Type 2 Diabetes Mellitus and Cancer: Phenotyping of Patients at a Third-level Diabetes Centre
Conditions: Diabetes Mellitus, Type 2, Cancer
Sponsor: Azienda Ospedaliero Universitaria Maggiore della Carita

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
 
 
CLINICAL STUDY, OBSERVATIONAL, NON-PROFIT 
 
 
TITLE: Type 2 Diabetes and Cancer: Phenotyping of patients followed 
in a tertiary diabetes center 
 
PROTOCOL CODE: TCPT2023 
 
MAIN PROMOTER: A.O.U. Maggiore della Carità, Novara 
 
PRINCIPAL INVESTIGATOR: Prof. Flavia Prodam 
 
 
 
 
Version 1.0 - 10/09/2023 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
SUMMARY 
1. INTRODUCTION………………………………………………………..………………………….…....3 
2. OBJECTIVES……………………………..…………………………………..………………………….5 
3. MATERIALS AND METHODS……………………………………………...……………………..…...5 
3.1 Study design…………………………………………………….……………………..……..5 
3.2 Participating Center……………………………………………………………………..…….5 
3.3 Patients………..…………….…………………………………………….…………………5 
3.3.1 Inclusion criteria………………….…………………………………………….…..5 
3.3.2 Exclusion criteria……………………………………………………………….….6 
3.4 Intervention…………..…………………………………………………………………...….6 
3.5 Study duration………………….……………………………………………………..…..….6 
3.6 Follow-up and events of interest…….……………..………………………………………..6 
3.7 Data collection………….……….…………………………………………………………...7 
3.8 Sample size………………………..….…………………………………..………………….8 
3.9 Statistical Analysis…………………………………………………………………………..8 
4. EXPECTED RESULTS………………………………………………………………………………..…9 
5. ETHICAL CONSIDERATIONS…………………………………………………………………..……..9 
5.1 Informed consent management………………………..……………………..………..……..9 
5.2 Management of sensitive data………………………..………..…………………..………..10 
5.3 Data processing methods………………………….……………….…………………....….10 
6. COSTS………………………………………………………………………….…………………..…...11 
7. REFERENCES…………………………………………………………………………….………..…...12 
 
 
 
