Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Apr 1.
Published in final edited form as: Curr Diab Rep. 2013 Apr;13(2):213–222. doi: 10.1007/s11892-012-0356-6

The Links Between Insulin Resistance, Diabetes, and Cancer

Etan Orgel 1, Steven D Mittelman 2,
PMCID: PMC3595327  NIHMSID: NIHMS431712  PMID: 23271574

Abstract

The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.

Keywords: Apoptosis, Caloric Restriction, Cancer, Chemotherapy Resistance, Glargine, Insulin, Insulin Resistance, Metabolic Syndrome, Metformin, Obesity, Proliferation, Diabetes

Introduction: A Divergence in Paths

Concern regarding a potential association between diabetes mellitus (DM) and cancer risk first arose at the turn of the previous century [1] based on clinical observations of the coincident disease processes. This was supported by the simultaneous and sustained increase in the incidence of both diseases until recently [2;3]. Despite frequent convergence of the diagnoses in individuals, a divergence is now present in the incidence of the two diseases. The latest estimates show increased incidence and prevalence of DM in both the United States and globally [3;4], with a forecast of over 500 million individuals with diabetes by the year 2030 [5;6]. In contrast, the incidence of cancer which had been steadily increasing since the 1970’s has currently plateaued. There is even a decreased incidence being reported for some malignancies, such as breast and colorectal cancer--two cancers strongly associated with the presence of DM [2;7;8]. The question facing clinicians therefore is: are these independent processes whose parallel rise is a result of similar responses to external forces (i.e. changes in the sensitivity of diagnosis, environmental influences, host changes in activity, nutrition, and other currently unknown factors) or does a true physiological link exist between the two diseases that will again accelerate the incidence of cancer? Furthermore, if a connection is present, do the existence of diabetes and the choices made in the treatment of the disease affect the development of, and/or outcome from, the various types of cancer? With the surge in publications within the field over the past year, this review will critically address these primary questions to help better understand the relationship between diabetes and cancer.

The Association between Diabetes and Risk for Developing Cancer

New evidence does, in fact, support an association between diabetes and cancer, albeit of a far more granular nature than the broad strokes of early reports. To be more precise, as displayed in Table 1, multiple meta-analyses and other large cohort studies published over the past year support an association between the presence of Type 2 DM (T2DM) and an increased incidence of many site-specific malignancies, including colorectal [9], hepatic [10], pancreatic [11], breast [12], endometrial [13], and urinary tract malignancies [14]. Most compelling is the persistence of this association across multiple international populations and the full spectrum of age and ethnic groups while controlling for all known confounders (e.g. smoking, body mass index, hormonal influences/menopause where relevant).

Table 1.

Association of Insulin Resistance and Site-Specific Cancer Incidence

Association With Specific Categories of Malignancy
Increased Incidence within Malignancy Category Decreased Incidence or No Effect Controversial or Unknown
Non-Insulin Dependent Diabetes Mellitus (Type 2 DM) Esophageal
Colorectal
Pancreatic
Hepatocellular Carcinoma
Renal Carcinoma
Breast
Endometrial
Urinary System
Prostate
Lung
Ovarian
Lymphoma
Acute & Chronic Leukemia
Bone Sarcomas
Soft Tissue Sarcomas
Thyroid
Brain
Skin
Metabolic Syndrome (MetS Pancreatic
Hepatocellular Carcinoma
Breast
Endometrial
Cervical
Lung
Ovarian
Brain
Skin
Thyroid
Lymphoma
Acute & Chronic Leukemia
Bone Sarcoma
Soft Tissue Sarcoma
Prostate
Urinary System

Yet, despite these strong statistical associations, many questions remain unanswered. For instance, if this is a broad physiologic oncologic effect as a result of T2DM, why does a protective association exist solely for prostate cancer? Adults with T2DM appear to actually have a 25–40% reduced lifetime risk of developing prostate cancer versus those without DM [15]. Similarly, while many hormonally-mediated tumors such as breast and endometrial cancers demonstrate an increased incidence in patients with T2DM, others such as ovarian cancer show no such increase in incidence [16]. Finally, common methodology constraints due to the observational cohort design lead to the presence of (A) detection bias (i.e. increased detection of cancer because of heightened levels of general health surveillance through treatment for T2DM) and/or (B) reverse causality (i.e. T2DM developing as a result of the malignancy). Two new studies help to shed light on the latter through accounting for the relative timing of diagnosis of T2DM and the malignancy. They found that while the association may not be as extreme as previously thought, the association between T2DM and certain cancer types is still present even when accounting for length of diagnosis of T2DM prior to diagnosis of malignancy and remains significant even with long periods of follow-up after diagnosis of the cancer [11;17]. A further understanding of the relationship between T2DM and malignancy is necessary through studies designed to specifically address causality, a question that has remained strictly beyond the purview of the trials to date.

Treatment for Type 2 Diabetes Mellitus and Cancer Incidence

Two primary hypotheses have been formulated regarding the potential mechanism of this relationship. The first such hypothesis combines the known episodic or continued hyperglycemia due to DM with the Warburg effect [18]; cancer’s reliance for energy on anaerobic metabolism requires high levels of glucose to fuel the reaction and therefore cancer growth may be facilitated by high levels of available glucose. Clinical studies supporting this idea are inconsistent. While a high glycemic load even in non-diabetic patients has been associated with increased risk for developing endometrial cancer [19], the association was not consistent across all malignancies [20]. Further, studies of intensive versus standard glycemic control in patients with diabetes failed to affect cancer incidence as would have been expected if the process is mediated by hyperglycemia [21]. The second proposed etiology attributes increased cancer incidence on the growth promoting effects of insulin [22]. Clinical examination of this theory can be drawn from studies of various oral agents and whether a difference in cancer incidence is present between oral agents that operate via heightened levels of insulin (i.e. sulfonylureas and meglitinides) and those that do not (i.e. glucosidase inhibitors, biguanides, thiazolidinediones). Studies comparing metformin, the most commonly used biguanide, to other hyperglycemic drugs are the clinical cornerstone of this theory. Use of metformin has been consistently associated with a reduced risk for developing a malignancy as compared to other oral drugs [23;24]. Conversely, and also consistent with the theory, a new study has reported sulfonylureas to be associated with greater incidence of cancer than metformin although not as high an incidence as with exogenous insulin [25]. Two new studies, however, challenge the relevancy of this clinical evidence for the insulin hypothesis through their identical finding that insulin-sensitizing thiazolidinediones are also associated with increased incidence of bladder and colorectal cancer despite the fact that they do not raise insulin levels [26;27]. Metformin continues to be tested as both an anti-cancer therapeutic agent in addition to whether it contributes to decreased incidence. Pending further information as to whether a true difference exists, the recommendation continues to be choosing the drug best clinically indicated for the treatment of the patient’s hyperglycemia.

