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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 494-502

A study of the relation between insulin resistance, insulin-like growth factor-1, and malignancy in type 2 diabetic patients


1 Department of Internal Medicine, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt

Date of Web Publication31-Aug-2015

Correspondence Address:
Doaa S Elgendy
Department of Diabetes and Endocrinology, Shebin Elkom, Menoufiya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163908

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  Abstract 

Objectives
This study was conducted to evaluate the effect of insulin resistance and insulin-like growth factor-1 (IGF-1) on the prevalance and the prognosis of cancer in type 2 diabetic patients detected by clinical examination and laboratory investigations.
Background
Diabetes and obesity are emerging as avoidable causes of cancer mortality. Many biological mechanisms link obesity and diabetes to cancer development through direct or indirect effects of obesity on insulin and IGF-1, sex hormones, adipokines, and inflammation. The activation of these mechanisms promotes an environment of increased proliferation, inhibited apoptosis, and increased genomic instability.
Patients and methods
Patients were categorized into three groups 'diabetic patients with cancer, diabetic patients without cancer, and nondiabetic patients with cancer'. They underwent evaluation in the form of thorough history taking, complete physical examination including anthropometric measurement, laboratory investigations including the fasting insulin level and C-peptide to detect insulin resistance by calculating the homeostasis model assessment of insulin resistance (HOMA-IR), the serum lipid profile, and serum IGF-1 by the enzyme-linked immunosorbent assay test.
Results
Results show a higher serum level of IGF-1, a higher fasting insulin and C-peptide and HOMA-IR among diabetic patients with cancer compared with nondiabetic patients with cancer. Diabetic patients with cancer (group I) had a significantly higher fasting insulin, fasting blood glucose, and HOMA-IR than nondiabetic patients with cancer (group II), who had a higher fasting insulin, fasting blood glucose, and HOMA-IR than diabetic patients without cancer (group III). Group I had a significantly higher C-peptide and IGF-1 than group III; group I had a significantly higher C-peptide than group II, whereas group II had a significantly higher IGF-1 than group III. This means that the presence of high insulin resistance and a high level of serum IGF-1 increase the incidence of cancer in diabetic patients.
Conclusion
The present study reported a profound effect of diabetes mellitus and insulin resistance on the incidence and the severity of cancer in type 2 diabetic patients. Diabetic patients with cancer had a significantly higher IGF-1 and HOMA-IR, and higher markers of insulin sensitivity, elevated glucose, elevated triglycerides, elevated low-density lipoprotein, and low high-density lipoprotein, compared with diabetic patients without cancer.

Keywords: insulin-like growth factor-1, insulin resistance, malignancy, type 2 diabetic patients


How to cite this article:
El Kafrawy NA, Glal AZ, Kandil MA, Eldin Dawood AA, Essa ES, Elgendy DS. A study of the relation between insulin resistance, insulin-like growth factor-1, and malignancy in type 2 diabetic patients. Menoufia Med J 2015;28:494-502

How to cite this URL:
El Kafrawy NA, Glal AZ, Kandil MA, Eldin Dawood AA, Essa ES, Elgendy DS. A study of the relation between insulin resistance, insulin-like growth factor-1, and malignancy in type 2 diabetic patients. Menoufia Med J [serial online] 2015 [cited 2020 Apr 3];28:494-502. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/494/163908


  Introduction Top


Diabetes and cancer are common diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that people with diabetes are at a significantly higher risk for many forms of cancer. Type 2 diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood. Moreover, evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either an increased or a reduced risk of cancer. Potential risk factors (modifiable and nonmodifiable) common to both cancer and diabetes include aging, sex, obesity, physical activity, diet, alcohol, and smoking [1] . Both diabetes and cancer are prevalent diseases, the incidence of which is increasing globally. Worldwide, the prevalence of cancer has been difficult to establish because many areas do not have cancer registries, but in 2008, there were an estimated 12.4 million new cancer cases diagnosed. The most commonly diagnosed cancers are lung/bronchus, breast, and colorectal cancers, whereas the most common causes of cancer deaths are lung, stomach, and liver cancer. Worldwide, cancer is the second and diabetes the 12th leading cause of death [2] .

Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age. Both diseases are complex, with multiple subtypes. Diabetes is typically divided into two major subtypes, type 1 and type 2 diabetes, along with less common types, whereas cancer is typically classified by its anatomic origin (of which there are over 50 types, for example, lymphoma, leukemia, lung, and breast cancer), within which there may be multiple subtypes (e.g. leukemia) [3] .

How can the increased cancer risk in diabetes be explained? To begin with, it should be noted that obesity, insulin resistance, and/or increased levels of insulin-like growth factor-1 (IGF-1) and insulin are strongly associated with most (but not all) of the diabetes-related cancers in the nondiabetic population [4] . This suggests that hyperglycemia does not play an essential role in the pathogenesis of these tumors, but does not exclude the possibility that it might have secondary effects; this is a more plausible mechanistic explanation for the overlapping risk of cancer in nondiabetic and diabetic populations. Hormones are mitogenic (but not mutagenic): both are present at high levels in insulin-resistant states, and their receptors are overexpressed on the surface of cancer cells associated with diabetes. They thus have the potential to act as tumor growth factors in vivo and in vitro [4] . Obviously, type 2 diabetes and obesity-related hyperinsulinemia may affect cancer development through ligand binding with the insulin receptor and/or by increasing circulating IGF-1 levels. Circulating IGFs are normally bound by insulin-like growth factor-binding proteins (IGFBPs). IGFBP-3 binds almost 90% of the circulating IGF-1 and IGF-2. Under conditions of prolonged hyperinsulinemia, the activities of IGFBP-1 and IGFBP-2 are diminished, potentially resulting in increased 'free' IGF-1 and IGF-2 [5] . In this study, we tried to determine the effect of insulin resistance and IGF-1 on the incidence of cancer in type 2 diabetic patients.


  Patients and methods Top


This is a cross-sectional study on type 2 diabetic patients with and without cancer to elucidate the role of insulin resistance and IGF-1 on the incidence and the prognosis of cancer. The study was carried out on 90 patients. They were selected from inpatient and outpatient clinics of the Department of Internal Medicine and the Oncology Institute of Menoufiya University Hospital during the period from January 2013 to April 2014. Their age ranged from 20 to 70 years.

Patients were categorized into three groups according to their history, examination, and investigation as follows: group I consisted of 36 diabetic patients with cancer. Group II consisted of 36 nondiabetic patients with cancer. Group III consisted of 18 diabetic patients without cancer.

Inclusion criteria

This study was conducted on a population known to have one of the three types of epithelial cell cancers: breast, colorectal, and bladder cancers diagnosed by histopathology of a biopsy from the site of cancer.

Exclusion criteria

The following patients were excluded from the study: patients with any organ failure, patients with any chronic illness (other than diabetes), patients with any active infection, patients with active alcohol use, and patients with a positive family history of cancer.

All patients and controls were enrolled during the same period and gave their consent to participate in the study, which was approved by the Investigation and Ethics Committee of the faculty.

Members of the study groups were subjected to the following examinations:

  1. Thorough history taking, including age, sex, occupation, residence, marital status, special habits, history of chronic illness, family history with special emphasis on symptoms of diabetes and its duration, complications, and treatment, symptoms of cancer and its duration, risk factors for both diabetes and cancer, including nonmodifiable risk factors, such as age and sex, and modifiable risk factors, such as obesity, the type of diet, the state of physical activity, and tobacco smoking.
  2. Complete physical examination including anthropometric measurement of the body weight, the height, and the BMI.
  3. Routine investigations included the following:


    1. Complete blood picture (using a Pentra 80 auto-counter, Biomedicine, England).
    2. Fasting blood glucose (the normal range of fasting blood glucose ranges between 70 and 110 mg/dl and the 2-h postprandial blood glucose up to 140 mg/dl).
    3. Renal function tests (blood urea and serum creatinine).
    4. Liver function tests (alanine transaminase, aspartate aminotransferase, serum albumin, and total bilirubin) were performed on the auto-analyzer
    5. synchron CX5 (Biocare, California, USA).