 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
1. INTRODUCTION 
The relationship between type 2 diabetes (T2D) and cancer has gained considerable attention and 
importance in recent years. These are two highly prevalent conditions in the global population with a 
significant impact on the healthcare system: in fact, estimates from the International Diabetes Federation 
(IDF) show that approximately 537 million people suffer from diabetes, the majority of whom have T2D. 
(1) 
The association between the two conditions has been widely studied, revealing how some metabolic 
processes can be common and influence each other. Hyperglycemia itself, caused by poorly controlled 
diabetes, can result in the development of a chronic low-grade systemic inflammatory state; this 
environment arises as a consequence of chronic glucose stimulation of certain mechanisms, including 
the calcium signal, which leads to the release and increase of inflammatory cytokines and consequent 
inflammatory cells. (2) Furthermore, in addition to perpetuating the inflammatory state, there is an 
escalation in ROS (reactive oxygen species) production, triggering oxidative stress and DNA damage, 
thus advancing cancer development. (3) 
Concerning the chronic inflammatory state, it is also crucial to consider the role of obesity, being one of 
the most important and studied common elements between the two pathologies. In response to hypoxia 
and oxidative stress, adipose tissue produces high levels of leptin, a pro-inflammatory adipokine. (3, 4) 
This overproduction can disrupt the equilibrium between leptin and other adipokines, encouraging a 
state of meta-inflammation that enhances cancer development. It promotes processes such as epithelial-
mesenchymal transition (EMT) and cellular adhesion to the extracellular matrix (ECM) (3), while also 
facilitating cancer immune evasion. (5) It is therefore important to understand how the increase in leptin 
related to obesity, a risk factor often present in the diabetic population, also plays a significant role in 
cancer. 
Finally, another factor contributing to this inflammatory microenvironment and cytokine production is 
dyslipidemia, particularly the increase in fatty acids. (3) 
Not surprisingly, in addition to these molecules, the microbiota also plays a significant role. Dysbiosis, 
implicated in various diseases, has been associated with cancer as well, owing to its capacity to influence 
the genomic stability of host cells and modulate numerous signaling pathways. Consequently, a 
correlation has been demonstrated between reduced richness of intestinal microbiota and metabolic 
dysfunctions, including insulin resistance and inflammation. (6) 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
Another important characteristic of T2D, namely hyperinsulinemia, can also be part of and contribute to 
the development of cancer. High levels of insulin stimulate not only the insulin receptor but also insulin-
like growth factor (IGF-1) (4), which is implicated in the onset and development of various types of 
cancers. Studies on murine models have shown how the administration of IGF-1 not only promotes the 
proliferation of cancer cells but also their ability to metastasize. (7) 
In addition to this hormone, mTOR is also a central molecule, which regulates processes such as growth 
and metabolism, (8) thus potentially playing a role in both pathologies. Dysregulations of metabolism 
with increased nutrient intake, as in the majority of patients with T2D, lead to hyperactivation and 
stimulation of this signal, which contributes to the worsening of diabetic pathology with increased 
insulin secretion. (9) 
The same signal can activate various mechanisms, including the MAP kinase pathway, which is 
frequently subject to mutations in some types of cancers. Furthermore, hyperactivation of the mTOR 
pathway contributes to the promotion of pro-oncogenic proteins, which control fundamental processes 
for the survival of cancer cells, such as angiogenesis, metabolism, and the capacity for metastatic spread. 
(10) 
An interesting metabolic phenomenon is the Warburg effect, which explains how, despite ample oxygen 
availability, cancer cells prefer to generate energy through glycolysis, which requires increased glucose 
uptake, making the hyperglycemic environment advantageous for cancer cells. Moreover, this process 
leads to increased production of a precursor of advanced glycation end products (AGEs), which means 
that the Warburg effect not only affects the metabolism of cancer cells but also contributes to the 
development of diseases by promoting the accumulation of AGEs. (3) 
Finally, even diabetes drugs could be implicated. One extensively studied drug is metformin, which has 
shown potential as an antineoplastic agent in diabetic subjects, unlike exogenous insulin, which seems 
to act as a growth factor potentially implicated in cancer proliferation. (11) 
All these common metabolic processes, as well as others, highlight the importance of carefully 
characterizing the population of diabetic patients also affected by cancer in order to understand the 
associated risk factors. As cancer represents a complication of diabetes, this study underscores the 
primary objective, which is to emphasize the necessity for tailored prevention strategies in clinical 
settings. These strategies aim to address specific diabetes-related risk factors that potentially contribute 
to cancer onset. 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
 
2. OBJECTIVES 
The primary objective of the study is to identify risk factors for cancer onset in the population affected 
by T2D.  
Secondary objectives include: 
1. Description of demographic, clinical, and first-line therapy characteristics of patients at the 
diagnosis of T2D. 
2. Evaluation of risk factors for recurrence, presence of a second cancer unrelated to the first, and 
presence of both events in patients who have had cancer. 
3. Investigating the correlation between patient characteristics and time to cancer onset. 
 
3. MATERIALS AND METHODS 
 
3.1 Study Design 
The study follows a retrospective, monocentric cohort design, utilizing data sourced from the Smart 
Digital Clinic electronic medical record (Meteda Srl). 
 
3.2 Participating Center 
Endocrinology and Diabetology Outpatient Clinic of the SCDU of Novara, University of Eastern 
Piedmont. Responsible: Professor Flavia Prodam. 
 
3.3 Subjects 
All patients visited at the Endocrinology and Diabetology Outpatient Clinic of the AOU Maggiore della 
Carità in Novara for a first diagnosis of T2D between 1990 and 2010 will be included in the study. 
 
