respectively [38]. A prospective cohort study in Iowa (41 837 women) showed that the relative risk for breast cancer in patients with a positive family history was 1.4 (95% CI51.1–1.7) and that it increased to 1.9 (95% CI50.91–3.8) when the patients had diabetes [39]. However, the assessment of family histories did not show any consistent association between breast cancer and diabetes in the families, with the exception of siblings (sisters) [40]. In a case-control study carried out in the Netherlands (1986–1987), which included 223 nondiabetic women with an early-stage breast cancer and 441 non-diabetic women without the malignancy, the cancer patients had higher serum C-peptide concentrations in contrast to the controls. The former had an increased relative risk simultaneous to an increased serum C-peptide concentration which, at a serum C-peptide level of 1.3 mg / l, was 1.0, but at a concentration of 3.0 mg / l, it reached the value of 2.9 (95% CI51.7–5.1) [41].
7. Renal cancer In the abovementioned Danish nationwide, populationbased cohort study, the SIR for renal cancer was increased by 40 and 70% among men and women, respectively. The calculated incidence ratios did not differ for patients under or over 50 years of age when they entered the cohort study [11]. The Swedish study showed a similar SIR increase, by 40% in men and by 70% in women. The increase in SIR remained steady for the entire follow-up period, and in men it even rose to 2.0 (95% CI51.0–3.7) after 15–25 years of follow-up. An analysis of birth dates showed that the increased incidence of renal cancer affected mainly patients with type 2 diabetes. In obese patients, the relative risk for renal cancer was also the greatest (3.2; 95% CI51.9–5.1) [25]. It is of interest that in both studies the increase in incidence for renal cancer proved to be higher for women than for men. The gender-related difference was particularly significant in a large case-control study conducted at the Roswell Park Memorial Institute, in which a prior history of diabetes was associated with a three-fold increase in the relative risk for renal cancer in women, but without any effect on the incidence of malignancy in men [20]. However, this gender-related difference was not found in the retrospective International Renal Cell Cancer Study, which showed that a 5- to
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10-year history of diabetes increased the relative risk for renal cancer by 40%, both in men and women [42].
8. Discussion The results of recent epidemiological studies seem to confirm the view that diabetes mellitus does increase the risk of cancer incidence. The increase in the risk varies according to the cancer site: it is the greatest for primary liver cancer, moderately high for pancreatic cancer, and relatively small for the remaining cancers mentioned above. The very reason for this association, however, has not been explained and remains the subject of different hypotheses. First, a question arises, namely, whether the diabetes itself is a factor increasing the risk of cancer incidence or whether it is a vehicle of associated effective causes. The linkage of the genetic background of both conditions appears not to be valid [12,40]. Autosomal recessive hemochromatosis (both homozygous and heterozygous) also appears to have limited significance in the association of diabetes mellitus with primary liver cancer or colon cancer [43,44]. However, there are many arguments supporting the role of environmental factors in this association: a high energy intake, a high-fat and low-fiber diet, and physical inactivity (all components of the western lifestyle) with resulting obesity which, on the one hand, is a risk factor for type 2 diabetes due to an increased insulin resistance and, on the other hand, is a risk factor for some of the cancers mentioned above [45,46]. This is particularly true for hormone-related malignancies: endometrial cancer and postmenopausal breast cancer due to extragonadal estrogen overproduction, resulting from aromatization of androstenedione in adipose tissue as well as to an increased release of ‘free’ and loosely albuminbound estrogens from sex hormone binding globulin (SHBG) [47,48]. Apart from this, the influence of obesity on the incidence of pancreatic, liver, and renal cancers has also been found in diabetic patients [12,14,25]. However, allowing for BMI showed a moderate reduction in the increased risk for these cancers, which suggests that other factors associated with diabetes may also be responsible. Among the causes of an increased incidence of primary liver cancer in patients with diabetes, attention has been drawn to the fatty liver commonly occurring in type 2 diabetes and a high incidence of hepatitis B and C virus infections [49]. With respect to colorectal cancer, interest has been focused on diabetes-related digestive disorders: a slower bowel transit, frequent constipation, increased production of cancerogenic bile acids and hydroxy-fatty acids and, regarding cancer of the biliary tract, decreased gallbladder emptying followed by gallstone formation [18,50]. However, in the extensive Swedish epidemiological study, no evidence was found to support the view that complications of diabetes may have any effect on the degree of the cancer risk [13].