The following procedures were performed for specific investigations of the patients:

(1) Fasting insulin level and HOMA-IR:

(a) Serum insulin: Assessment of serum insulin by enzyme-linked immunosorbent assay using the Monobind Inc. (Biocare Company, California, USA) Insulin product. Essential reagents required for an immunoenzymometric assay included high-affinity and high-specificity antibodies with different and distinct epitope recognition. In this procedure, the immobilization occurred during the assay at the surface of a microplate well through the interaction of streptavidin coated on the well and the exogenously added biotinylated monoclonal insulin antibody. Upon mixing the monoclonal biotinylated antibody, the enzyme-labeled antibody, and a serum containing the native antigen, a reaction occurs between the native antigen and the antibodies without competition or steric hindrance to form a soluble sandwich complex. The homeostasis model assessment of insulin resistance (HOMA-IR) is used in clinical diabetes research to measure the insulin sensitivity. The HOMA-IR value is the product of the patient's blood glucose and serum insulin levels after fasting, divided by a constant value.

Determine the patient's fasting plasma level (U/ml); determine the patient's serum glucose level (mg/dl); multiply the result from step (1) by the result from step (2); divide by 405. The result obtained is the patient's HOMA-IR value [26] . The optimal cutoff point of HOMA-IR for insulin resistance diagnosis is 1.775 in nondiabetic patients and ~4 in diabetic individuals [27] .

(2) Serum IGF-1: The AssayMax Human IGF-1 ELISA kit (Assaypro Company, Newyork, USA) is designed for the detection of human IGF-1 in plasma, serum, and cell culture supernatants. This assay uses a quantitative sandwich enzyme immunoassay technique, which measures IGF-1 in 5 h. A monoclonal antibody specific for human IGF-1 is precoated onto a microplate. The human IGF-1 in standards and samples is sandwiched by the immobilized antibody and biotinylated polyclonal antibody specific for the human IGF-1, which is recognized by a streptavidin-peroxidase conjugate. All unbound material is then washed away, and a peroxidase enzyme substrate is added. The color development is stopped, and the intensity of the color is measured.

Statistical analysis

Parametric data are expressed as mean ± SD values and categorical variables as percentages. The χ2 -test was used for the comparison of dichotomous variables and the Student t-test for continuous variables. One-way analysis of variance, with the least significant difference, was used to test differences on multiple levels by a single factor (independent) variable. A P-value less than 0.05 was considered statistically significant. Post-hoc comparisons were performed using the SPSS software 13.0 for Windows (Biomedicine, England).


  Results Top


Ninety Egyptian individuals participated in this study and were classified into three groups:

Group I:

Thirty-six diabetic patients with cancer: 19 male and 17 female patients, with a mean age of 55.3 ± 11.4 years.

Group II:

Thirty-six nondiabetic patients with cancer: 15 male and 21 female patients, with a mean age of 49.9 ± 11.8 years.

Group III:

Eighteen diabetic patients without cancer: 11 male and seven female patients, with a mean age of 53.5 ± 9.4 years.

Sociodemographic characteristics of the three groups of patients are shown in [Table 1]. There was no statistically significant difference regarding age, sex, and physical activity (P > 0.05) among the three groups.
Table 1 Sociodemographic characteristics of the studied groups

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Anthropometric measurements and the blood pressure of the studied groups are shown in [Table 2]. There was a statistically significant difference regarding the BMI and the waist circumference (P < 0.05). Diabetic patients with cancer in 'group I' had a significantly higher BMI and waist circumference than diabetic patients without cancer in 'group III', who had a higher BMI and waist circumference compared with nondiabetic patients with cancer in 'group II'; however, there was no statistically significant difference regarding the blood pressure (P > 0.05) among the three groups.
Table 2 Anthropometric measurements and blood pressure of the studied groups