3.3.1 Inclusion Criteria 
• Adult age 
• Diagnosis of T2D 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
3.3.2 Exclusion Criteria 
• Diagnosis of tumor before the diagnosis of T2D 
• Diagnosis of secondary diabetes due to other pathologies 
• Diagnosis of secondary diabetes due to other medications 
• Diagnosis of secondary diabetes due to surgical interventions 
 
3.4 Intervention 
No intervention of any kind. 
 
3.5 Study Duration 
24 months. 
 
3.6 Follow-up and Events of Interest 
Patients included in the study will be followed from the date of diagnosis of T2D until the date of the 
last available visit. 
During the follow-up, for all included patients, the year of onset of the first cancer occurring after the 
diagnosis of diabetes and the type of cancer will be recorded. From this information, it will be possible 
to calculate the time elapsed between the diagnosis of diabetes and the onset of the tumor (measured in 
years). 
For patients who have developed cancer, the following will also be recorded: 
• Cancer recurrence (year of recurrence onset) 
• Diagnosis of a second cancer unrelated to the primary cancer (year of onset, type of cancer) 
Cancer diagnosis will be identified through the extraction system from the Smart Digital Clinic 
electronic medical record (Meteda Srl), using relevant keywords in the cancer domain, identified in the 
medical history section. The keywords will include: metastasis, adenocarcinoma, carcinoma, neoplasm, 
secondary, sarcoma, cancer, adenoma, lymphoma, leukemia, glioma, glioblastoma, basal cell carcinoma, 
squamous cell carcinoma, melanoma, mesothelioma, chordoma, anaplastic, differentiated, 
undifferentiated, meningioma, multiple myeloma, small cell carcinoma, thymoma, craniopharyngioma, 
neuroendocrine, LH, NHL, K, GIST, HCC, and NET. 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
3.7 Data Collection 
For each patient, the following variables will be extracted from the Smart Digital Clinic electronic 
medical record extraction system, when possible: 
• Gender and age; 
• Smoking habit and alcohol consumption (units per day); 
• Weight and body mass index (BMI) at the first (T0) and last visit (T1); 
• Date of diagnosis of T2D; 
• Date of the first visit; 
• Treatment for T2D at T0 and T1; 
• Levels of glycated hemoglobin (HbA1c) at T0 and T1, average HbA1c, and average fasting blood 
glucose; 
• Creatinine clearance at T0 and T1; 
• Liver enzymes at T0 and T1: alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST); 
• Lipid profile at T0 and T1: low-density lipoprotein (LDL-c) and triglycerides (TG); 
• Complications of T2D; 
• Treatment for the cancer; 
• Family history of cancers. 
The diagnosis of T2D is confirmed at diabetic centers or, in some cases, by general practitioners who 
refer patients to specialized diabetic centers. The accuracy of the diagnosis will be confirmed by cross-
referencing with the Piedmont Diabetic Registry (PDR) and involving a second person to ensure precise 
assessment. 
 
Glycated hemoglobin will be considered high if its values exceed or equal 8%, indicating glycemic 
decompensation, while it will be considered low if it presents values below 8%. 
 
BMI categories will be divided into underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 – 25 
kg/m2), and overweight (BMI >25 kg/m2). 
 
Regarding the treatment of T2D, participants will be categorized and grouped for statistical purposes 
into the following classes: 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
• Dietary therapy; 
• Metformin/Acarbose; 
• Sulfonylurea; 
• Metformin + GLP1/DPP4 inhibitors (DPP4i) or only GLP1 or only DPP4i; 
• Metformin + SGLT2 inhibitors (SGLT2i) or only SGLT2i; 
• Basal insulin + GLP1/DPP4i +/- Metformin; 
• Basal insulin +/- Metformin +/- SGLT2i; 
• Basal bolus insulin; 
• Basal bolus insulin +/- Metformin +/- SGLT2i. 
Furthermore, complications of metabolic pathology will be extracted from the dedicated section of the 
program, where they are systematically recorded and organized, and their diagnosis is conducted in 
accordance with appropriate guidelines. These complications will be divided into the following 
categories: vasculopathy, neuropathy, hypertension, heart disease, renal failure, and retinopathy. 
Finally, regarding cancer, treatment will be categorized into three classes: chemotherapy, surgery, and 
radiotherapy. Additionally, cancer types will be divided to ensure greater homogeneity among groups, 
including the nervous system, head and neck, thorax, gastrointestinal, gynecological, urinary tract, male 
genital system, skin, blood, breast, soft tissues, endocrine glands, and neuroendocrine cancers. 
Such information will be collected at the diabetes diagnosis visit and the last visit before cancer onset 
for subjects experiencing the event, and at the last available visit for the remaining subjects. 
 
