|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 1
| Issue : 2 | Page : 31-37 |
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Diabetes and cancer: Treacherous associations
Rahul Saxena1, Manisha Naithani2, Rohit Saluja3
1 Amity Institute of Biotechnology, Amity University, Uttar Pradesh, Noida, India
2 Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 All India Institute of Medical Sciences, Bibinagar, Telangana, India
| Date of Submission | 20-May-2021 |
| Date of Acceptance | 19-Oct-2021 |
| Date of Web Publication | 28-Feb-2022 |
Correspondence Address:
Manisha Naithani
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand.
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/JCDM.JCDM_9_21
Diabetes and cancer are two severe, heterogeneous, and multifactorial chronic diseases. The frequency of these diseases occurring in the same individual is increasing worldwide at an alarming rate. Multiple research studies indicate the presence of shared modifiable and non-modifiable risk factors between the two diseases. Hyperinsulinemia is one such condition which favors cancer development in patients with diabetes as insulin shares some pre-eminent metabolic and mitogenic effects. While the drugs which are used to treat diabetes exhibit a lower risk of cancer development, the drugs taken to treat cancer may either cause diabetes or worsen pre-existing diabetes. Other hypothesized mechanisms comprehending the relationship between diabetes and cancer include insulin resistance, insulin-like growth factor-1, hyperglycemia, and dyslipidemia. Meta-analyses of many studies indicate that diabetes and cancer are the two sides of the same coin. There may also be a risk of escalation of one disease while treating the other. This phenomenon of reverse effect has been reported in cases of liver and pancreatic cancer, which leads to the progression of diabetes. In our review, we highlight some of the most promising mechanisms which attempt to comprehend this relationship between the two diseases. We conclude that diabetes and cancer have a very complex relationship that requires more clinical attention and better-designed studies. Keywords: Cancer, diabetes mellitus, hyperinsulinemia, reverse causality
How to cite this article:
Saxena R, Naithani M, Saluja R. Diabetes and cancer: Treacherous associations. J Cardio Diabetes Metab Disord 2021;1:31-7 |
| Introduction | |  |
Diabetes and cancer have now become a few of the many frequently diagnosed diseases. Prevalence of diabetes increased from 4.7% in 1980 to 8.5% in 2014.[1],[2] An estimated 1.5 million deaths were directly caused by diabetes in 2019.[1] On the contrary, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths occurred in 2020.[3] Cancer is the second and diabetes the 12th leading causes of death worldwide.[4] India will have 134.3 million persons with diabetes by 2045, as per projections.[5] India also recorded 1.16 million cancer incidence and 784,800 mortalities related to cancer in the year 2018.[6]
| Association: Multitude of Factors | | |
Cases of both diseases are increasing worldwide at a perilous scale, and there are a multitude of factors which need to be uncovered in attempts to define this association of cancer and diabetes.[7] Obesity along with type 2 diabetes mellitus is found to be associated with an increased risk of cancer development and reduced life expectancy. These comorbid conditions are also found to be related with each other in many stages. They get highlighted at the time of diagnosis, therapy resistance, and in cases of disease recurrence.[4],[8-10] Type 2 diabetes and cancer have many common modifiable and non-modifiable risk factors, but probable biologic associations between the two diseases is still unclear. So far, strength and direction of this relationship are observed to be dependent on the cancer site.[7] Moreover, evidence suggests that glucose-lowering therapies are regulating the risk of cancer prevalence in individuals with type 2 diabetes.[11] Being overweight or obese is a definitive risk for the development of various cancers, in both genders.[12] Obesity is a known predisposing factor for type 2 diabetes,[13] which leads to insulin resistance. This in turn may provide a partial explanation for association with cancer. Visceral adiposity [independent of body mass index (BMI)] can be considered as a marker for insulin resistance along with its association with both type 2 diabetes[14] and certain cancers (e.g., colon).[15] Additionally, the socioeconomic status[16] was also found to be closely related to the primary modifiable behavioral risk factors for diabetes and cancer. Likewise, tobacco smoking, more commonly found in individuals with type 2 diabetes, is also a known source of carcinogens.[17] In this review, we will discuss several pieces of evidence which establish an association between type 2 diabetes and cancer, while showcasing few aspects of diabetes which influence this association and understand the mechanism behind it.
| Risk Factors | | |
Diabetes and cancer share a few common modifiable and non-modifiable risk factors such as age, sex, obesity, physical activity, diet, alcohol, and smoking; 78% of all diagnosed cancers occur usually among individuals with age 55 years and above.[18] In contrast, type 2 diabetes has also become common among young adults, increasing the future risk of other diseases such as cancer.[19],[20] The prevalence of cancer and resulting mortality rates are higher in men than in women. Men also have a slightly higher age-adjusted risk of diabetes than women.[21] The age-standardized incidence of cancer and diabetes varies significantly among different populations. Factors that may contribute to this variability include differences in the prevalence of major risk factors, genetic factors, medical practices such as screening, and completeness of reporting.