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Lipid profiles of the studied groups are shown in [Table 3]. There was no statistically significant difference regarding the total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein (HDL) (P > 0.05) among the three studied groups.
Table 3 Lipid profiles of the studied groups

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Markers of insulin sensitivity (fasting blood glucose, fasting insulin, HOMA-IR), IGF-1, and C-peptide in the studied groups are shown in [Table 4].
Table 4 Markers of insulin sensitivity, C-peptide, and serum insulin-like growth factor-1 in the studied groups

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Diabetic patients with cancer in 'group I' had a significantly higher fasting insulin, fasting blood glucose, and HOMA-IR than nondiabetic patients with cancer in 'group II', who had a higher fasting insulin, fasting blood glucose, and HOMA-IR compared with diabetic patients without cancer in 'group III'.

Group I had a significantly higher C-peptide and IGF-1 than group III, group I had a significantly higher C-peptide than group II, whereas group II had a significantly higher IGF-1 than group III.

[Table 5] shows a comparison between diabetic patients with cancer and diabetic patients without cancer regarding the duration of diabetes mellitus (DM), microvascular complications, and antidiabetic treatment. The mean duration of diabetes in the studied patients was statistically higher among diabetic patients with cancer than in those without cancer (P < 0.05) and the percentage of patients treated with insulin was significantly higher among diabetic patients with cancer (P < 0.05).
Table 5 Comparison between diabetic patients with cancer and diabetic patients without cancer regarding the duration of diabetes mellitus, complications, and antidiabetic treatment

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[Table 6] shows the following:
Table 6 The correlation coeffi cient between serum insulin-like growth factor-1 and fasting blood glucose, fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance in the three groups of patients

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There was a statistically significant positive correlation between serum IGF-1 and fasting insulin, C-peptide, and HOMA-IR in the studied patients with cancer. This mean increased fasting insulin, increased C-peptide level, and increased HOMA-IR level (insulin resistance) are associated with increased serum IGF-1.

However, no significant correlation was found between serum IGF-1 and fasting blood glucose in the three groups of patients.

[Table 7] shows the following logistic regression for the prediction of cancer in type 2 DM. After exclusion of all confounding variables, it was found that serum IGF-1 is an independent risk factor for the prediction of cancer in type 2 DM at a serum level of IGF-1 greater than 127.5 ng/ml (P < 0.001, odds ratio 26.5).
Table 7 Logistic regression for the prediction of cancer in type 2 diabetes mellitus

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Cancer is 7.4-fold more common in diabetic patients with HOMA-IR greater than 4 ng/ml than in diabetic patients with HOMA-IR less than 4 ng/ml.

Cancer is eight-fold more common in diabetic patients with C-peptide less than 3.2 ng/ml than in diabetic patients with C-peptide greater than 3.2 ng/ml.

Cancer is 26.5-fold more common in diabetic patients with a serum level of IGF-1 greater than 127.5 ng/ml than in diabetic patients with serum IGF-1 less than 127.5 ng/ml.


  Discussion Top


Many proposed biological mechanisms link diabetes and obesity to cancer development through the direct or the indirect effects of insulin and IGF-1, sex hormones, adipokines, and inflammation [6] . The collective activation of these individual mechanisms promotes an environment of increased proliferation, inhibited apoptosis, and increased genomic instability [7] . Obesity is emerging as a leading avoidable cause of mortality, including cancer mortality. In an analysis of data from 57 prospective cohort studies with ~900 000 total participants, the BMI was a strong predictor of death above and below the apparent optimum of 22.5-25 kg/m 2 . Obesity-related hyperinsulinemia may affect cancer development through ligand binding with the insulin receptor and/or by increasing circulating IGF-1 levels. Circulating IGFs are normally bound by IGFBPs. IGFBP-3 binds almost 90% of the circulating IGF-1 and IGF-2. Under conditions of prolonged hyperinsulinemia, the activities of IGFBP-1 and IGFBP-2 are diminished, potentially resulting in increased 'free' IGF-1 and IGF-2. Direct relationships among increased obesity (or percentage body fat), increased insulin, and 'free' IGF-1 levels have been demonstrated [8] . Diabetes is also associated with an increase in cancer mortality. Multiple meta-analyses of case-control and cohort studies have shown that diabetes is associated with a significantly increased risk of breast, colorectal, endometrial, pancreatic, and hepatic cancer and non-Hodgkin lymphoma. Bladder cancer has also been shown to be positively correlated with diabetes, although a recent prospective cohort study of over 170 000 patients indicated that this positive association may be limited to patients with long-standing diabetes (>15 years) or insulin users [9] . Prostate cancer risk appears to be decreased in patients with diabetes; one possible explanation is that testosterone levels have been shown to be reduced in men with diabetes. The conversion of testosterone to dihydrotestosterone promotes prostate cell growth [10] .