3.8 Sample Size 
Assuming a type I error of 0.05, a power of 80%, a prevalence of subjects with high glycated hemoglobin 
levels of 13%, and a correlation between covariates in the model of 0.1, it will be necessary to identify 
779 cancer cases to highlight a Hazard ratio of 1.2 for the association between glycated hemoglobin and 
cancer onset. 
 
3.9 Statistical Analysis 
Descriptive statistics will be calculated to summarize patient information. 
Categorical variables will be reported as absolute frequencies and percentages, while numerical variables 
will be reported as mean and standard deviation or median (Q1-Q3) if not distributed according to a 
normal random variable according to the Shapiro-Wilk test and observation of the QQ plot. 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
Univariate and multivariate Cox proportional hazards regression models will be used to estimate hazard 
ratios (HRs) and corresponding 95% confidence intervals (95% CI) for the association between some 
risk factors, including particularly glycemic level, and cancer onset. The stepwise method will be used 
to select variables to include in the model. For this analysis, time to event will be calculated as the 
number of years between cancer onset and diabetes diagnosis for subjects who develop the cancer, and 
as the number of years between the last available visit and the date of diabetes diagnosis. The possibility 
of conducting an analysis separately for cancer type or considering specific cancer types based on the 
number of observed events will be evaluated. The same models will be used to estimate the association 
with the risk of recurrence, second cancer, or both in patients who have developed cancer. In this case, 
time to event will be calculated considering the difference in years between recurrence onset, second 
cancer, or last visit and the onset of the first cancer. 
Linear regression models will be used to evaluate the relationship between variables measured at 
diagnosis and time to cancer onset. In case the assumptions of the linear model are not met (normality 
of residuals and homoscedasticity), the Spearman correlation coefficient will be calculated to measure 
the correlation between numerical variables and time to tumor onset, while the Mann-Whitney or 
Kruskall-Wallis tests will be used when variables measured at baseline are categorical. 
The significance level will be set at 0.05, and all tests performed will be two-tailed. Finally, the analyses 
will be conducted using SAS software (version 9.4; SAS Institute, Cary, NC, USA). 
 
4. EXPECTED RESULTS 
Through this research, we aim to obtain new information about the study population in order to better 
understand the possible correlation between the two pathologies. This will enable us to identify risk 
factors associated with metabolic pathology that may influence the development time of cancer, as well 
as to identify those that may contribute to carcinogenesis itself. 
This knowledge will allow us to define the role of hyperglycemia, obesity, and other risk factors or 
behaviors in the context of cancers in order to act with appropriate prevention strategies, considering 
cancer as one of the possible complications of T2D. 
 
5. ETHICAL ASPECTS 
The study has been designed and will be conducted in accordance with international and national ethical 
standards for biomedical research involving human subjects, particularly: 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
• 
Ethical principles for medical research involving human subjects (Declaration of Helsinki - 
World Medical Association, current version); 
• 
Good Clinical Practice (ICH/GCP) guidelines of the European Union; 
• 
Convention on Human Rights and Biomedicine (Oviedo Convention of 04/04/1997); 
• 
Italian codes of ethics for healthcare professions and specific national legislation regarding 
clinical studies. 
The study is observational compared to what is done in normal clinical practice. 
 
5.1 Informed Consent Management 
An informative sheet is available explaining the type of study, the purposes, procedures, sample and data 
collection, potential benefits of the research, the absence of specific risks, as it is an observational study. 
This information will be presented to interested individuals, who will have the freedom to give consent 
or to withdraw it from the ongoing study. 
 