It is also worth mentioning the research that has provided evidence of the effect of fatty acids and their metabolites (eikosanoids) stimulating the DNA transcription factor, peroxysome proliferator activated receptor g (PPAR g), whose increased expression has been found in rat and human colon cancer cell lines [51]. As many neoplasmatic cells express on the transcriptional and protein level several growth factors, the question arises as to whether diabetes exerts its cancerogenic effect in this way [52–55]. However, in studies of rats with streptozotocin-induced diabetes, the expression of these factors (insulin growth factor 1, platelet-derived growth factor, epidermal growth factor) in renal cells was differentiated, as was the modification of their expression by metabolic control of the disease [56]. It is still an open question whether the increased expression of the growth factors in tumors is a cause or rather a manifestation of neoplasia. A hypothesis was also made that a factor predisposing to cancerogenesis in diabetes may be oxidative stress, leading to DNA damage and limiting its repair [57]. Undoubtedly, further studies are needed to establish the role of the abovementioned mechanisms underlying the increased association of diabetes with cancer. Similarly, a report on an elevated plasma amylin concentration in patients with diabetes and pancreatic cancer requires further investigations to establish its epidemiological significance for the association between diabetes and cancer [58]. At present, the most frequent hypothesis proposed to explain the mechanism by which diabetes mellitus contributes to the increased tumor incidence, is that of a potential effect of insulin [12,19,41,50–62]. This hormone arises from the same precursor as insulin-like growth factor 1 (IGF-1) and, although it has a weaker affinity for the IGF-1 receptor, in high concentrations it may demonstrate its effects as a mitogenic factor. It is also possible that impaired insulin signalling, characteristic of type 2 diabetes, through upregulation of insulin receptor substrate 1, may lead to increased IGF-1 signalling and subsequent cell growth [63]. The ‘insulin’ hypothesis is supported by the following arguments: 1. Present epidemiological studies show mainly the association between an increased cancer risk and type 2 diabetes which, in the majority of cases, is primarily conditioned by insulin resistance, leading to secondary hyperinsulinemia. The numbers of patients with type 1 diabetes in these studies were small and selected mainly on the grounds of birth year or year of entry into the cohort, which had its impact on a more thorough classification. However, the large populationbased cohort studies showed that, in these subgroups, the increase in the incidence of cancer was lower than in the patient populations with type 2 diabetes [21,25,38]. It is also significant that the greatest risk for cancer in diabetic patients is to the organs in which
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concentrations of endogenous insulin reach particularly high values (liver, pancreas). In type 1 diabetes, these organs are exposed to much lower levels of exogenously administered insulin. The decrease observed in some studies in the cancer risk in longlasting type 2 diabetes may reflect the inverse relationship between the duration of this type of diabetes and insulin secretion [12,19,22,28,34]. 2. In animals with decompensated streptozotocin-induced diabetes, the induction of pancreatic cancer with an appropriate carcinogen or with implantation of cancer cells was less effective than in animals in which the effect of streptozotocin is compensated with insulin or nicotinamide [64,65]. 3. The present studies support the view that signals released, due to the binding of insulin with its receptor, pass parallel along the metabolic pathway and along the pathway stimulating mitogenesis and growth [66]. Interestingly, in the obese (fa / fa) Zucker rat, which is an animal model of human type 2 diabetes, it was found that the defect of insulin signaling, leading to insulin resistance, relates only to the former pathway and does not, or on a significantly smaller scale, refer to the latter pathway [67]. In insulin resistance (also prior to manifest diabetes), the pancreas compensates for the defect with an increased secretion of insulin sufficient (at least at the early stage) to control the disturbed glucose metabolism, but probably excessive for the pathway of protein synthesis and cell proliferation, which may be manifested by the progression of atherogenesis [68] and expression of cancerogenic activity. Hyperinsulinemia-dependent adipose tissue proliferation, through secondary extragonadal hyperestrogenism (and possibly other effects), may also contribute to an increased incidence of endometrial and breast cancers in postmenopausal women with diabetes. It is obvious that the ‘insulin hypothesis’ should be reexamined in appropriately programmed prospective studies employing modern biochemical, hormonal, and molecular techniques that should consider not only the relevant significance of insulin, but also a likely role of insulin precursors and particular growth factors and cytokines. However, the hypothesis may already be helpful in choosing an adequate treatment for type 2 diabetes that may make it possible to achieve optimal metabolic control of the disease with a simultaneous reduction in frequently present hyperinsulinemia, i.e. via diet, physical exercise, metformin, and acarbose.
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