Exogenous insulin has also been studied in the context of the hypothesized insulin-mediated oncogenic effect. The alarm over exogenous insulin causing cancer was first raised in 2004 in the context of colorectal carcinoma [28]; in 2009, the concern became more widespread through a landmark cohort study by Hemkens et al that found that insulin dose and use of the long-acting insulin analogue, glargine, both correlated with increased risk for malignancy [29•]. From the time of publication, this finding raised a storm of controversy, with conflicting reports concurrently extracted from registry studies [30;31]. It is notable that the initial corroboratory study from the Swedish cohort reported by Jonasson et al, was reported this past year to show no further evidence of association now that the cohort has been expanded to include the intervening years since the initial report [32]. Contemporary studies predominantly show no association between insulin glargine and site-specific malignancies although certain exceptions exist for particular subsets such as pancreatic and prostate cancer [3335]. The strongest evidence to date supporting the absence of a relationship between insulin and cancer was recently published in the New England Journal of Medicine [36]. It reports the results of a large prospective clinical trial (“The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial”) in which a subset of individuals were randomized between insulin glargine and standard of care to determine its impact on cardiovascular outcomes. The study also measured the incidence of overall and site-specific cancers and showed no differences between the two study groups. Unfortunately, as cancer incidence was only a secondary outcome, interpretation of the results remains complicated by the use in both study groups of a mixture of insulin, metformin and other oral glycemic agents, which as describe above, may directly influence cancer incidence. In summary, the ideal prospective studies specifically targeting the relationship between insulin and cancer have yet to be done and are unlikely to be performed due to issues of cost and feasibility caused by the necessity of complicated clinical regimens such as those found within the ORIGIN trial. Therefore, while current evidence supports the safety of insulin glargine, the concern over the oncogenic potential of insulin glargine will likely remain inconclusive.

Diabetes and Cancer Outcomes

Earlier cohort studies also raised the concern that DM was related not just to cancer incidence but cancer survival too. Around this time, a large cohort study also reported DM to be associated with increased mortality across a wide variety of site-specific malignancies including colon, pancreatic, breast, liver, and bladder cancers [37••]. The deleterious effect of pre-existing DM on survival continues to be validated across multiple cohorts and the full spectrum of cancer types [38;39] and appears to potentially be correlated even with the degree of hyperglycemia itself [40]. Similar to the evidence regarding choice of glycemic agent and incidence of cancer, multiple reports implicate metformin as the lone drug that consistently improves cancer survival across multiple cancers [41;42] although it should be noted a lack of benefit has been reported in a few cancers as well [41;43].

Insulin Resistance, Metabolic Syndrome & Cancer Incidence

Hyperinsulinemia and/or hyperglycemia are central components to current theories regarding the link between diabetes and cancer; elevated insulin levels due to insulin resistance (IR) in so-called “pre-diabetic” individuals has the potential to shed further light on the nature of this hypothesized relationship. To examine the potential association between IR and cancer across large cohorts and time periods is difficult, however, without an associated clinical diagnosis. Metabolic syndrome (MetS) supplies the key to this doorway. MetS is the definition for a group of diagnoses strongly associated with IR and may therefore be a potential surrogate marker of IR that can be found in clinical studies. In fact, a vast pooled cohort study titled the “Metabolic Syndrome and Cancer Project” or “Me-Can Study” provides exactly this opportunity to examine a connection between IR and cancer. The cohort consists of nearly a million subjects assembled from various Europe prospective studies over the course of the past 40 years and analyzes a collection of self-reported risk factors and clinical measurements for any association with various site-specific cancers [44]. Contemporary publications from this large cohort and others describe metabolic syndrome to be closely associated with the increased incidence of and/or mortality from a broad range of site-specific malignancies (including colorectal [45] cervical [46], liver [47], bladder [48], breast [49;50], and pancreatic cancer [45]) along with similar exceptions (ovarian and lung cancers) [51;52]. Interestingly, both skin and brain cancer, whose association with DM remains currently unexplored, showed no relationship with metabolic syndrome [53;54].

The MetS literature is complicated, however, by its clinical definition remaining a loosely-defined entity causing vast discrepancies in the diagnosis of MetS and reports of its prevalence [55]. This variation must be recognized in analysis of the above historical cohorts. Recent estimations have become more precise due to a composite definition disseminated in 2009 that will facilitate ongoing investigation [56]. Despite these limitations, the large cohorts included and the consistent effect found across multiple populations supports the existence of an association between MetS and cancer. The similarity in the associated oncogenic findings between MetS and clinical DM also promotes the concept that this is in fact mediated by a common factor, whether it is hyperinsulinemia, hyperglycemia, or some currently unrecognized feature.

In summary, a large number of prospective observational trials support the relationship between T2DM and increased cancer incidence and mortality. The strength of this association was formally recognized by the American Diabetes Association and the American Cancer Society in a joint statement in 2010 [57••]. Much remains to be learned regarding the nature of the connection between DM and cancer that can guide clinical decision making. An urgent need exists for further in-depth trials targeted at answering the question of causality as well as any differences in incidence or mortality due to different glucose-lowering strategies.

Laboratory Evidence & the Basis for Further Clinical Trials

Despite the well-established epidemiological links between obesity, DM, IR, and cancer, the mechanisms linking these phenomena remain unclear. In vitro and animal models help provide some hint to this complex relationship and provide information regarding potential therapeutic targets for intervention.

The Role of Insulin in Cancer

Insulin is secreted by the beta cells of the pancreas in response primarily to glucose and other fuels. Obesity-induced IR is compensated for by an increase in insulin secretion, leading to fasting and post-prandial hyperinsulinemia. For individuals in whom IR progresses to T2DM, treatment frequently includes insulin secretagogues, insulin, or insulin analogues, which often requires achieving elevated levels of insulin to maintain appropriate glycemia in the face of continued IR. Thus, many patients with MetS and/or frank T2DM live in a persistent state of hyperinsulinemia.

In fact, insulin’s role extends beyond glucose metabolism. The insulin receptor is a tyrosine kinase which exists in two isoforms: IR-A and IR-B. IR-B is expressed primarily in insulin-sensitive tissues and signals its metabolic effects through activation of the phosphoinositide 3-kinase (PI3K) pathway. IR-A is expressed in fetal tissue and cancer cells, and signals cell survival and proliferation through the Ras-mitogen-activated protein kinase (MAPK) pathways [58]. Both receptors signal through activation of insulin receptor substrate (IRS) family proteins, including IRS-1.

The involvement of insulin signaling in cancer pathogenesis has become evident from studies that show expression of insulin signaling proteins are poor prognostic markers. Recently, insulin receptor expression was found to be an independent, albeit weak, predictor of decreased overall survival in non-small cell lung cancer (NSCLC) [59]. Insulin receptor phosphorylation and/or IRS1 expression have been implicated in risk for metastases in colorectal [60] and endometrial [61] cancer.

Further, Morvan et al. showed that culturing human melanocytes at twice the standard glucose and insulin concentrations for 3 weeks was associated with carcinogenesis, as shown by increased rates of proliferation, DNA content, chromosomal aberrations, p-Akt, and c-Myc [62]. IRS-1 overexpression has also been shown to have oncogenic effects through promoting cell proliferation, inhibiting basal and oxidative stress-induced autophagy, and ultimately decreasing cell death in NIH/3T3 fibroblasts [63]. Conversely, insulin’s cancer-promoting role is also demonstrated through studies in which insulin signaling is blocked. Indole-3-Carbinol (I3C), a hydrolysis product of glucobrassicin which is found in cruciferous vegetables, arrests proliferation of breast cancer cells through decreased expression of both the IGF1 receptor and IRS1 [64]. Dual inhibition of the insulin and IGF-1 receptors enhances breast cancer sensitivity to doxorubicin [65] and decreases hormone-independent growth [66]. All of these associations between insulin signaling and cancer demonstrate its important role in cancer cell pathogenesis.

