The Relation Of Breast Cancer With Usage Of Insulin Glargine In Kuwait

Objectives of the Research

The research is intended to focus over the relation of breast cancer with the usage of insulin Glargine in Kuwait. The objectives of the research imply the risk factors related to breast cancer as a result of the long-term utilization of Insulin Glargine amongst those women who have Type 2 and type 1 diabetes.  . Both qualitative and quantitative methods  would be applied for the research in order to analyse the data and statistics procured and retrieved. The qualitative method would be the data derived from sources such as online books and journals and presenting them in a literal form. The quantitative methods would include statistical data and the budgetary consideration. The scope of further research related to cancer genes, relevant hormones,enzymes, tumour markers, with mammography density.

The research would imply the review of the relevant literature in order to demonstrate the  relation between breast cancer and insulin accordingly. An analysis of the literature gap would also be provided in order to imply the aspects which need to be addressed in the future if any further research or analysis is to be conducted. The qualitative and quantitative methods of research are to be reviewed accordingly in order to conduct the research in an effective and efficient manner. The research is also intended to benefit the general public through the healthcare perspective.

Insulin analogues defined as biosynthetic hormone designed to simulate human insulin pattern. Insulin analogues divided into two groups. First, Fast-acting insulin analogues as Lispro,  Aspart, and  Glulisine, this group have onset time between 5-15 minutes and they can reach the peak of concentration level in serum during 45-90 minutes, and overall duration of about 4 hours. Second, long-acting insulin analogues as Detemir, Degludec, and Glargine. Besides, they characterized by an effective duration end within 24-42 hours and onset action range 30 mins-3hrs.

Insulin glargine is an artificial form of human insulin hormone, Insulin glargine produced by used non-pathogenicE. coli bacteria through biotechnology rule called recombinant DNA technology. Insulin glargine used in the treatment of type 1 and type 2 diabetes. In type 1 diabetes the pancreas failed to release insulin due to an autoimmune reaction destroys beta cells. In general, type1 diabetes patients born with pancreatic failure which lead them to start their medication regimes with insulin injections. Otherwise, type 2 diabetes patients can not generate anenough insulin, and that will progress until complete lack of insulin release, which leads them to consume exogenous insulins. The chemical structure of insulin glargine is a 51-amino acid protein consisting of two polypeptide chines connected by disulphide bonds. On the other hand, insulin glargine works by binding in the cell membrane receptors particularly on Tyrosine Kinase receptor which leads to activate glucose transporters GLUT-1 and GLUT-4 to allow to glucose pass to the cell.

Type 1 and Type 2 Diabetes and Treatment with Insulin Glargine

Consequently, Insulin promotes the liver to store glucose as glycogen, improve muscles to protein and potassium uptake within glycogen synthesis and helps adipose tissue to load triglycerides. The suggested initial dose of insulin glargine in diabetic patients with type 2 diabetes is 0.2 Units/kg or up to 10 Units once daily,

afterward, a consultant can titrate the dose to target optimal fasting blood glucose (FPG) the American diabetes association recommended that FPG is 80-30 mg/dl while American association of clinical endocrinologists recommended less than 110 mg /dl. In contrast, diabetic patients type1 recommended a starting dose of ( Basaglar® and Lantus®)   should be around a third of the total daily insulin demands. 

Breast cancer ranked as the second place among cancer types in the UK and USA. Breast cancer more prevalence in females rather than males. Otherwise, benign tumours are more common than malignant ones in the female breast. Although, breast cancer is rare in those women under 25 years old. The risk factors of breast cancer are exposure to high radiation levels, the presence of family and personal history associated with breast cancer. The genetic mutations play a crucial role in breast cancer incident; both genes BRCA1 and BRCA2 link strongly with increase incident chance of breast and other types of cancer.