In the present study, regarding the demographic data, there was no statistically significant difference with respect to age, sex, physical activity, and smoking (P > 0.05) among the three groups. This was in disagreement with Liese and colleagues, who stated that the occurrence of most cancers increases with age. In economically developed countries, 78% of all newly diagnosed cancers occur among individuals aged 55 years and older. Overall, cancer occurs more frequently in men. Men have a slightly higher age-adjusted risk of diabetes than women. Diabetes also becomes increasingly common with age, occurring in up to 23.8% of individuals 60 years of age or older [8] . This was also in disagreement with Law and colleagues who showed that higher levels of physical activity are associated with a lower risk of colon, postmenopausal breast, and endometrial cancer. Physical activity after diagnosis may improve cancer survival for some cancers, including breast and colorectal cancer. Also, in contrast to this finding about smoking [28] , reported that tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths; other cancers strongly associated with smoking are larynx, upper digestive tract, bladder, kidney, pancreas, leukemia, liver, stomach, and uterine cervix cancers; they also state that smoking is an independent risk factor for the development of diabetes, and it has an adverse effect on diabetes-related health outcomes.

There was a statistically significant difference regarding the BMI and the waist circumference. Diabetic patients with cancer had a significantly higher BMI and waist circumference compared with diabetic patients without cancer. This finding coincides with a recent study in one cohort of the prospective Cancer Prevention Study II: BMI in the obese range (≥30 kg/m 2 ) was associated with increased overall cancer mortality compared with normal weight (18.5-24.9 kg/m 2 ) in both men and women [10] . Increased BMI was associated with worsened outcomes for breast, colon, and aggressive prostate cancer, but improved outcomes for renal cell carcinoma and endometrial cancer [11] . Furthermore, Sinicrope and colleagues observed decreased mortality (hazard ratio 0.54; 95% confidence interval 0.37-0.78; P = 0.001) for obesity-related cancers with bariatric surgery in women with a BMI of at least 35 kg/m 2 .

There was no statistically significant difference regarding systolic and diastolic blood pressures, and this was in agreement with a study in Italy, which found a modest nonsignificant increase in the risk associated with hypertension (relative risk = 1.28). A similar modest nonsignificant association was found in another prospective study [12] .

In the present study, there was no statistically significant difference with regard to the total cholesterol, triglycerides, low-density lipoprotein, and HDL (P > 0.05) among the three studied groups. This was in agreement with Sinicrope and colleagues, who found in a prospective study that men and women in the top quartile of triglycerides have a nonsignificant 40% increased risk of colorectal cancer.

Likewise, in another prospective study in the USA, an elevated triglyceride level was not a risk factor for colon cancer (n = 132 cases) [13] .

Regarding HDL, our finding was in agreement with a study conducted in Italy that found no association between the HDL-cholesterol level and the colorectal cancer risk [14] . Also, in a cohort study, men and women in the top quartile of HDL-cholesterol had about a 40% nonsignificant reduction in the risk relative to those in the bottom quartile [15] .