Although insulin signaling via both the PI3K and MAPK pathways can contribute to cancer cell proliferation [67], several recent studies across multiple cancer types highlight the importance of the PI3K/AKT pathway in cancer pathogenesis. Insulin stimulates proliferation and migration of breast and colon cancer, and these effects are reversed by AKT inhibitor A6730 and PLCγ inhibitor U73122 [68]. IRS-1 and -2 overexpression also prevents glucose-induced caspase 3 cleavage in human neuroblastoma cells, and this effect is reversed by PI3K inhibition [69]. Inhibiting PI3K similarly reduces the growth of Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse model [70].

In addition to outright hyperinsulinemia, individuals with IR and T2DM have elevated circulating levels of proinsulin, thought to be due to impaired beta cell processing [71]. Since proinsulin binds to the IR-A isoform and stimulates receptor phosphorylation, it too can potentially contribute to the IR-cancer link [72].

Although most studies support the cancer-promoting effect of insulin signaling, there are a couple recent exceptions which highlight the complexity of these pathways. Cao et al. showed that αPGG, an insulin receptor activator, induces apoptosis in cancer cells [73]. Porter and colleagues found that IRS1 expression in 32D myeloid cells actually enhances sensitivity to chemotherapy induced apoptosis, an effect mediated through Annexin A2 [74]. While these exceptions may be from differences in experimental techniques, they also raise the concern that the effects of insulin signaling may not be uniform and likely vary between cancer cell types and subtypes.

insulin analogues

Diabetes treatment is becoming more reliant on the use of insulin analogues, which allow patients to attain more physiological pharmacodynamic patterns of insulin action. Glargine, a basal insulin analogue, has come under recent scrutiny, as discussed above. Glargine does exhibit similar effects on cancer cells as endogenous insulin, as one would expect. For example, glargine promotes proliferation and suppresses apoptosis in the MCF-7 breast cancer cell line [75]. However, there is little mechanistic evidence that glargine has disproportionate cancer promoting activity. One recent study showed that glargine may stimulate the insulin receptor/IGF-1 receptor hybrid with more potency than insulin and similar potency to IGF-1. However, the EC50 of this stimulation was well above (~50–100 times) levels normally obtained in vivo, and the primary breakdown products of glargine actually had less potency than insulin [76]. Another study found that glargine can upregulate expression of miRNAs in pancreatic cancer cells which promote cell proliferation; however, this was at concentrations roughly 1000 times physiological levels. [77]. In contrast, Pan et al. found that glargine at a near-physiological concentration of ~350 pM increased proliferation of ALL cells by 20–30%, which was slightly higher than equimolar regular insulin and aspart insulin [78]. Glargine also appeared to cause ALL resistance to daunorubicin in this study. Since peak glargine concentration is on the order of 200 pM [79], these findings are concerning, and should stimulate further work in this area.

Metformin

A number of in vitro and animal studies have addressed whether metformin has a direct anti-cancer effect, and have shown some promising results. For example, metformin enhances UVB-induced DNA repair in skin, which could potentially prevent malignant transformation [80]. In addition, metformin decreases leukemia cell proliferation rates and enhances sensitivity to daunorubicin [78]. These effects appear to be mediated via a variety of mechanisms, including inhibition of growth via NFκB and mTOR pathway inhibition [81], increasing mitochondrial ROS production [82], targeting of STAT3 [83], and direct cytotoxicity via both caspase-dependent and PARP-dependent mechanisms [84]. Earlier studies had found metformin to selectively target cancer stem cells [85], with recent studies extending these findings to ovarian [86], pancreatic [87], and thyroid cancer [88]. Cufi et al. showed that breast cancer initiating cells resistant to Trastuzumab are particularly susceptible to metformin cytotoxicity [89]. Similarly, Appleyard et al. showed that metformin can slow xenograft breast cancer cells, and phenformin can do so more potently [90].

In all, there is exciting in vitro evidence supporting the epidemiological finding of metformin’s direct, anti-cancer effects. Given the beneficial safety profile of metformin, further work is certainly justified to continue exploring its potential use as adjunctive therapy.

Insulin-like Growth Factor-1 (IGF-1)

IGF-1 is a potent growth factor with a role in cancer pathogenesis, which has been linked in epidemiological studies to cancer. In obese individuals, total IGF-1 levels are often normal or even low due to decreased concentrations of IGF binding proteins, though the free/active IGF-1 levels are generally higher than in the non-obese. IGF-1 signals some of the same pathways as insulin, including PI3K, ERK, AKT, and mTOR, which as described above could increase cancer cell proliferation and impair apoptosis. IGF-1 can also increase normal cell cycling, leading to increased risk of mutation and malignant transformation. Most circulating IGF-1 is produced by the liver, though paracrine secretion of IGF-1 occurs at the growth plate, and perhaps other tissues [91]. Although a thorough review of the links between IGF-1 and cancer are beyond the scope of this article (see [92] for a recent review) we will describe some of the basic understanding of the role of IGF-1 in cancer, as well as highlight some recent findings of interest in this area.

IGF-1 receptor expression has been linked to poor prognosis in a number of cancers. Increased IGF-1 receptor expression in NSCLC is associated with poor prognosis [93], and IGF-1 receptor expression was noted to be higher in hepatocellular carcinoma cancer stem cells [94]. Cisplatin resistant lung cancer cells were found to have increased IGF-1 receptor signaling [95].

IGF-1 has recently been shown in vitro to enhance proliferation in prostate cancer cells [96]. Interestingly, adipocyte secretion of IGF-1 has been demonstrated to directly stimulate breast cancer cell proliferation in vitro [97••]. IGF-1 similarly modulates colon tumor cell growth via stimulation of NFκB signaling and inflammatory response [98]. Lau et al. showed that IGF-1, perhaps via an autocrine signal, represses E-cadherin expression in ovarian cancer cells [99], which could thereby increase the risk of metastasis.

As with insulin, inhibition of IGF-1 signaling has anti-cancer effects. Knockdown of the IGF-1 receptor enhances chemotherapy sensitivity in some studies [95;100]. IGF-1 receptor antibody has been explored as a treatment, and recently shown to have in vitro efficacy against a small subset of gastric cancer and hepatocellular carcinoma cells, specifically those that express a high level of IGF-1R/Insulin Receptor heterodimer [101]. A few recent studies have explored the role of miRNA in IGF-1R expression in cancer. IGF-1 receptor expression was shown to be downregulated by miR-497 [102] and miR-139 [103] in colorectal cancer, and miR-7 in gastric cancer [104], both highlighting the potential roles of these miRNAs as anticancer agents and reaffirming IGF-1’s apparent oncogenicity.

