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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 2  |  Issue : 2  |  Page : 50-55

Need of integrated management of type ii diabetes mellitus as a serious risk factor in modifying outcomes in cancer management: A literature review


Rasayu Cancer Clinic, Pune, Maharashtra, India

Date of Submission19-May-2021
Date of Decision12-Oct-2021
Date of Acceptance13-Oct-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Yogesh Narayan Bendale
Rasayu Cancer Clinic, B-1, Amrutkumbh Apartment, Laxmi Park Soci., Karve Nagar, Pune - 411 052, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaim.ijaim_18_21

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  Abstract 


The Rasayu cancer treatment protocol is based on the philosophy of normalizing the natural cell cycle and enhancing the apoptosis pathways. Rasayana chikatsa modulates Dhatus and Ojas being important therapeutic targets in cancer treatment. Diabetes mellitus can be correlated to Prameha in Ayurveda. Ayurveda believes that Prameha reduce the strength of all the dhatus and also reduce the Ojas. Considering this pathophysiological aspect of Prameha, it can be hypothesized that it cannot only make the dhatus more susceptible to cancer but can also increase the risk of metastasis and recurrence thereby negatively affecting the overall therapeutic outcomes. To support this hypothesis based on fundamental Ayurveda principles, we conducted this literature review with an aim to study and evaluate the available evidence regarding the role of diabetes in pathophysiology and prognosis of cancer. A literature review was done in PubMed from their inception to 1 January 2018. Review was performed using the keywords such as diabetes mellitus, cancer treatment, mortality, cancer metastasis, and quality of life. The present article highlights the available evidence suggesting that diabetes has major impact on various cancer types which directly affects recurrence of cancer, spread of cancer, overall survival, mortality, and morbidity. The approach of targeting Dhatus and Ojas in cancer treatment has shown favorable outcomes in cancer treatment. Hence, besides having strict glycemic control the diabetic treatment should target improving strength of dhatus and increasing ojas using appropriate Rasayana chikitsa. Similar approach should be followed more meticulously in the management of diabetic cancer patients. Further clinical studies are required to validate this hypothesis.

Keywords: Cancer, diabetes mellitus, mortality, quality of life, recurrence, survival


How to cite this article:
Bendale YN, Bendale V, Gund P, Kadam A. Need of integrated management of type ii diabetes mellitus as a serious risk factor in modifying outcomes in cancer management: A literature review. Indian J Ayurveda lntegr Med 2021;2:50-5

How to cite this URL:
Bendale YN, Bendale V, Gund P, Kadam A. Need of integrated management of type ii diabetes mellitus as a serious risk factor in modifying outcomes in cancer management: A literature review. Indian J Ayurveda lntegr Med [serial online] 2021 [cited 2022 Jan 19];2:50-5. Available from: http://www.ijaim.com/text.asp?2021/2/2/50/331489




  Introduction Top


Diabetes and cancer are diseases showed a remarkable impact on health worldwide. In many forms of cancer, people with diabetes are at significantly higher risk which was shown by epidemiologic evidence.[1] There is a close relationship between diabetes and different malignancies; however, potential biologic links between the two diseases are incompletely understood.[2],[3] In 2035, number of diabetes patients will increase from 382 million (in 2015) to 592 million according to the WHO data.[4] There is an increased risk of developing different types of cancers in diabetes patients, generally including breast, pancreatic, liver, bladder, colorectal, and endometrial cancers.[5] These risks may be developed due to special diabetic pathologies such as enhanced inflammatory processes, hyperglycemia, hyperinsulinemia, insulin resistance, oxidative stress, distorted insulin-like growth factor-1 (IGF-1) pathway, and aberrant sex hormone production.[6] It was hypothesized that hyperglycemia is one of the key factors associated with diabetes increases the risk of cancers shown by studies.[7],[8] Elevated blood glucose was associated with tumorigenesis, first proposed by Warburg O.[9]