It should be noted, obesity and high BMI values considered as the second preventable cause of cancer UK. Meanwhile, starting of menstruation at age less 12 years or end of menopause stage at a period after 50 years boost opportunity of breast cancer. Also alcoholism, infertility and consuming pre or post menopausal therapy*. The sorts of breast cancer are ductal carcinoma in situ, inflammatory breast cancer, invasive lobular carcinoma, male breast cancer Paget’s disease of the breast and finally, the most common type is an angiosarcoma. Further, symptoms of breast cancer include the appearance of foreign masses or changes in breast size, morphological changes in breast skin, newly inverted nipples and scaling in a pigmented zone surrounding the nipple. Apoptosis is programmed death of cells. Usually, the apoptosis  regarded by proteins groups and pathways such as [Phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB)]; another pathway is [RAS / Mitogen-Activated Protein Kinase (MAPK)/ Extracellular signal-regulated kinase (ERK)] sometimes the genes relevant to these pathways mutated which leads to activated the previous pathways continually consequently the cell lack the ability to die. This process related directly to the insulin-like growth factor IGF-1.

Risk Factors for Breast Cancer

According to (Busko, 2017), long-term insulin glarginecanincrease the possibility of breast cancer occurring. As per the statistical report of observational study, the type 2 diabetes has negative effect compared to the intermediate acting neutral protamine hagedron insulin for increasing the breast cancer risks (Rose and Vona-Davis, 2012). More specifically, women, who have received NPH insulin glargine increase the risk of breast cancer by 1.4-fold.  Likewise, the men also suffer from the problem of breast cancer after intaking of insulin glargine. Nonetheless, the adjusted hazard ratio of intaking insulin glargine for the men is 2.15% less compared to the women (Rose and Vona-Davis, 2012). In this regard, it can bed stated that the men between the age group of 60 years to 70 years, mostly suffer from the disease of breast cancer.

1. Wu et al.(2017) found, if women receive 30 IUinsulin glarginegreater than or equal to five years, then it can increase the risks of breast cancer. Therefore, it can be inferred that if the patients receive insulin glargineinjection such as Lantus® and Toujeo®long term, it would tend to maximize the risks of breast cancer. Since, the stability of Toujeo is more than Lantus, therefore, it have strong impact on the minimization of diabetes. However, Toujeo has adverse impact on the breast cancer.

As opined by Christopoulos, PMsaouel and Koutsilieris (2015), the increase in insulinlike Growth Factor 1(IGF-1) in blood level linked clearly with breast cancer via impaction on Estrogen Receptors positive (ER+) also the increase of (IGF-1) serum level connected withBreast cancer 1-early onset protein (BRCA-1) mutation. Furthermore, Mammography density could be associated with (IGF-1) elevation in serum.

Ahmed (2010) adds that, though receiving of insulin is beneficial to remove the excessive sugar from the human body, however, it would increase the occurrence of degenerative disease risk. Therefore, receiving of higher level of insulin would be the development of different kinds of cancer. For instance, if the women would receive 10 IU insulin glargine every day, then the occurrence of breast cancer risks would be increased by9%, while the women would take 50 IU insulin glargine each of the day, then the cancer risks would be increased by 31% more. (Hemkens et al.,2009)

Human Insulin not only signals glucose uptake into cells, But Human Insulin also has effects on cell proliferation, growth, survival, and apoptosis. It has properties that can influence an accretion in cell proliferation, and possibly the potential for malignancy. Insulin analogs have an increased mitogenic potential — they will cause the cells to proliferate more. Especially, insulin glargine has about seven times the mitogenic potential as human insulin. Thus when Human insulin replaced by Insulin glargine, that is mean the responding of insulin receptors will change because Insulin glargine is more than six times affinity toward IGF-1 receptors compared with human insulin.

Calle and Kaaks (2004) demonstrate that the mechanism of breast tumor formation is related to hyperinsulinemiahigh serum insulin levels. Raised insulin levels lead to activate insulin receptors then accretion in releasing mutagenic signal to epithelial cell ofmammarygland. Besides, elevated insulin levels result in a drop in the synthesis of both sorts of IGF-binding proteins (IGFBP) one and two including sex-hormone-binding globulins (SHBG) which results in increased bioavailability of IGF-I and estradiol (E2), respectively. Both IGF-I and E2 have carcinogenic abilities to mutate mammary cells, which can play a crucial role in the initiation or development of breast cancer.