Given the cross-talk between signaling of the IGF-1 receptor, insulin receptor, and other growth receptors, some have hypothesized that IGF-1 signaling could represent a mechanism of resistance to therapies targeting signaling pathways [105]. For example, Qi et al demonstrated that IGF-1 receptor blockade acts synergistically with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, in gefitinib-resistant NSCLC [106]. In addition, Kim et al. showed that an IGF-1 receptor tyrosine kinase inhibitor was cytotoxic to NSCLC cells which expressed wild-type, but not those with EGFR mutations [107]. Conversely, immunohistochemistry measured expression of IGF-1 receptor in NSCLC from patients previously treated with gefitinib was not associated with prognosis, and in fact co-expression of IGF-1 receptor and EGFR appeared to be associated with improved outcome [108]. A recent Phase II clinical trial of erlotinib (EGFR antibody) and R1507 (IGF1-R antibody) in patients with NSCLC showed no significant benefit of IGF1R targeting [109], while another Phase II trial showed no effect of the small molecule IGF1R inhibitor nordihydroguaiaretic acid to decrease prostate specific antigen levels in patients with non-metastatic, hormone sensitive prostate cancer [110].

In addition to EGFR, IGF-1 may also impair targeting of other signaling pathways. In ovarian cancer xenografts, increased IGF-1 expression was shown to be a potential mechanism of resistance to bevacizumab, an anti-VEGF therapy [111]. IGF1 increased protein expression of the G-protein coupled estrogen receptor (GPR30) in breast and endometrial cancer cells [112], a protein which has been implicated in tamoxifen resistance. Further, IGF-1 was shown to directly impair tamoxifen cytotoxicity of ER+ breast cancer cells by a mechanism requiring MEK activation [113].

Thus, the preponderance of evidence shows that IGF-1 is associated with increased incidence and poor prognosis in a number of cancers and has direct effects on cancer cells in vitro. Further studies examining modulation of IGF-1 pathway will hopefully lead to therapeutic advances in the near future.

Adipose Tissue and Metabolic Fuels

Obesity is a central component of the metabolic syndrome, and much recent literature has focused on the role of adipose tissue in cancer progression and treatment resistance. There are a number of potential mechanisms whereby adipose tissue could impair cancer prognosis. Excess adiposity makes appropriate chemotherapy dosing difficult, particularly for lipophilic drugs [114], but we have also shown that adipocytes protect acute lymphoblastic leukemia cells from chemotherapy via secretion of one or more soluble factors [115]. Adipokines, such as leptin and IL-6, have been shown in vitro to have cancer promoting activity [116].

Cancer cells have high metabolic requirements to maintain cell proliferation rates, and can utilize “metabolic fuels” present in obese and insulin resistant patients. In particular, in vitro evidence has been reported for the relationship between the Warburg Effect and hyperglycemia. A recent study by Tomas et al. found that diabetic levels of glucose in culture were associated with an increase in Akt expression, proliferation rate, and migratory activity of MB-468 breast cancer and SW480 colon cancer cells [68].

In addition to glucose, cancer cells appear to be exquisitely dependent on free fatty acids (FFA). FFA are needed to produce plasma and organelle membranes, as metabolic fuels, and can act as signaling molecules. A landmark study by Nomura et al. demonstrated that expression of monoacylglycerol lipase, an enzyme which releases a FFA chain from monoacylglycerol, is associated with worse prognosis in a number of different cancer types [117•]

Glutamine is another metabolic fuel that plays a central role in cellular metabolism, with importance as a contributor to the Kreb cycle, nucleic acid synthesis, and as a nitrogen source. Cancer cells appear to have higher glutamine needs than most other tissues, which has led some to explore this as a potential exploitable pathway. In particular, neural tumors and leukemia cells exhibit high glutamine utilization rates. As adipose tissue is a significant contributor to the whole body glutamine pool, we have investigated the role of adipocyte glutamine release in leukemia proliferation and resistance to chemotherapy. Although obese individuals do not appear to have higher plasma glutamine levels, glutamine concentrations at the site of adipocytes (e.g. adipose tissue, bone marrow, breast tissue) are likely to be elevated. However, little work has yet been done to evaluate the role of adipocyte glutamine production in other cancers.

Caloric restriction

If the insulin resistant state can increase cancer, then it stands to reason that treatments that enhance insulin sensitivity could improve cancer. Caloric restriction has been shown to improve cancer survival, and it is thought that this could be in part through decrease in insulin and IGF1 concentrations [118]. Fine et al showed that low carb diet/ketosis induced disease stabilization or partial remission in some patients. However, disease progression was measured with PET scanning, which depends on glucose uptake and therefore might be confounded by a low carb diet and decreased insulin levels [119].

Conclusion

The landmark study by Eugenia Calle and colleagues in 2003 highlighted the substantial effect of obesity to increase cancer mortality [120]. Since that time, much epidemiologic and bench research has been done to elucidate the mechanisms of this link. Some themes have emerged, such as the importance of insulin resistance and IGF-1 to cancer prognosis, which have led to the recent evaluation of therapies targeting these pathways. Other questions, such as how best to adjust chemotherapy doses for increasingly obese patients have received less attention. It is clear that the obesity epidemic is not going away any time soon. More concerning is the fact that our youth are becoming more and more obese, which in time will yield an adult population with a high prevalence of lifelong obesity and IR—people who are likely to be at the highest risk of obesity-related cancer. It is imperative that we continue to clarify the effects of the metabolic syndrome on cancer, while at the same time strive to reverse the obesity epidemic to help our and future generations.

Footnotes

Disclosure

No potential conflicts of interest relevant to this article were reported.

Contributor Information

Etan Orgel, Email: eorgel@chla.usc.edu, Jonathan Jaques Children’s Cancer Center, Keck School of Medicine, University of Southern California, Miller Children’s Hospital, 2801 Atlantic Avenue, Long Beach, CA 90806, 562-933-8600 phone.

Steven D. Mittelman, Email: smittelman@chla.usc.edu, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Blvd., MS #93, Los Angeles, CA 90027, 323-361-7653 phone.