5.2 Management of Sensitive Data 
The following European and national regulations are taken into account: 
• 
Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 and 
subsequent amendments published in the Official Journal of the European Union 127 of 23 May 
2018 (GDPR); 
• 
Legislative Decree 30 June 2003, n. 196 (Personal Data Protection Code), as amended by 
Legislative Decree 10 August 2018, n. 101 containing "Provisions for the adaptation of national 
legislation to the provisions of Regulation (EU) 2016/679"; 
• 
Article 8 of Legislative Decree 101/2018 of 19 September 2018, for the processing of data 
concerning minors under the age of 16, for the expression of informed consent. The Legislative 
Decree harmonizes the Privacy Code (Legislative Decree 196/2003) with EU Regulation 
2016/679. 
 
5.3 Data Processing Methods 
The study involves the collection of information regarding lifestyles and pathologies of the subjects 
involved. The personal/sensitive data collected will be immediately pseudonymized by randomly 
assigning alphanumeric anonymous codes, which will be known and held only by the responsible 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
research experimenter. Therefore, only the responsible research experimenter will be able to link the 
information and data obtained from their analysis to a specific subject. 
Personal data will be processed for the purposes outlined in the project, according to the principles of 
lawfulness, fairness, transparency, purpose limitation, data minimization, and accuracy (Art. 5 GDPR) 
in both paper and electronic form by authorized data processors. The availability, management, access, 
storage, and usability of the data are guaranteed by the adoption of technical and organizational measures 
to ensure adequate levels of security (Arts. 25 and 32 GDPR). 
The data obtained from the research will not be retained beyond the time necessary for data analysis. 
Only researchers involved in the study will have access to the data. The research results will be made 
public or used for communications/scientific publications, only in anonymous and aggregated form. 
The data controller is the A.O.U. Maggiore della Carità in Novara. 
 
6. COSTS 
The funds available to the Investigator derive from the NODES project, which has received funding 
from the MUR - M4C2 1.5 of the PNRR with grant agreement number ECS00000036. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AZIENDA OSPEDALIERO-UNIVERSITARIA “MAGGIORE DELLA CARITÀ” 
UNIVERSITÀ DEL PIEMONTE ORIENTALE 
SCDU di Endocrinologia 
Direttore: Prof. Gianluca Aimaretti 
 
SCDU di Endocrinologia  
AOU Maggiore della Carità, Via Mazzini 18, Padiglione G, 28100 Novara 
Tel. 03213733209 (Reparto); Fax. 03213733905 
segreteria.endodiab@maggioreosp.novara.it 
 
 
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Fu Z, Gilbert ER, Liu D. Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell 
Dysfunction in Diabetes. Vol. 9, Curr Diabetes Rev. 2013.  
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales MA. Association between diabetes and 
cancer. Current mechanistic insights into the association and future challenges. Molecular and Cellular 
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Cignarelli A, Genchi VA, Caruso I, Natalicchio A, Perrini S, Laviola L, et al. Diabetes and 
cancer: Pathophysiological fundamentals of a ‘dangerous affair.’ Vol. 143, Diabetes Research and 
Clinical Practice. Elsevier Ireland Ltd; 2018. p. 378–88.  
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Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez- Gay MA, et 
al. Obesity, fat mass and immune system: Role for leptin. Vol. 9, Frontiers in Physiology. Frontiers 
Media S.A.; 2018.  
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Chiefari E, Mirabelli M, La Vignera S, Tanyolaç S, Foti DP, Aversa A, et al. Insulin resistance 
and cancer: In search for a causal link. Vol. 22, International Journal of Molecular Sciences. MDPI; 
2021.  
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Yakar S, LeRoith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in 
tumor growth and progression: Lessons from animal models. Vol. 16, Cytokine and Growth Factor 
Reviews. 2005. p. 407–20.  
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Mao Z, Zhang W. Role of mTOR in glucose and lipid metabolism. Vol. 19, International Journal 
of Molecular Sciences. MDPI AG; 2018.  
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Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Vol. 168, Cell. 
Cell Press; 2017. p. 960–76.  
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Laplante M, Sabatini DM. MTOR signaling in growth control and disease. Vol. 149, Cell. 
Elsevier B.V.; 2012. p. 274–93.  
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Shlomai G, Neel B, LeRoith D, Gallagher EJ. Type 2 diabetes mellitus and cancer: The role of 
pharmacotherapy. Vol. 34, Journal of Clinical Oncology. American Society of Clinical Oncology; 2016. 
p. 4261–9.