Nine percentage of all cancer patients had type 2 diabetes at the time of cancer diagnosis. There is a major impact of diabetes mellitus on various cancer treatment outcomes. The cancer burden is increased all over the world, mostly in less developed countries. As per GLOBOCAN 2012, it is observed that due to cancer, worldwide 14.1 million new cancer cases and 8.2 million deaths occurred in 2012.[10],[11] The cancer patient who has diabetes has major influence of diabetes in outcomes as it is seen that there is more mortality in cancer patient who has diabetes and vice versa.[12],[13] Exogenous insulin uses are associated with increased cancer risk.[14] The common causative factors to diabetes and cancer are aging, obesity, diet, and physical inactivity. A possible mechanisms for direct link in diabetes and cancer may be hyperinsulinemia, hyperglycemia, and inflammation.[15] The relative risks imparted by diabetes are most significant (approximately 2-fold or higher) for liver cancers, endometrium and pancreas, and fewer (approximately 1.2-fold to 1.5-fold) for cancers of the colon/rectum, breast, and bladder.[15] Mostly diabetes person has a major risk of to develop hepatocellular carcinoma (HCC) and pancreatic cancer.[16],[17]

Dhatus

Dhatus; a common therapeutic target in the management of cancer as well as diabetes.

In Ayurveda, there are various schools of thought with different approaches to treating cancer. Our system at Rasayu cancer clinic treatment is based on the philosophy of normalizing the natural cell cycle and enhancing the apoptosis pathways; this approach has demonstrated improvement in several therapeutical outcomes of cancer patients.[18],[19],[20],[21]

In terms of Ayurveda, this is achieved using the principles of Rasayana chikatsa which, works by qualitatively improving the Dhatus (tissues) and normalizing their function. Besides this Ojas (essence of healthy dhatus) is also targeted as improvement in Ojas can ultimately lead to enhanced immune response and better overall survival. Thus, Dhatus and Ojas are two important therapeutic targets in cancer treatment.[22]

Diabetes mellitus can be correlated to Prameha in Ayurveda. Ayurveda believes that Prameha reduces the strength of all the Dhatus and also reduces the Ojas. (Ch. Ni 4/27) Both Dhatus and Ojas are the essential therapeutic targets in cancer management as per Ayurveda. As Prameha has a negative impact on both of these, it can be hypothesized that prameha can make the Dhatus more susceptible to cancer and increase the risk of metastasis and recurrence, thereby negatively affecting the overall therapeutic outcomes.

To support this hypothesis based on fundamental Ayurveda principles, we conducted this literature review to study and evaluate the available evidence regarding the role of diabetes in pathophysiology and prognosis of cancer.


  Method Top


Search terms

A literature review was done in PubMed from its inception to January 1, 2018. The review was performed using the keywords such as diabetes mellitus, cancer treatment outcome, mortality, cancer metastasis, quality of life, chemoresistance, and disease free survival.

Study selection

These terms were used to search in PubMed from their inception to January 1, 2018. English language studies on evaluating the effect of preexisting diabetes on numerous types of cancer treatment outcomes used. Search terms and yields are depicted [Table 1].
Table 1: Search terms and yields

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  Results Top


The processed summary of this systematic review on the impact of diabetes mellitus on various types of cancer treatment outcomes are as follows.

Impact of diabetes on pancreatic cancer treatment outcome

Pancreatic cancer is the fourth most commonly found cancer in the world. The pancreatic cancer of early stages does not generally generate symptoms, so the disease is generally advanced when it gets diagnosed. Majorly, the pancreatic cancer patients are diagnosed in the metastatic stage.[23] Combined risk factors include smoking, chronic pancreatitis, and family history. The history of diabetes was considerably more associated to pancreatic cancer mortality in both men and women. The death rate from pancreatic cancer is twice as high in people with diabetics as in nondiabetics. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with a 5-year survival rate of approximately 5%. Diabetes and PDAC had a complex relationships. Insulin released by the β-cells is discharged into an intra-pancreatic portal circulation which provides blood to acinar and ductal cells present adjacent to the islets. These two cell types can be adjacent to the islets and supplied by blood from the intra-pancreatic portal circulation. This proximity permits high levels of islet hormones to directly reach the groups of acinar and ductal cells, which results in exerting proxicrine effects on insulin receptors that are present on acinar cells and on IGF-1 receptors present in any transformed cells that may arise in this region, thereby increasing their survival and proliferation. Consequently, hyperinsulinemia, particularly intrapancreatic, resulting from obesity and insulin resistance in prediabetes or early type 2 diabetes mellitus (T2DM) can probably contribute to the detected increased risk in PDAC.[24]