References

  • 1.GDM A Statistical Study in Cancer Death Rates. Biometrika. 1910;7:276–304. [Google Scholar]
  • 2.Eheman C, Henley SJ, Ballard-Barbash R, Jacobs EJ, Schymura MJ, Noone AM, Pan L, Anderson RN, Fulton JE, Kohler BA, Jemal A, Ward E, Plescia M, Ries LA, Edwards BK. Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. 2012;118:2338–2366. doi: 10.1002/cncr.27514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. doi: 10.1186/1478-7954-8-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M, GBoMRFoCDCGB National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet. 2011;378:31–40. doi: 10.1016/S0140-6736(11)60679-X. [DOI] [PubMed] [Google Scholar]
  • 5.Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94:311–321. doi: 10.1016/j.diabres.2011.10.029. [DOI] [PubMed] [Google Scholar]
  • 6.Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–1053. doi: 10.2337/diacare.27.5.1047. [DOI] [PubMed] [Google Scholar]
  • 7.Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:1679–1687. doi: 10.1093/jnci/dji375. [DOI] [PubMed] [Google Scholar]
  • 8.Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856–862. doi: 10.1002/ijc.22717. [DOI] [PubMed] [Google Scholar]
  • 9.Deng L, Gui Z, Zhao L, Wang J, Shen L. Diabetes mellitus and the incidence of colorectal cancer: an updated systematic review and meta-analysis. Dig Dis Sci. 2012;57:1576–1585. doi: 10.1007/s10620-012-2055-1. [DOI] [PubMed] [Google Scholar]
  • 10.Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, Li G, Wang L. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130:1639–1648. doi: 10.1002/ijc.26165. [DOI] [PubMed] [Google Scholar]
  • 11.Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, Zhang H, Li Z. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer. 2011;47:1928–1937. doi: 10.1016/j.ejca.2011.03.003. [DOI] [PubMed] [Google Scholar]
  • 12.Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, Fairley LL, Zheng T, Zhang Y, Pasterk M, Smans M, Curado MP, Mullie P, Gandini S, Bota M, Bolli GB, Rosenstock J, Autier P. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer. 2012 doi: 10.1038/bjc.2012.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Lambe M, Wigertz A, Garmo H, Walldius G, Jungner I, Hammar N. Impaired glucose metabolism and diabetes and the risk of breast, endometrial, and ovarian cancer. Cancer Causes Control. 2011;22:1163–1171. doi: 10.1007/s10552-011-9794-8. [DOI] [PubMed] [Google Scholar]
  • 14.Larsson SC, Wolk A. Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies. Diabetologia. 2011;54:1013–1018. doi: 10.1007/s00125-011-2051-6. [DOI] [PubMed] [Google Scholar]
  • 15.Wotton CJ, Yeates DG, Goldacre MJ. Cancer in patients admitted to hospital with diabetes mellitus aged 30years and over: record linkage studies. Diabetologia. 2011;54:527–534. doi: 10.1007/s00125-010-1987-2. [DOI] [PubMed] [Google Scholar]
  • 16.Gapstur SM, Patel AV, Diver WR, Hildebrand JS, Gaudet MM, Jacobs EJ, Campbell PT. Type 2 Diabetes Mellitus and the Incidence of Epithelial Ovarian Cancer in the Cancer Prevention Study-II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev. 2012 doi: 10.1158/1055-9965.EPI-12-0867. [DOI] [PubMed] [Google Scholar]
  • 17.Carstensen B, Witte DR, Friis S. Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia. 2012;55:948–958. doi: 10.1007/s00125-011-2381-4. [DOI] [PubMed] [Google Scholar]
  • 18.Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–8930. doi: 10.1158/0008-5472.CAN-06-1501. [DOI] [PubMed] [Google Scholar]
  • 19.Nagle CM, Olsen CM, Ibiebele TI, Spurdle AB, Webb PM Group TANECS, Group TAOCS. Glycemic index, glycemic load and endometrial cancer risk: results from the Australian National Endometrial Cancer study and an updated systematic review and meta-analysis. Eur J Nutr. 2012 doi: 10.1007/s00394-012-0376-7. [DOI] [PubMed] [Google Scholar]
  • 20.Nothlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr. 2007;86:1495–1501. doi: 10.1093/ajcn/86.5.1495. [DOI] [PubMed] [Google Scholar]
  • 21.Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia. 2011;54:25–31. doi: 10.1007/s00125-010-1933-3. [DOI] [PubMed] [Google Scholar]
  • 22.Boyd DB. Insulin and cancer. Integr Cancer Ther. 2003;2:315–329. doi: 10.1177/1534735403259152. [DOI] [PubMed] [Google Scholar]
  • 23.Baur DM, Klotsche J, Hamnvik OP, Sievers C, Pieper L, Wittchen HU, Stalla GK, Schmid RM, Kales SN, Mantzoros CS. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism. 2011;60:1363–1371. doi: 10.1016/j.metabol.2010.09.012. [DOI] [PubMed] [Google Scholar]
  • 24.Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, La Vecchia C, Mancia G, Corrao G. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist. 2012;17:813–822. doi: 10.1634/theoncologist.2011-0462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97:E1170–E1175. doi: 10.1210/jc.2012-1162. [DOI] [PubMed] [Google Scholar]
  • 26.Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA. Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology. 2012;55:1462–1472. doi: 10.1002/hep.25509. [DOI] [PubMed] [Google Scholar]
  • 27.Colmers IN, Bowker SL, Majumdar SR, Johnson JA. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis. CMAJ. 2012;184:E675–E683. doi: 10.1503/cmaj.112102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology. 2004;127:1044–1050. doi: 10.1053/j.gastro.2004.07.011. [DOI] [PubMed] [Google Scholar]
  • 29•.Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, Sawicki PT. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732–1744. doi: 10.1007/s00125-009-1418-4. The initial study that raised the concern over a heightened risk with insulin glargine. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Colhoun HM, Group SE. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755–1765. doi: 10.1007/s00125-009-1453-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdóttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52:1745–1754. doi: 10.1007/s00125-009-1444-2. [DOI] [PubMed] [Google Scholar]
  • 32.Ljung R, Talböck M, Haglund B, Jonasson JM, Gudbjörnsdóttir S, Steineck G. Insulin glargine use and short-term incidence of breast cancer - a four-year population-based observation. Acta Oncol. 2012;51:400–402. doi: 10.3109/0284186X.2011.624118. [DOI] [PubMed] [Google Scholar]
  • 33.Fagot JP, Blotière PO, Ricordeau P, Weill A, Alla F, Allemand H. Does Insulin Glargine Increase the Risk of Cancer Compared With Other Basal Insulins?: A French nationwide cohort study based on national administrative databases. Diabetes Care. 2012 doi: 10.2337/dc12-0506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, Straus SM, Herings RM, Stricker BH. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51–62. doi: 10.1007/s00125-011-2312-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Chang CH, Toh S, Lin JW, Chen ST, Kuo CW, Chuang LM, Lai MS. Cancer risk associated with insulin glargine among adult type 2 diabetes patients--a nationwide cohort study. PLoS ONE. 2011;6:e21368. doi: 10.1371/journal.pone.0021368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–328. doi: 10.1056/NEJMoa1203858. [DOI] [PubMed] [Google Scholar]