Relation between Insulin and Breast Cancer

Insulin receptors can be divided into two isoforms IRA and IRB, each of which has a different binding affinity toward insulin-like growth factor. The IRB have metabolic action presence in adults’ tissues while IRA highlights in the fetal and prenatal period with mutagenic activities. In this context, any dysregulation in both IR isoforms could be associated with different pathologies. For instance, insulin resistance, obesity, diabetes atherosclerosis and cancer. Worth mentioning that IRB and IRA are affected by insulin analogues and human insulin.

It is fair to say the adjustment of synthetic insulin chemical structure to enhance thebioavailability of insulin has been a revolutionary trend in promoting diabetic patients’lifestyle — unfortunately, this chemical modification reflected in the increase of insulin analogues affinity for IGF-IR verses human insulin. Lantus ® showed up to eight-fold higher mutagenic potency compared to human insulin. Insulin Glargine was also demonstrated to have higher mutagenicity in primary cultures of normal fibroblasts and smooth muscle cells which expressed high levels of IGF-IR and IRS-1 proteins. Furthermore, excess overexpression of IRS-1 has been shown to have carcinogenic effects through promoting cell generation, inhibiting basal and oxidative stress-induced autophagy, and finally minimizing cell death rate. (Orgel&Mittelman,2013);(Christopoulos,Msaouel&Koutsilieris, 2015)

Shukla (2009) states that insulin analogues were more potent than regular insulin by inducing “MCF7” colonies formation. On the other hand, insulin analogues have a noticeable effect on Estrogen receptors type alpha (ERα) that means insulin glargine can play estrogen role in initiate and progression of breast cancer.

As per theKuwait Times (2018)report, Kuwait is at the top 7^th positionworldwide in the prevalence of diabetes. Otherwise,The International Diabetes Federation (IDF)out of 2.9 million adults in Kuwait, 441000 people had diabetes.According toKuwait Life Sciences Company (2016)in 2015the annual growth rate of insulin glargine in Kuwait had touched 67.3% equivalent to 26.7 million Kuwaiti dinars ~ £ 67.4 million. As per the recent study,Alkandari, et al., (2018) cited that the percentage of prevalence the disease has enhanced to17.4% in the year 2014 among female population in Kuwait. Similarly, WHO (2016) pointed out that the number of diabetic Kuwaiti women jumped by one-third between 1994 and 2014. According to Al Hassan (2017), the Kuwait state has one of the largest proportions of type I diabetes with a yearly occurrence of 41 cases per 100,000 children between the age groups of 0 to 14 years. Logically this rise in diabetic patient’s numbers will be accompanied by a steady increase in selling rate of insulin glargine in Kuwait.Because insulin glargine is more common in anti-hyperglycemic medication regimes for both types diabetes (type 1& type2) due to administrative convenience (one dose every 24 hours) andaccuracy in controlling blood glucose level.

Mitogenic Potential of Insulin Analogues

Al Ramadhan, (2017) claims that cases of breast cancer among women in Kuwait represent 38.3% of the newly reported cancer cases in 2012.In this context, Wu et al. (2017)mentioned that long-term exposure to insulin glargine is associated with an increased opportunity for breast cancer incidence in females with diabetes mellitus type 2 in contrast with insulin detemir by (HR, 1.44; 95% CI, 1.11 to 1.85).

Worth mentioning that Lantus ® produced earnings of USD 5.65 billion in 2017, a drop of 6.61% from the previous year. A legitimate question arises, namely what has changed in medical practices leads to this decline in Lantus ® sales.