Impact of preexisting diabetes on liver cancer treatment outcomes

Liver cancer is the worldwide 6th most commonly found cancer and the second leading cause of death from cancer; the most common liver cancer types are HCC and cholangiocarcinoma. Its major cause is chronic liver inflammation, chronic viral hepatitis infection (hepatitis B or C). Diabetes mellitus patient has a two-fold risk to have cancer and most important is the prognosis of liver cancer also changes as per the presence of diabetes. Four studies show a high risk of liver cancer recurrence if preexistence of DM in liver cancer.[25] There are some studies show that high mortality and morbidity in liver cancer patients who have preexisting diabetes.[25] Some studies suggest that DM is enhancing to spread colon cancer to spread at liver cancer.[26]

The liver is an important organ, which responsible for many essential processes necessary for homeostasis. The liver is responsible for detoxification as well as for the production of certain digestive biochemicals like bile and also a production of albumin, coagulation factors, and a multitude of other basic compounds. The liver performs many roles in carbohydrate metabolism including glycogenesis, gluconeogenesis, and glycogenolysis, as well as lipid metabolism, including triglyceride and cholesterol production. The liver is capable of producing and utilizing amino acids resulting in protein synthesis through the transaminases. The transaminases are also known as aminotransferases consist of two enzymes; aspartate aminotransferase (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (serum glutamic-pyruvic transaminase [SGPT]). Usually, due to locating inside the hepatocytes, their serum concentrations of these enzymes are low. In liver injury, the hepatocyte cell membrane permeability changes and becoming leaky; as a result, enzymes (SGOT and SGPT) enter the blood. The extreme release of transaminases in advanced grade cancer cells may likely be due to the increased nonadaptive physiological activities in tumorigenic and stoned or inflamed tissues in liver.[27]

Impact of preexisting diabetes on endometrial cancer treatment outcomes

Some study shows that endometrial cancer is associated with excessive estrogen exposure, high blood pressure, and diabetes. Endometrium cancer is the third most common cause of death in cancers which only affect women, after ovarian and cervical cancer.[28] Endometrial cancer may be hereditary and causes a contribution of around 2%–10% of endometrial cancer cases. Three studies show preexisting diabetes endometrial cancer patients have a high recurrence and poor overall survival.[28] Preexisting diabetes enhances to spread endometrium cancer to lymph node.[29] Diabetes mellitus is correlated with raised incidence and disease-specific mortality in endometrial cancer.[30] There is an increasing risk of breast and endometrial cancer in postmenopausal women who do not use hormone replacement therapy because body fat becomes the primary site of estrogen synthesis, and obesity is associated to elevated serum estrogen. Estrogen bioavailability increases since hyperinsulinemia decreases the liver production of sex hormone-binding globulin. Hyperinsulinemia enhances bioavailable testosterone, which is also associated to cancer risk in women.[31]

Impact of preexisting diabetes on bladder cancer treatment outcomes

Bladder cancer is the type of cancer found in tissues of the urinary bladder. Males are more affected than females and its onset often in between 65 and 85 years. Diabetic individuals have an increased mortality of bladder cancer.[32] Diabetes increases the risk of bladder cancer recurrence.[33] Furthermore, diabetes mellitus has an impact on progression-free survival on bladder cancer.[34]

The probable mechanisms underlying the relation of DM with bladder cancer risk have been indecisive. Several possible mechanisms have been proposed, including the impact of hyperglycemia, insulin resistance, or hyperinsulinemia. Aside from the direct effects of insulin on cancer cells, the effects of promoting tumor cell growth may also be mediated indirectly through IGF-1 receptors. Elevated insulin concentrations reduce the level of IGF-binding protein 1, which increases the amount of bioactive IGF-1. IGF-1 has mitogenic and anti-apoptotic activities and might be act as a stimulus for growing neoplastic and preneoplastic cells. It was proposed that patients with bladder cancer have elevated plasma levels of IGF-1.[35]

Impact of preexisting diabetes on colorectal cancer treatment outcomes

Many colorectal cancers are diagnosed in old age, and some cases have hereditary risk. Colorectal cancer is considered as the third most common type of cancer. Around 1.4 million new cases and 694,000 deaths from the disease in 2012. Three studies suggest colon cancer patients with diabetes have poor survival.[36] Some research shows preexisting diabetes cancer patients who do the surgery has more risk of mortality.[37] Preexisting diabetes mellitus colon cancer has a risk of cancer recurrence.[38] Patients with colorectal cancer and T2DM have a higher risk of mortality than patients with colorectal cancer who do not have T2DM, particularly an advanced risk of death from cardiovascular disease.[13],[39],[40]