  • 37••.Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159:1160–1167. doi: 10.1093/aje/kwh161. Large study that outlines the increased mortality associated with diabetes across a wide variety of malignancies. [DOI] [PubMed] [Google Scholar]
  • 38.Bakhru A, Buckanovich RJ, Griggs JJ. The impact of diabetes on survival in women with ovarian cancer. Gynecol Oncol. 2011;121:106–111. doi: 10.1016/j.ygyno.2010.12.329. [DOI] [PubMed] [Google Scholar]
  • 39.Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE. 2012;7:e33411. doi: 10.1371/journal.pone.0033411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, Laughlin GA, Saquib N, Rock CL, Pierce JP. Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol. 2011;29:54–60. doi: 10.1200/JCO.2010.29.3183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35:299–304. doi: 10.2337/dc11-1313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Dehal AN, Newton CC, Jacobs EJ, Patel AV, Gapstur SM, Campbell PT. Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol. 2012;30:53–59. doi: 10.1200/JCO.2011.38.0303. [DOI] [PubMed] [Google Scholar]
  • 43.Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, Hortobagyi GN, Gonzalez-Angulo AM. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. 2012;118:1202–1211. doi: 10.1002/cncr.26439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Stocks T, Borena W, Strohmaier S, Bjørge T, Manjer J, Engeland A, Johansen D, Selmer R, Hallmans G, Rapp K, Concin H, Jonsson H, Ulmer H, Stattin P. Cohort Profile: The Metabolic syndrome and Cancer project (Me-Can) Int J Epidemiol. 2010;39:660–667. doi: 10.1093/ije/dyp186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Stocks T, Rapp K, Bjørge T, Manjer J, Ulmer H, Selmer R, Lukanova A, Johansen D, Concin H, Tretli S, Hallmans G, Jonsson H, Stattin P. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): analysis of six prospective cohorts. PLoS Med. 2009;6:e1000201. doi: 10.1371/journal.pmed.1000201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Ulmer H, Björge T, Concin H, Lukanova A, Manjer J, Hallmans G, Borena W, Häggström C, Engeland A, Almquist M, Jonsson H, Selmer R, Stattin P, Tretli S, Kleiner A, Stocks T, Nagel G. Metabolic risk factors and cervical cancer in the metabolic syndrome and cancer project (Me-Can) Gynecol Oncol. 2012;125:330–335. doi: 10.1016/j.ygyno.2012.01.052. [DOI] [PubMed] [Google Scholar]
  • 47.Borena W, Strohmaier S, Lukanova A, Bjørge T, Lindkvist B, Hallmans G, Edlinger M, Stocks T, Nagel G, Manjer J, Engeland A, Selmer R, Häggström C, Tretli S, Concin H, Jonsson H, Stattin P, Ulmer H. Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer. 2012;131:193–200. doi: 10.1002/ijc.26338. [DOI] [PubMed] [Google Scholar]
  • 48.Almquist M, Johansen D, Bjørge T, Ulmer H, Lindkvist B, Stocks T, Hallmans G, Engeland A, Rapp K, Jonsson H, Selmer R, Diem G, Häggström C, Tretli S, Stattin P, Manjer J. Metabolic factors and risk of thyroid cancer in the Metabolic syndrome and Cancer project (Me-Can) Cancer Causes Control. 2011;22:743–751. doi: 10.1007/s10552-011-9747-2. [DOI] [PubMed] [Google Scholar]
  • 49.Bjørge T, Lukanova A, Jonsson H, Tretli S, Ulmer H, Manjer J, Stocks T, Selmer R, Nagel G, Almquist M, Concin H, Hallmans G, Häggström C, Stattin P, Engeland A. Metabolic syndrome and breast cancer in the me-can (metabolic syndrome and cancer) project. Cancer Epidemiol Biomarkers Prev. 2010;19:1737–1745. doi: 10.1158/1055-9965.EPI-10-0230. [DOI] [PubMed] [Google Scholar]
  • 50.Porto LA, Lora KJ, Soares JC, Costa LO. Metabolic syndrome is an independent risk factor for breast cancer. Arch Gynecol Obstet. 2011;284:1271–1276. doi: 10.1007/s00404-011-1837-6. [DOI] [PubMed] [Google Scholar]
  • 51.Bjørge T, Lukanova A, Tretli S, Manjer J, Ulmer H, Stocks T, Selmer R, Nagel G, Almquist M, Concin H, Hallmans G, Jonsson H, Häggström C, Stattin P, Engeland A. Metabolic risk factors and ovarian cancer in the Metabolic Syndrome and Cancer project. Int J Epidemiol. 2011;40:1667–1677. doi: 10.1093/ije/dyr130. [DOI] [PubMed] [Google Scholar]
  • 52.Petridou ET, Sergentanis TN, Antonopoulos CN, Dessypris N, Matsoukis IL, Aronis K, Efremidis A, Syrigos C, Mantzoros CS. Insulin resistance: an independent risk factor for lung cancer? Metabolism. 2011;60:1100–1106. doi: 10.1016/j.metabol.2010.12.002. [DOI] [PubMed] [Google Scholar]
  • 53.Edlinger M, Strohmaier S, Jonsson H, Bjørge T, Manjer J, Borena WT, Häggström C, Engeland A, Tretli S, Concin H, Nagel G, Selmer R, Johansen D, Stocks T, Hallmans G, Stattin P, Ulmer H. Blood pressure and other metabolic syndrome factors and risk of brain tumour in the large population-based Me-Can cohort study. J Hypertens. 2012;30:290–296. doi: 10.1097/HJH.0b013e32834e9176. [DOI] [PubMed] [Google Scholar]
  • 54.Nagel G, Bjørge T, Stocks T, Manjer J, Hallmans G, Edlinger M, Häggström C, Engeland A, Johansen D, Kleiner A, Selmer R, Ulmer H, Tretli S, Jonsson H, Concin H, Stattin P, Lukanova A. Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can) Br J Dermatol. 2012;167:59–67. doi: 10.1111/j.1365-2133.2012.10974.x. [DOI] [PubMed] [Google Scholar]
  • 55.Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U. S Diabetes Care. 2005;28:2745–2749. doi: 10.2337/diacare.28.11.2745. [DOI] [PubMed] [Google Scholar]
  • 56.Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC. International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645. doi: 10.1161/CIRCULATIONAHA.109.192644. [DOI] [PubMed] [Google Scholar]
  • 57••.Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–1685. doi: 10.2337/dc10-0666. This reference consists of the consensus statement by the American Cancer Society and American Diabetes Association that affirms the presence of a relationship between diabetes and cancer, reviews current gaps in our knowledge, and highlights future avenues for investigation. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Belfiore A, Malaguarnera R. Insulin receptor and cancer. Endocr Relat Cancer. 2011;18:R125–R147. doi: 10.1530/ERC-11-0074. [DOI] [PubMed] [Google Scholar]
  • 59.Kim JS, Kim ES, Liu D, Lee JJ, Solis L, Behrens C, Lippman SM, Hong WK, Wistuba II, Lee HY. Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer. Cancer. 2012;118:2454–2465. doi: 10.1002/cncr.26492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Esposito DL, Aru F, Lattanzio R, Morgano A, Abbondanza M, Malekzadeh R, Bishehsari F, Valanzano R, Russo A, Piantelli M, Moschetta A, Lotti LV, Mariani-Costantini R. The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PLoS ONE. 2012;7:e36190. doi: 10.1371/journal.pone.0036190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Wang Y, Hua S, Tian W, Zhang L, Zhao J, Zhang H, Zhang W, Xue F. Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent. Gynecol Oncol. 2012;125:734–741. doi: 10.1016/j.ygyno.2012.03.012. [DOI] [PubMed] [Google Scholar]
  • 62.Morvan D, Steyaert JM, Schwartz L, Israel M, Demidem A. Normal human melanocytes exposed to chronic insulin and glucose supplementation undergo oncogenic changes and methyl group metabolism cellular redistribution. Am J Physiol Endocrinol Metab. 2012;302:E1407–E1418. doi: 10.1152/ajpendo.00594.2011. [DOI] [PubMed] [Google Scholar]