Being overweight or obese brings increased risk of cancers, breast cancer in particular,[22] and cancer-related mortality, as in cases of prostate cancer.[23] Being obese is linked with the dietary intake of an individual. Studies suggest diets rich in monounsaturated fatty acids, fruits, vegetables, whole grain cereals, and dietary fiber, which are linked with a decreased risk of cancer development[23],[24],[25] and protection against type 2 diabetes.[26],[27] On the contrary, a high glycemic index diet may increase the risk of type 2 diabetes.[24] The association of a high glycemic index diet with increased cancer risk is still unclear.[24],[25],[26] Overcoming obesity is critical and physical activity plays a crucial role in saving an individual from obesity. Evidence from many observational epidemiologic studies suggests that individuals with a higher level of physical activity have a lower risk of endometrial and colon cancer.[23],[27],[28] Physical activity plays a crucial role in averting lung and prostate cancer and improves cancer survival for some cancers, including breast[29] and colorectal.[30]
Moreover, the risk of cancer is also associated with the consumption of alcohol and smoking tobacco. Worldwide, tobacco smoking accounts for an estimated 71% of all lung cancer deaths.[31] Besides lung cancer, smoking is found to be strongly linked with cancers of the larynx, upper digestive, bladder, kidney, pancreas, leukemia, liver, stomach, and uterine cervix. Studies suggest that smoking is also an independent risk factor for the development of diabetes.[32],[33] Additionally, smoking also increases the risk of cardiovascular diseases, retinopathy, and other complications of diabetes; smoking has an adverse effect on diabetes-related health outcomes.[34] Similarly, consumption of alcoholic beverage increases the risk of many types of cancer including those of the oral cavity, pharynx, larynx, esophagus, liver, colon/rectum, and female breast.[35],[36],[37]
| Epidemiology of Type 2 diabetes and Cancer Incidence | | |
Type 2 diabetes has been linked with higher occurrence of many cancers and cancer-related mortalities.[38],[39],[40],[41],[42] The relationship between diabetes and cancer risk is independent of BMI as this association has been reported among Asian and western populations.[43],[44],[45],[46] The risks of breast,[47] colorectal,[48] bladder,[49] non-Hodgkin’s lymphoma (NHL),[50] and kidney[51] cancers are about 20–40% higher among individuals with type 2 diabetes. Additionally, the risk of endometrial cancer also appears to be doubled among women with diabetes.[46] In contrast, prostate cancer incidence is about 10% to 20% lower among men with type 2 diabetes.[52] This negative association could be due to the reduced levels of circulating testosterone in these diabetics.[7] Additionally, lung[53] and ovarian[54] cancer appears not to be associated with diabetes, data for renal cancer and lymphomas are inconclusive.
Preoperative diagnosis of diabetes appears to increase the risk of postoperative mortality for some cancers. In a meta-analysis of 15 reported studies, pre-existing diabetes was associated with increased odds of postoperative mortality across all cancer types, compared with their non-diabetic patients undergoing operative treatment for cancer.[55],[56] In patients with breast cancer, the hazard ratio for 5-year mortality among patients with diabetes was 1.39 compared with non-diabetic women with breast cancer.[57] Similar results are seen in colorectal cancer, with a 32% increased all-cause mortality.[58] Analyses of type 1 diabetes cohorts, compared with the general population, suggest increased risks in ovarian cancer,[54] but these are not consistent across all studies.[59],[60],[61],[62] Notably, there does not appear to be associations between type 1 diabetes and the cancers as much as it is linked with type 2 diabetes.