Are doubts and questions about the relationship between insulin glargine and cancers related to this decline?Or the appearance of new generations drugs such as Trulicity ® (dulaglutide)&Victoza® (liraglutide) impact on Lantus ® revenues?Or that Common sideeffects connected with Lantus ® such as hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain were cause that decay.

This paper has discussed the open question about the relationship between insulin glargine and breast cancer risks. Based on the analysis, it can be observed that receiving insulin glargine would have a direct effect on the breast cancer of the patients. However, the FDA, Medicines and Healthcare products Regulatory Agency and European Agency for the evaluation of medicinal products have not made any recommendations to prevent or restrict the use of insulin Glargine, which shows a gap between hypothesis or theory and evidence-based practice to coping withdoubts surrounding insulin glargine.

Some of the previous studies failed to put in accounts smoking, BMI, the relation of cancer and metformin as a milestone in the diabetic treatment regimes, the medication periods, ages and impaction of diabetes upon cancer progression.(Buse, 2009)

This is where you outline the research need(s) and justify what you are wanting to study and why. You haven’t done this yet…

The main aim of the research is to derive an understanding/explanation of any association between breast cancer and insulin intake, and the nature of that association.

Any objectives (stages/steps/phases) in achieving this goal?

Research approach refers to the plans and procedures consisting of the steps associated with the data to be collected, the analysis and findings of the research and interpretation derived from it. The research approach can be categorized into approach ofdata generation and the approach of data analysis. The research approach focuses on a single concept and brings a value to the study conducted. It helps in validating the accuracy of the findings and creates an agenda for change. It also helps in analyzing the variable to study and relates them to the research questions framed.

The following research will involve collecting both quantitative and qualitative secondary data and develops a rationale to the study. The qualitative data will require the use of inductive approach of analysis while the quantitative data will use deductive approach. A consistency in both the methods and analysis will be maintained while conducting the research further. In this research proposal, the data will be collected keeping in mind the risks associated with it and how it can be mitigated. The possible risks may arise due to quality of the studies collected, issues of merging with previous information or studies, and risks associated with breast cancer. The data so collected will hold authenticity and acceptable data collection methods to derive the desired results.

The following research will involve information based on the relationship between insulin glargine and breast cancer risks. This will require to identify the collection of secondary qualitative and quantitative data. In this context, secondary qualitative data and quantitative data refers to collecting evidence from previously available information and studies. The qualitative and quantitative data will be collected from the published data available in various publications of the state government and 5 major health areas in Kuwait.

The qualitative data will constitute of articles on the rise of diabetes in Kuwait, scholarly journals, books and researches conducted on diabetes and its cure which can be identified by using specific keywords Glargine, Breast Cancer, Insulin, and rise of cancer in Kuwait region. The research will focus on identifying the studies conducted to analyze the link between cancer and prolonged use of insulin and its long-term effects.

The quantitative data will be collected from Google scholar, Cochrane library, PubMed in Kuwait. The information will be collected for over the span of last 20 years from 1998 to 2018 on number of patients affected by prolonged use of Insulin and also patients suffering from breast cancer. As Kuwait is considered as top 10 countries suffering from diabetes, there are medicines available to mitigate the risk of rising diabetes in the people of Kuwait. The quantitative data will be collected from previous published researches on diabetes and its relation with insulin. The relevant information will be derived from already published medical data on diabetes and breast cancer from Medical websites of Kuwait. The data will be collected from the laboratory results of the patients suffering from breast cancer.These results can be identified from their medical prescriptions from the government pharmacies to know about their glargine consumption. This will specify if the risk of increase in breast cancer is due to taking insulin or not. The data and facts will be gathered from database available on women of different age groups treated with either Insulin glargine (Basaglar, Lantus and, Toujeo) used to cure diabetes in Kuwait. The research will also focus on collecting evidences that will determine the rate at which breast cancer is rising and how much more it will rise soon.