  • 63.Chan SH, Kikkawa U, Matsuzaki H, Chen JH, Chang WC. Insulin receptor substrate-1 prevents autophagy-dependent cell death caused by oxidative stress in mouse NIH/3T3 cells. J Biomed Sci. 2012;19:64. doi: 10.1186/1423-0127-19-64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Marconett CN, Singhal AK, Sundar SN, Firestone GL. Indole-3-Carbinol disrupts Estrogen Receptor-alpha dependent expression of Insulin-like Growth Factor-1 Receptor and Insulin Receptor Substrate-1 and proliferation of human breast cancer cells. Mol Cell Endocrinol. 2012;363:74–84. doi: 10.1016/j.mce.2012.07.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Zeng X, Zhang H, Oh A, Zhang Y, Yee D. Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor. Breast Cancer Research and Treatment. 2012;133:117–126. doi: 10.1007/s10549-011-1713-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Fox EM, Miller TW, Balko JM, Kuba MG, Sanchez V, Smith RA, Liu S, Gonzalez-Angulo AM, Mills GB, Ye F, Shyr Y, Manning HC, Buck E, Arteaga CL. A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res. 2011;71:6773–6784. doi: 10.1158/0008-5472.CAN-11-1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Rose DP, Vona-Davis L. The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. Endocr Relat Cancer. 2012 doi: 10.1530/ERC-12-0203. [DOI] [PubMed] [Google Scholar]
  • 68.Tomas NM, Masur K, Piecha JC, Niggemann B, Zanker KS. Akt and phospholipase Cgamma are involved in the regulation of growth and migration of MDA-MB-468 breast cancer and SW480 colon cancer cells when cultured with diabetogenic levels of glucose and insulin. BMC Res Notes. 2012;5:214. doi: 10.1186/1756-0500-5-214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Stohr O, Hahn J, Moll L, Leeser U, Freude S, Bernard C, Schilbach K, Markl A, Udelhoven M, Krone W, Schubert M. Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. Biochim Biophys Acta. 2011;1812:573–580. doi: 10.1016/j.bbadis.2011.02.006. [DOI] [PubMed] [Google Scholar]
  • 70.Gallagher EJ, Fierz Y, Vijayakumar A, Haddad N, Yakar S, Leroith D. Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. Oncogene. 2012;31:3213–3222. doi: 10.1038/onc.2011.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D., Jr Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia. 1987;30:698–702. doi: 10.1007/BF00296991. [DOI] [PubMed] [Google Scholar]
  • 72.Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A. Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway. Endocrinology. 2012;153:2152–2163. doi: 10.1210/en.2011-1843. [DOI] [PubMed] [Google Scholar]
  • 73.Cao Y, Evans SC, Soans E, Malki A, Liu Y, Liu Y, Chen X. Insulin receptor signaling activated by penta-O-galloyl-alpha-D: -glucopyranose induces p53 and apoptosis in cancer cells. Apoptosis. 2011;16:902–913. doi: 10.1007/s10495-011-0614-0. [DOI] [PubMed] [Google Scholar]
  • 74.Porter HA, Carey GB, Keegan AD. Insulin receptor substrate 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death. Exp Cell Res. 2012;318:1745–1758. doi: 10.1016/j.yexcr.2012.04.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Teng JA, Hou RL, Li DL, Yang RP, Qin J. Glargine promotes proliferation of breast adenocarcinoma cell line MCF-7 via AKT activation. Horm Metab Res. 2011;43:519–523. doi: 10.1055/s-0031-1280780. [DOI] [PubMed] [Google Scholar]
  • 76.Pierre-Eugene C, Pagesy P, Nguyen TT, Neuillé M, Tschank G, Tennagels N, Hampe C, Issad T. Effect of Insulin Analogues on Insulin/IGF1 Hybrid Receptors: Increased Activation by Glargine but Not by Its Metabolites M1 and M2. PLoS ONE. 2012;7:e41992. doi: 10.1371/journal.pone.0041992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Li WG, Yuan YZ, Qiao MM, Zhang YP. High dose glargine alters the expression profiles of microRNAs in pancreatic cancer cells. World J Gastroenterol. 2012;18:2630–2639. doi: 10.3748/wjg.v18.i21.2630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Pan J, Chen C, Jin Y, Fuentes-Mattei E, Velazquez-Tores G, Benito JM, Konopleva M, Andreeff M, Lee MH, Yeung SC. Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells. Cell Cycle. 2012;11:2314–2326. doi: 10.4161/cc.20770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Luzio S, Dunseath G, Peter R, Pauvaday V, Owens DR. Comparison of the pharmacokinetics and pharmacodynamics of biphasic insulin aspart and insulin glargine in people with type 2 diabetes. Diabetologia. 2006;49:1163–1168. doi: 10.1007/s00125-006-0243-2. [DOI] [PubMed] [Google Scholar]
  • 80.Wu CL, Qiang L, Han W, Ming M, Viollet B, He YY. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene. 2012 doi: 10.1038/onc.2012.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L, Athar M. Metformin, an Antidiabetic Agent Reduces Growth of Cutaneous Squamous Cell Carcinoma by Targeting mTOR Signaling Pathway. Photochem Photobiol. 2012;88:1149–1156. doi: 10.1111/j.1751-1097.2012.01165.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Chan DK, Miskimins WK. Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures. J Ovarian Res. 2012;5:19. doi: 10.1186/1757-2215-5-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, Wahdan-Alaswad R, Thor AD. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:367–376. doi: 10.4161/cc.11.2.18813. [DOI] [PubMed] [Google Scholar]
  • 84.Zhuang Y, Miskimins WK. Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol. Cancer Res. 2011;9:603–615. doi: 10.1158/1541-7786.MCR-10-0343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507–7511. doi: 10.1158/0008-5472.CAN-09-2994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK, Buckanovich RJ. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 2012 doi: 10.1016/j.ygyno.2012.07.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH, Banerjee S, Kong D, Li Y, Thakur S, Sarkar FH. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res(Phila) 2012;5:355–364. doi: 10.1158/1940-6207.CAPR-11-0299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Chen G, Xu S, Renko K, Derwahl M. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 2012;97:E510–E520. doi: 10.1210/jc.2011-1754. [DOI] [PubMed] [Google Scholar]
  • 89.Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, Martin-Castillo B, Menendez JA. Metformin-induced preferential killing of breast cancer initiating CD44+CD24−/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012;3:395–398. doi: 10.18632/oncotarget.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Appleyard MVCL, Murray KE, Coates PJ, Wullschleger S, Bray SE, Kernohan NM, Fleming S, Alessi DR, Thompson AM. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer. 2012;106:1117–1122. doi: 10.1038/bjc.2012.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Isaksson OG, Ohlsson C, Nilsson A, Isgaard J, Lindahl A. Regulation of cartilage growth by growth hormone and insulin-like growth factor I. Pediatr Nephrol. 1991;5:451–453. doi: 10.1007/BF01453680. [DOI] [PubMed] [Google Scholar]