Impact of diabetes on renal cancer treatment outcome

It is the cancer of cells of the kidney; there are two main types of kidney cancers, renal cell carcinoma (RCC), and transitional cell carcinoma. Diabetes mellitus is associated with decreased overall survival in patients with surgically treated clear cell RCC.[39] Patients with clear cell RCC has a risk of mortality in diabetes mellitus.[39] Diabetes mellitus with obesity is an interpreter of recurrence in renal cancer patients.[41],[42]

Type 2 diabetes has been correlated with increased prevalence and poor oncologic outcomes across numerous cancers. Studies yielded conflicting results evaluating the connection between type 2 diabetes and the risk of RCC. As type 2 diabetes and RCC incidences increases, it is very important to understand their association. Since hypertension and obesity are strongly linked with type 2 diabetes, addition to both are the established risk factors for RCC; considering these conditions, evaluation of the association between type 2 diabetes and RCC is critical. However, studies were carried out to evaluate this correlation and have adjusted for these important confounders. The studies were varied accordingly in the ascertainment of diabetes status (physician-confirmed vs. self-reported), use of RCC versus total kidney cancer as the outcome, and inclusion of patients with type 1 diabetes.[43],[44]

Impact of diabetes on lung cancer treatment outcome

Lung cancer occurred in 1.8 million people among them 1.6 million deaths resulted worldwide in 2012. It is the main common cause of cancer-related death in men and also the second most common in women after breast cancer. Small-cell lung carcinoma (SCLC) and non-SCLC (NSCLC) are the two main types of lung cancer. If lung cancer patients have diabetes mellitus, then it affects treatment outcomes. Progression-free survival and overall survival of lung cancer with an advanced stage is very low who have diabetes even after first-line chemotherapy.[45] Diabetes people have a higher risk of lung cancer mortality, and the most affected group is the youngest age.[46] Diabetes was established to be an independent predictor of the local recurrence risk following resection of NSCLC.[47]

The lung cancer incidence might be different in diabetes patients and the general population. For lung cancer, major risk factor is smoking and in smokers, both insulin resistance and type 2 diabetes were increased.[48],[49]

Impact of diabetes on breast cancer treatment outcome

Breast cancer is mostly found leading type of cancer in women and accounts for 25% of all cases. Around 1.68 million new cases and 522,000 deaths occurred worldwide in 2012, in developed countries, it is more common and is more than 100 times common in women than in men. Breast cancer patients and preexisting diabetes have more risk of mortality. Some studies show that around 37% risk increased to breast cancer about mortality who has diabetes compared to nondiabetes.[50] Diabetes mellitus is also responsible for an increased risk of cancer recurrence or a second breast cancer event.[51] Insulin use in a breast cancer patient who has diabetes has more risk for mortality.[51] Obesity and type 2 diabetes are characterized by chronic low-grade inflammation, which increases free radicals production that can damage DNA and disrupt insulin signaling. Ensuring genetic mutations can lead to cancer. Adipose cells produce a variety of pro-inflammatory cytokines (cell-to-cell signaling proteins), including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). IL-6 and TNF-α trigger activation of signaling pathways that induce the expression of genes that promote cell proliferation and angiogenesis and inhibit apoptosis. Human studies showed that elevated levels of IL-6, TNF-α, and C-reactive protein (a biomarker of inflammation) are considered the most significant risks for breast, prostate, and lung cancers.[52],[53]


  Conclusions Top


Considering all published research of preexisting diabetes to various types of cancer patients, it can be concluded that diabetes has a major impact on various cancer types that directly affects recurrence of cancer, spread of cancer, overall survival, mortality, and morbidity. Although a large number of Ayurveda physicians follow the Dhatu and Ojas based approach to treat various cancers, there is a paucity of scientific evidence to support this. This literature review provides evidences to support the concept behind the treatment based on Ayurveda about targeting Dhatus and Ojas in cancer treatment. This also leads to the insight that while treating cancer, we have to consider diabetes as a risk factor and improve quality of dhatus and ojas besides strict glycemic control. There should be an approach to minimize the depraved impact of diabetes on the cancer patient. Rasayana chikitsa provides important pharmacological as well as nonpharmacological approaches to qualitatively improve dhatus and ojas. Hence, improving the strength of all the Dhatus and increasing Ojas using appropriate Rasayana chikitsa should be an integral part of the cancer management protocol in diabetic patients. Further, clinical studies are required to validate this hypothesis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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