The following research proposal will be a well-documented report on the link between the prolonged use of insulin and the risk of breast cancer in women in Kuwait. The findings from the secondary data will be analyzed in this section of the research proposal. The secondary quantitative data on number of patients affected from diabetes and suffering from breast cancer will be derived either by using Excel or SPSS. The secondary qualitative data will be analyzed to justify the information collected from the previous researches. The findings will help in analyzing the various researches and studies on conducting the effect of using diabetic medicines such as Insulin glargine (Basaglar, Lantus and, Toujeo) the analysis will identify the other factors associated with breast cancer such as age and BMI. Otherwise, fluctuation of estrogen and progesterone as a result of using insulin glargine. Relation of mammography readings and consumed insulin glargine units. The data collected will analysedusing either SPSS or Microsoft Excel.

Every research conducted carries potential risks attached to it which requires to be mitigated in order to continue with the research.The challenges associated might arise due to conducting systematic literature review is merging previous findings of different studies because it were carried out by different ways in terms of participants numbers and study lengths. Further, judging studies in terms of quality wither low or high is complicated job. Also biased researcher to  select subjects more likely to generate the desired outcomes considered as one of briars     The risks can be related to collecting official statistics which limit the data required to continue the research. Apart from this, the risks can be associated with the fact that breast cancer can happen from many other factors. For example, family history, chemicals, radiations, alcoholism, stress, race and smoking. Evaluating these issues is difficult.

Provide details on the expected costs of the research using the table format provided below.

 7. Time lines 

Ethical Issues

In order to conduct any kind of research and analysis, ethics are to be followed properly and complied with accordingly. For example, the permission of the authorities to access patients’ registry. The permission of the government authorities would also be obtained in order to access their records relevant to the research. The data retrieved from the internet would be given due credibility regarding the websites, online journals and eBooks. It implies that approval of the ethics committee must be obtained prior to the commencement on the research. There would be no hacking of websites for the collection of the appropriate data for the research as such kinds of activities give rise to various kinds of cybercrimes to a huge level.

As a result of the research, various kinds of people would be benefitted. The academic researchers and analysts in the areas medical research in the future would be provided with an evidence-base on which to conduct further research and analysis into aspects of breast cancer and its cure in the desired manner. The alternatives to the use of insulin for diabetic patients based on the fact regarding its side-effects would also be analyzed. The public, in general, would also be benefitted as such research would imply an improvement in the healthcare sector and patients would not have to spend vast amounts on cancer treatment as they would be helped with the dosage to be taken in an appropriate manner.

Attempting to help create recommendations for contributing to medical guidelines, clarifying and interpret insulin glargine and breast cancer relationship. If causes any harms should be taken with precautions if not clarifying for medical staff and patients also the drug safety matter. As well as reconsidering or consider giving insulin to breast cancer patients had diabetes.

The outcomes of the research would be imparted into the scientific community through its publication in scientific journals and relevant online websites and forums. Various conferences amongst doctors may also be conducted for the same at the global level. Peers in Kuwait would also be benefitted as a result of the research. Feedback must be provided related to the research with respect to clinics in Kuwait. The health care institutes in Kuwait must also equip themselves with the aspects of the research and aid the potential researchers with the outcomes of the research to carry out further analysis.  Events related to seminars and networking would help the general public to get a brief overview of the research. Impartment of training to the future scientists may also help the carrying forward of the research.

References 

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D’Esposito, V., Passaretti, F., Hammarstedt, A., Liguoro, D., Terracciano, D., Molea, G., … &Formisano, P. (2012). Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro. Diabetologia, 55(10), 2811-2822.

Dalamaga, M. (2013). Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets. World Journal of Experimental Medicine, 3(3), 34.

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Kuwait Times. (2019). Living with diabetes. Retrieved from https://news.kuwaittimes.net/living-diabetes/

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Wu, J.W., Azoulay, L., Majdan, A., Boivin, J.F., Pollak, M.D., &Suissa, S. (2017). Long-Term Use of Long-Acting Insulin Analogs and Breast Cancer Incidence in Women With Type 2 Diabetes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35 32, 3647-3653 .

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