  • 92.Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 2012;41:335–50. vi. doi: 10.1016/j.ecl.2012.04.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Yamamoto T, Oshima T, Yoshihara K, Nishi T, Arai H, Inui K, Kaneko T, Nozawa A, Adachi H, Rino Y, Masuda M, Imada T. Clinical significance of immunohistochemical expression of insulin-like growth factor-1 receptor and matrix metalloproteinase-7 in resected non-small cell lung cancer. Exp Ther Med. 2012;3:797–802. doi: 10.3892/etm.2012.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Shan J, Shen J, Liu L, Xia F, Xu C, Duan G, Xu Y, Ma Q, Yang Z, Zhang Q, Ma L, Liu J, Xu S, Yan X, Bie P, Cui Y, Bian Xw, Qian C. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology. 2012;56:1004–1014. doi: 10.1002/hep.25745. [DOI] [PubMed] [Google Scholar]
  • 95.Sun Y, Zheng S, Torossian A, Speirs CK, Schleicher S, Giacalone NJ, Carbone DP, Zhao Z, Lu B. Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. Int J Radiat Oncol Biol Phys. 2012;82:e563–e572. doi: 10.1016/j.ijrobp.2011.06.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Heidegger I, Ofer P, Doppler W, Rotter V, Klocker H, Massoner P. Diverse Functions of IGF/Insulin Signaling in Malignant and Noncancerous Prostate Cells: Proliferation in Cancer Cells and Differentiation in Noncancerous Cells. Endocrinology. 2012;153:4633–4643. doi: 10.1210/en.2012-1348. [DOI] [PubMed] [Google Scholar]
  • 97••.D’Esposito V, Passaretti F, Hammarstedt A, Liguoro D, Terracciano D, Molea G, Canta L, Miele C, Smith U, Beguinot F, Formisano P. Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro. Diabetologia. 2012;55:2811–2822. doi: 10.1007/s00125-012-2629-7. Interesting study which uncovers a possible paracrine effect of adipose tissue IGF-1 on breast cancer pathogenesis. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Harvey AE, Lashinger LM, Otto G, Nunez NP, Hursting SD. Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression. Mol Carcinog. 2012 doi: 10.1002/mc.21940. [DOI] [PubMed] [Google Scholar]
  • 99.Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett. 2012;326:191–198. doi: 10.1016/j.canlet.2012.08.016. [DOI] [PubMed] [Google Scholar]
  • 100.Zhang YW, Yan DL, Wang W, Zhao HW, Lu X, Wu JZ, Zhou JR. Knockdown of insulin-like growth factor I receptor inhibits the growth and enhances chemo-sensitivity of liver cancer cells. Curr Cancer Drug Targets. 2012;12:74–84. doi: 10.2174/156800912798888974. [DOI] [PubMed] [Google Scholar]
  • 101.Kim JG, Kang MJ, Yoon YK, Kim HP, Park J, Song SH, Han SW, Park JW, Kang GH, Kang KW, Oh dY, Im SA, Bang YJ, Yi EC, Kim TY. Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. PLoS ONE. 2012;7:e33322. doi: 10.1371/journal.pone.0033322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Guo ST, Jiang CC, Wang GP, Li YP, Wang CY, Guo XY, Yang RH, Feng Y, Wang FH, Tseng HY, Thorne RF, Jin L, Zhang XD. MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer. Oncogene. 2012 doi: 10.1038/onc.2012.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Shen K, Liang Q, Xu K, Cui D, Jiang L, Yin P, Lu Y, Li Q, Liu J. MiR-139 inhibits invasion and metastasis of colorectal cancer by targeting the type I insulin-like growth factor receptor. Biochem Pharmacol. 2012;84:320–330. doi: 10.1016/j.bcp.2012.04.017. [DOI] [PubMed] [Google Scholar]
  • 104.Zhao X, Dou W, He L, Liang S, Tie J, Liu C, Li T, Lu Y, Mo P, Shi Y, Wu K, Nie Y, Fan D. MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor. Oncogene. 2012 doi: 10.1038/onc.2012.156. [DOI] [PubMed] [Google Scholar]
  • 105.Tognon CE, Sorensen PH. Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets. 2012;16:33–48. doi: 10.1517/14728222.2011.638626. [DOI] [PubMed] [Google Scholar]
  • 106.Qi HW, Shen Z, Fan LH. Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line. Exp Ther Med. 2011;2:1091–1095. doi: 10.3892/etm.2011.324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Kim WY, Prudkin L, Feng L, Kim ES, Hennessy B, Lee JS, Lee JJ, Glisson B, Lippman SM, Wistuba II, Hong WK, Lee HY. Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors. Cancer. 2012;118:3993–4003. doi: 10.1002/cncr.26656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Fidler MJ, Basu S, Buckingham L, Walters K, McCormack S, Batus M, Coon J, Bonomi P. Utility of insulin-like growth factor receptor-1 expression in gefitinib-treated patients with non-small cell lung cancer. Anticancer Res. 2012;32:1705–1710. [PubMed] [Google Scholar]
  • 109.Ramalingam SS, Spigel DR, Chen D, Steins MB, Engelman JA, Schneider CP, Novello S, Eberhardt WE, Crino L, Habben K, Liu L, Janne PA, Brownstein CM, Reck M. Randomized phase II study of erlotinib in combination with placebo or R1507; a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J Clin Oncol. 2011;29:4574–4580. doi: 10.1200/JCO.2011.36.6799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Friedlander TW, Weinberg VK, Huang Y, Mi JT, Formaker CG, Small EJ, Harzstark AL, Lin AM, Fong L, Ryan CJ. A phase II study of insulin-like growth factor receptor inhibition with nordihydroguaiaretic acid in men with non-metastatic hormone-sensitive prostate cancer. Oncol Rep. 2012;27:3–9. doi: 10.3892/or.2011.1487. [DOI] [PubMed] [Google Scholar]
  • 111.Shao M, Hollar S, Chambliss D, Schmitt J, Emerson R, Chelladurai B, Perkins S, Ivan M, Matei D. Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer. Mol Cancer Ther. 2012;11:1576–1586. doi: 10.1158/1535-7163.MCT-11-0961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.De MP, Bartella V, Vivacqua A, Lappano R, Santolla MF, Morcavallo A, Pezzi V, Belfiore A, Maggiolini M. Insulin-like growth factor-I regulates GPER expression and function in cancer cells. Oncogene. 2012 doi: 10.1038/onc.2012.97. [DOI] [PubMed] [Google Scholar]
  • 113.Periyasamy-Thandavan S, Takhar S, Singer A, Dohn MR, Jackson WH, Welborn AE, Leroith D, Marrero M, Thangaraju M, Huang S, Schoenlein PV. Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim. Breast Cancer Res. 2012;14:R52. doi: 10.1186/bcr3153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Behan JW, Avramis VI, Yun JP, Louie SG, Mittelman SD. Diet-Induced Obesity Alters Vincristine Pharmacokinetics in Blood and Tissues of Mice. Pharmacol Res. 2010 doi: 10.1016/j.phrs.2010.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS, Avramis VI, Louie SG, Butturini A, Heisterkamp N, Mittelman SD. Adipocytes impair leukemia treatment in mice. Cancer Res. 2009;69:7867–7874. doi: 10.1158/0008-5472.CAN-09-0800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Drew JE. Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin. Proceedings of the Nutrition Society. 2012;71:175–180. doi: 10.1017/S0029665111003259. [DOI] [PubMed] [Google Scholar]
  • 117•.Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140:49–61. doi: 10.1016/j.cell.2009.11.027. An elegant study demonstrating the importance of free fatty acid metabolism and cancer pathogenesis. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, Conti PS, Chen TC, Longo VD. Fasting enhances the response of glioma to chemo- and radiotherapy. PLoS One. 2012;7:e44603. doi: 10.1371/journal.pone.0044603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, Bontempo AF, Negassa A, Sparano JA. Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–1035. doi: 10.1016/j.nut.2012.05.001. [DOI] [PubMed] [Google Scholar]
  • 120.Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638. doi: 10.1056/NEJMoa021423. [DOI] [PubMed] [Google Scholar]

RESOURCES