The current work showed a statistically significant difference regarding the insulin sensitivity profile (fasting blood glucose, fasting insulin, HOMA-IR, and C-peptide) between the studied groups (P < 0.05). Diabetic patients with cancer had significantly higher fasting blood glucose, fasting insulin, and HOMA-IR than nondiabetic patients with cancer. This was in agreement with [29] , who observed that fasting insulin levels in the highest quartile were found to be significantly positively associated in patients with early breast cancer [16] . Duggan and colleagues also found in a meta-analysis of 12 epidemiological studies that before diagnosis, C-peptide or insulin levels at the highest subgrouping were significantly predictive of pancreatic, colorectal, breast, and bladder cancer when compared with lower levels before diagnosis. In contrast to this, at least one study showed no association of insulin levels with breast cancer risk although in a smaller cohort [12] .

Regarding C-peptide and serum IGF-1, diabetic patients with cancer had a significantly higher C-peptide and IGF-1 than diabetic patients without cancer. Diabetic patients with cancer had a significantly higher C-peptide than nondiabetic patients with cancer, whereas diabetic patients without cancer had a significantly higher IGF-1 than nondiabetic patients with cancer. This means that the presence of insulin resistance and a high level of serum IGF-1 increase the incidence of cancer in diabetic patients. This finding coincides with [30] in a prospective observational study of 373 patients with diagnosed nonmetastatic colorectal cancer, who observed a nearly two-fold higher age-adjusted mortality risk in patients in the top quartile of plasma C-peptide levels compared with those in the lowest quartile.

Men from the Physician's Health Study in the highest quintile for IGF-1 concentration before cancer diagnosis had an increased risk of colorectal cancer compared with those in the lowest quintile (relative risk 2.51; 95% confidence interval 1.15-5.46) [1] . Finally, IGF-1 levels and an IGF-1/IGFBP-3 ratio at the highest quintile in women with breast cancer has been observed to confer an approximate three-fold increased risk of adjusted all-cause mortality compared with patients in the lowest quintiles of these measures [17] .

This was also in agreement with Jenab et al. [18] , Ma et al. (2008) [27] , Gunter et al. [12] , Roddam et al. [19] , Chen et al. [20] , and Rinaldi et al. [21] in prospective cohorts including the Nurses' Health Study, the Physicians' Health Study, the Women's Health Initiative, and the European Prospective Investigation into Cancer and Nutrition (EPIC) studies, which have measured plasma levels of insulin, C-peptide, IGF-1, and IGFBP-3 in an attempt to correlate these levels with cancer risk.

They reported a significant increase in colorectal, breast (especially postmenopausal), endometrial, and advanced prostate cancer risk in association with elevated C-peptide, insulin, and IGF-1 levels.

Also, in a cohort of men older than 50 years from the Rancho Bernardo Study, Major et al. [22] found a significant association between IGF-1 levels and cancer mortality after adjusting for other risk factors. Men with an IGF-1 concentration greater than 100 ng/ml had an adjusted risk of cancer mortality of 1.82 compared with men whose IGF-1 concentration was less than 100 ng/ml.

In the current study, diabetic patients with cancer had a significantly longer duration of DM than diabetic patients without cancer (P < 0.05), and the percentage of patients treated with insulin was significantly higher among diabetic patients with cancer (P < 0.05). This is in agreement with Newton and colleagues, who found a positive association between bladder cancer and patients with long-standing diabetes (>15 years) or insulin users in a recent prospective cohort study of over 170 000 patients.

This work shows a significant interrelation between diabetic and nondiabetic patients with cancer as follows: there was a statistically significant positive correlation between serum IGF-1 and fasting insulin, C-peptide, and HOMA-IR in the studied patients with cancer. This mean increased fasting insulin, increased C-peptide level, and increased HOMA-IR level (insulin resistance) are associated with increased serum IGF-1 ([Figure 1] [Figure 2] [Figure 3]).
Figure 1: Fasting insulin levels in the three groups of studied patients

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Figure 2: The C-peptide level in the three groups of studied patients

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Figure 3: The homeostasis model assessment of insulin resistance (HOMA-IR) values in the three groups of studied patients

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This was in agreement with Ma and colleagues and Giovannucci and colleagues, who examined relations between fasting insulin concentrations or C-peptide concentrations and cancer risk and prognosis. Results reported to date show that the analysis of samples obtained near the time of cancer diagnosis suggest that higher concentrations are associated with a worse prognosis of common epithelial cancers, whereas prospective studies of healthy individuals suggest that those with higher concentrations of these analytes are at an increased risk of aggressive cancer or cancer with a fatal outcome [13] .