Meta-analyses of few studies have reported some degree of reverse effect, with cancers like liver and pancreatic[45] itself leading to the onset of diabetes. Particularly in pancreatic cancer, the causative effect of the association with diabetes may be due to the abnormal glucose metabolism caused by cancer itself. However, in reverse scenarios, a positive association between diabetes and higher risk of pancreatic cancer has been found. In such cases, diabetes precedes the diagnosis of pancreatic cancer by 5 years. Thereby, the reverse causative effect is not entirely responsible for the association.
| Biological Mechanisms Linking Diabetes and Cancer | | |
There are a lot of hypothesized mechanisms comprehending the association between diabetes and cancer. The relationship of cancer with type 2 diabetes indicates some common factors which plays a crucial role in the increased risk of cancer in these conditions.[7],[63],[64] Some promising mechanisms to elucidate the relationship between type 2 diabetes and cancers include insulin resistance, hyperinsulinemia, insulin-like-growth-factor-1 (IGF-1), hyperglycemia, and dyslipidemia.[63],[65],[66] Moreover, inflammatory cytokines and adipokines may also be a factor for metabolic dysfunction and promote cancer development.[62],[67] For tumor growth, invasion, and metastasis to happen, healthy cells must undergo few morphologic changes. These changes can be influenced by type 2 diabetes through IGF-1, hyperinsulinemia, hyperglycemia, or chronic inflammation.[68] Such healthy cells which have obtained oncogenic mutations are considered to be vulnerable to the effects of type 2 diabetes, metabolic syndrome, and obesity, enabling cancer progression.
| Insulin: The Missing Linkage | | |
Insulin is a growth factor which upon rising beyond normal becomes a risk factor for several cancers [Figure 1]. Several meta-analyses link higher levels of circulating C-peptide/insulin with increased risk of pancreatic, colorectal, breast cancer and markers of glycemia.[69] Additionally, insulin also has a mitogenic effect on various tissues, especially proven in-vitro in estrogen receptor-positive breast cancer cell lines.[70] Insulin-like growth factor-1 (IGF-1) receptors are responsible for mitogenic effects. Individuals with high circulating IGF-1 are more prone to common epithelial cancers such as colon, breast, and prostate.[70] Particularly, with cases of breast cancer, insulin induces aromatase activity and reduces sex hormone-binding globulin. This also indicates an increase in free estrogen levels, which further increases mitogenicity.[71] Moreover, elevated levels of insulin receptors (IRs)[72] appear to be present in various breast cancer tissues and cancer cell lines. Therefore, hyperinsulinemia may promote the progression of breast cancer. Hyperinsulinemia has also been found to cause a decrease in levels of IGF binding protein-1 (IGFBP-1), thus increasing levels of bioactive IGF-1. Moreover, hyperinsulinemia is found to be associated with decreased recurrence-free survival and overall survival in breast cancer.[57],[73],[74] Additionally, insulin resistance is also associated with a higher production of NEFA, interleukin-6, plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-α.[75] | Figure 1: Potential mechanisms to explain the relationship between type 2 diabetes and cancer include insulin resistance, hyperinsulinemia, insulin-like growth factor-1 (IGF-1), hyperglycemia, and dyslipidemia
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Another mechanism causing an upsurge of risk of cancer development is elevated blood glucose levels. This hypothesis suggests that hyperglycemia can either be a confounder in studies observing increased risk of cancer associated with the use of exogenous insulin therapy or it may contribute to cancer development by underlying “glucose supply hypothesis.”[76] These cancer cells are avid glucose users, and tumor growth might be regulated by glucose availability. The hypothesis is supported by the well-established observation of the correlation between HbA1C and cancer risk in diabetes.[77] A recent meta-analysis also supports the same by demonstrating that elevated serum insulin or C-peptide levels are linked with a significantly increased risk of certain cancers.[68]
Drugs increasing endogenous insulin levels (sulfonylureas, subcutaneous insulin) have been reported to increase cancer risk. Besides this elevated levels of endogenous insulin have also been linked with poor prognosis in breast cancer patients.[78] Although cancer cells constitutively have a higher glucose uptake enabling them to fully satisfy their needs even in normoglycemia,[79] it is still possible that hyperglycemia provides a relative growth advantage. Experimental studies exploring a dose–response relationship between tumor growth and glucose concentration[80] generally show that increasing glucose concentration does favor cell proliferation, but hits a plateau at around 5 mmol/L. Moreover, drugs reducing insulin levels and improving insulin sensitivity (biguanides and thiazolidinediones) may diminish cancer risk. There may also exist a relationship between the duration of therapy and the timing of cancer diagnosis. If cancer risk is exposure-related, a time-related upsurge in cancer development should be documented and current analyses are focussing upon this issue.
| Reverse Effect | | |
Reverse causality should be considered while understanding the temporal relationship between diabetes and cancer. Pancreatic cancer, which by resultant dysfunction of insulin secretion may be sufficient to induce hyperglycemia, is one such example. Similarly, metabolically active liver infiltrated with cancer may result in instabilities in glycemic control. However, it is unlikely that reverse causality is responsible for all observed associations. In the case of pancreatic cancer, which is a fatal and rapidly progressing disease, chances of reverse causality with diabetes can only be justified within a very short time window of fewer than 6 months after the onset of cancer. So forth, increased risk of pancreatic cancer after a long period of diabetes onset is unlikely to be due to reverse causality.[44],[81]
| Discussion | | |
There is emerging epidemiological evidence connecting diabetes with a higher risk of several cancer types from various observational studies. The intrinsic heterogeneity of both diseases makes studies on the association of the two diseases difficult to carry out. Difficulty arises taking into consideration multiple hypothesized mechanisms which may lead to increased cancer prevalence and mortality in diabetic patients, thus making it very difficult to define the selection criteria for subjects in such studies. Establishing an appropriate design for the study has also become a challenge. Recently, consensus report by the American and European Diabetes and Oncology on diabetes and cancer[7] agreed upon an association between diabetes and breast, colorectal, endometrial, liver, and pancreatic cancers as pointed out by many observational evidences. Reports also suggested that a possible pathogenesis link is hyperglycemia, hyperinsulinemia, inflammation, and possibly even diabetes therapies. Their conclusion states that metformin is likely to decrease but insulin is possibly increasing the risk of cancer in diabetic patients. The report also suggested that, in choosing between available therapies for diabetes, cancer risk cannot be a major factor.
In-vitro studies using breast cancer cell lines have pointed out on reduced efficacy of chemotherapy due to concomitant hyperglycemia.[82] Thus, hyperglycemia has emerged as a central player having much say in causation but also a response to therapy. Poorer glycemic control appears to escalate morbidity as well as mortality in patients with cancer.[55]
To further our understanding of the relationship between the incidence of diabetes and cancer with the probable role of glucose-lowering treatments we need more studies. There is an intrinsic heterogeneity in both cancer type and diabetes, with studies on the association becoming more difficult to carry out. Importantly, consideration of various confounding factors and recognition of potential selection bias are important. Observational studies may be riddled with many such problems, and results should be critically reviewed keeping in mind that these assumptions can be tested through sensitivity analyses and definitive demonstration of dose–response relationships. Thus, it calls for the conduction of more rigorous observational studies. By getting a clearer picture of mechanisms linking diabetes and cancer, not only targeted screening for prevention can be introduced but even better therapeutic strategies targeting specific pathways can be sought, thereby reducing mortality in individuals with type 2 diabetes and cancer. To decode this association between diabetes and cancer, we need significant research directed to uncover underlining mechanisms.
| Conclusion | | |
Diabetes and cancer are two synergistic diseases that share many common risk factors. Obesity is one significant risk factor for both diseases which leads to disruption in metabolic processes and increased inflammation. Fat deposits located around internal organs secrete chemicals and send signals that make cells more aggressive, initiating tumor growth and creating insulin resistance, leading to type 2 diabetes. And one illness may feed on the other, suggesting abnormally high insulin levels ultimately leading to cancer. The individual suffering with one of these diseases has a higher chance of developing the other in future years. The mortality rate is also higher among individuals with diabetes-cancer comorbidities. A diabetic woman with breast cancer has a higher mortality rate than women with breast cancer alone. Recent studies reveal that the coexistence of such condition is not coincidental. Diabetes and cancer are two sides of the same coin. For cancer to initiate in the body, a higher blood sugar level is favorable. Cancer cells consume and metabolize glucose at 200 times the average rate. Positron emission tomography scans are designed to detect cancer in the body by locating areas of high glucose consumption. Hence, a medication that lowers blood sugar levels in people with diabetes could also potentially fight cancer by starving malignant cells to death. Metformin, a drug that is used for the treatment of type 2 diabetes, has decreased the risk of cancer development. In contrast, chemotherapy is one successful method to treat cancer, which has reported to induce insulin resistance, bringing on symptoms of diabetes. Similarly, immunotherapy, which is another method of cancer treatment, may bring on the less-common type 1 diabetes, which is essentially an autoimmune disorder. With immunotherapy, the body’s immune system attacks the critical insulin-producing cells in the pancreas. Immunotherapy can cause permanent diabetes. It is conclusive that diabetes and cancer are two sides of the same coin which points to the necessity of researchers in cancer and diabetes to work together. A method for the treatment of one disease may promote another disease. Thus, it is essential to work in close coordination with sharing and dispensing of new information to overcome this association of diabetes and cancer.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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