A more recent work of Renehan and colleagues has provided evidence that specific germline polymorphisms in certain genes encoding proteins involved in the IGF signaling pathway, including IGF-1 itself, are associated with a variation in cancer risk. In addition, a considerable body of circumstantial evidence relating IGF physiology to cancer risk has accumulated. For example, a high mammographic breast density and a high birth weight, both of which are known to predict increased breast cancer risk, have been associated with higher concentrations of circulating IGF-1 or umbilical cord IGF, respectively [23] .

Also, a weak but detectable positive correlation between the height and the risk of certain cancers may exist because height acts as a crude surrogate for adolescent concentrations of circulating IGF-1 [23] .

In seven studies, individuals with higher levels of circulating IGF-1 and a relatively low level of IGFBP-3 had modest, mostly nonsignificant, increases in the risk of colorectal cancer or adenoma, except in one study, which found a stronger 2-3-fold increased risk [21] . However, in most of the studies, after IGF-1 and IGFBP-3 levels were mutually adjusted for in the statistical analysis, the association between IGF-1 and colorectal neoplasia became stronger and a significant inverse association was observed for IGFBP-3 [21] .

Thus, individuals who have a high level of IGF-1 relative to their level of IGFBP-3 may be at an elevated risk of colorectal cancer. This conclusion is also supported by the fact that acromegalic individuals, who have abnormal levels of IGF-1 due to excessive growth hormone secretion, appear to have an elevation in the colorectal cancer risk [19] .

Univariate and multivariate regression analyses showed that after exclusion of all confounding variables, serum IGF-1 is an independent risk factor for the prediction of cancer in type 2 DM at a serum level of IGF-1 greater than 127.5 ng/ml (P < 0.001, odds ratio 26.5).

After examining the relative contributions of obesity, insulin, IGFs, and diabetes to cancer development, it would appear that the most compelling scenario for cancer development may include a combination of prolonged obesity due to excess caloric intake and the resulting increase in circulating insulin, IGFs, cytokines, and inflammatory molecules.

Compelling research in animals has shown that caloric restriction (>10 to 40% of daily intake) can prevent cancer development with diminished levels of IGF-1, which is believed to play a central role in mediating this effect [24] .

Some differences were noted between our study and other studies. These differences could be related to the variability in the study sample (e.g. ethnicity), the disease duration, and the methodology to assess clinical and outcome variables.

The present study has several limitations including the small patient number. Thus, our results need to be confirmed in larger study samples. In addition, this study was cross-sectional in design and not retrospective. Patients with cancer may often need a longer period of follow-up. Also, other factors known to be associated with cancer, particularly proinflammatory cytokines or inflammatory molecules, were not measured. The presence of these factors could play a role in the emergence of cancer in patients with diabetes.


  Conclusion Top


Thus, this study demonstrates a significant increase of cancer in obesity, insulin-resistant states, and ultimately diabetes. The intriguing data suggest that this increased risk is related to higher levels of insulin and IGF-1. We also noticed that increased insulin and IGF-1 signaling through insulin receptors and IGF-1 receptors can infact induce tumorigenesis by upregulating the insulin receptor and IGF-1 receptor signaling pathways.

Obesity and diabetes are associated with statistically significant and clinically important increased risks of multiple malignancies. This suggests that cancer screening and counseling on lifestyle changes should be a part of regular preventive care in people with obesity and/or diabetes. Conversely, individuals who develop 'typical' obesity-related cancers, especially at a younger age, should be screened for metabolic abnormalities such as insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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Abstract
Introduction
Patients and methods
Results
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Acknowledgements
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