CoChat
Sign Up
Cited by 2,366Metabolism, Diabetes, and CancerCancer Risks and FactorsPancreatic and Hepatic Oncology Research

Diabetes and Cancer

Open access
Giovannucci, Edward, Harlan, David M., Archer, Michael C., Bergenstal, Richard M., Gapstur, Susan M., Habel, Laurel A., Pollak, Michael, Regensteiner, Judith G. +1 more·2010·Diabetes Care
DOI 10.2337/dc10-0666PMC PMC2890380
Open this paper in CoChat — free accountOpen PDF

Abstract

Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes treatments.This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis, 2) risk factors common to both diabetes and cancer, 3) possible biologic links between diabetes and cancer risk, and 4) whether diabetes treatments influence risk of cancer or cancer prognosis.In addition, key unanswered questions for future research are posed.Diabetes Care 33:1674-1685, 2010 D iabetes and cancer are common diseases with tremendous impact on health worldwide.Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer.Type 2 diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood.Moreover, evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer.Against this backdrop, the American Diabetes Association and the American Cancer Society convened a consensus development conference in December 2009.Following a series of scientific presentations by experts in the field, the writing group independently developed this consensus report to address the following questions:1. Is there a meaningful association between diabetes and cancer incidence or prognosis?2. What risk factors are common to both diabetes and cancer?3. What are possible biologic links between diabetes and cancer risk? 4. Do diabetes treatments influence risk of cancer or cancer prognosis?For each area, the authors were asked to address the current gaps in evidence and potential research and epidemiologic strategies for developing more definitive evidence in the future.Table 1 includes a summary of findings and recommendations.Recommendations in this report are solely the opinions of the authors and do not represent official position of the American Diabetes Association or the American Cancer Society.•

AI snapshot

Written from the paper’s full text.

TL;DR

This ADA/ACS consensus report concludes that diabetes (primarily type 2) is associated with increased risk for several cancers and reduced risk for prostate cancer, with shared risk factors and possible biologic links through hyperinsulinemia, hyperglycemia, and inflammation. Evidence on diabetes treatments and cancer risk is limited; metformin may be associated with lower cancer risk and exogenous insulin with increased risk, but cancer risk should not be a major factor in choosing diabetes therapies for the average patient.

Key findings

  • Diabetes is associated with increased risk for liver, pancreas, and endometrium cancers (relative risks about twofold or higher), and for colon/rectum, breast, and bladder cancers (about 1.2–1.5-fold); it is associated with reduced prostate cancer risk, no clear association for lung cancer, and inconclusive evidence for kidney cancer and non-Hodgkin lymphoma.
  • Shared risk factors include aging, sex, obesity, physical activity, diet, alcohol, and smoking. In the Diabetes Prevention Program, intensive lifestyle intervention targeting 5–7% weight loss plus physical activity was associated with a 58% reduction in diabetes incidence; ~30 min of moderate-intensity exercise at least 5 days/week substantially reduces type 2 diabetes risk by 25–36%.
  • Possible mechanisms include hyperinsulinemia, hyperglycemia, and chronic inflammation, with the insulin/IGF axis, sex hormone changes, and inflammatory cytokines as plausible pathways.
  • Treatment evidence is mixed and limited: metformin is associated with lower cancer risk or cancer mortality in observational studies; exogenous insulin is associated with increased cancer risk; evidence for insulin glargine, thiazolidinediones, insulin secretagogues, and incretin-based therapies is inconclusive or insufficient.

Methods

  • The American Diabetes Association and American Cancer Society convened a consensus development conference in December 2009; after scientific presentations, the writing group independently developed this consensus report addressing four questions on diabetes–cancer association, shared risk factors, biologic links, and treatment effects.
  • The report synthesizes epidemiologic, clinical trial, and in vitro/in vivo evidence and includes a summary Table 1 of findings and recommendations.
  • No formal systematic review or meta-analysis methods are described; it is a narrative consensus synthesis.

Limitations

  • The paper states that evidence for specific drugs affecting cancer risk is limited, and observed associations may be confounded by indications for specific drugs, effects on body weight and hyperinsulinemia, and the progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes.
  • The paper states that most studies had limited power for site-specific cancers, few examined dose, duration, or recency of medication use, and newer agents have only short-term exposure data; biologic mechanisms rely largely on in vivo and in vitro studies, and many epidemiologic studies measure only a single time point or fasting insulin levels.
  • The paper states that recommendations are solely the opinions of the authors and do not represent official positions of the American Diabetes Association or the American Cancer Society; the text also makes evident that many research questions remain unanswered.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/dc10-0666

Cites

144 of 144 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 149 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Few studies have explored links between type 1 diabetes and cancer.

    “Few studies have explored links with type 1 diabetes.”
    Quote in the paperNot a substantial claim
  • Premisenone given
    § Diabetes and Cancer

    Early evidence suggests that metformin is associated with a lower risk of cancer.

    “Although still limited, early evidence suggests that metformin is associated with a lower risk of cancer”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning
    § Diabetes and Cancer

    Observed associations between diabetes drugs and cancer risk may have been confounded by indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes.

    “observed associations may have been confounded by indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes.”
    Quote in the paperSubstantial claim
  • Premisereasoning
    § Diabetes and Cancer

    The evidence for specific drugs affecting cancer risk is limited.

    “The evidence for specific drugs affecting cancer risk is limited, and observed associations may have been confounded by indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes.”
    Quote in the paperSubstantial claim
  • Premisecitation
    § Diabetes and Cancer

    Diabetes is associated with reduced risk of prostate cancer.

    “Diabetes is associated with reduced risk of prostate cancer.”
    • Also stated in: § 1. Is there a meaningful association between diabetes and cancer incidence or prognosis? · plain
      “Only for prostate cancer is diabetes associated with a lower risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Vigneri, 2009, Diabetes and cancer, Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims. 61
  • Classified as probably not a substantial claim. 37

  • May combine two claims.

    Premisecitation

    Obesity has not been associated, and in some studies is even inversely associated, with prostate cancer incidence.

    “While obesity has not been associated, and in some studies is even inversely associated, with prostate cancer incidence”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Ma, 2008, Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis, Lancet Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Diabetes and Cancer

    For some other cancer sites there appears to be no association or the evidence is inconclusive.

    “For some other cancer sites there appears to be no association or the evidence is inconclusive.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Vigneri, 2009, Diabetes and cancer, Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The association between diabetes and lower prostate cancer risk has been observed both before and after the advent of PSA screening, so detection bias due to differential PSA utilization does not account for this finding.

    “This association has been observed both before and after the advent of screening with prostate-specific antigen (PSA), so detection bias due to differential PSA utilization does not account for this finding.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Some metabolic factors associated with diabetes, such as reduced testosterone levels, may be involved in the lower prostate cancer risk.

    “Some metabolic factors associated with diabetes, such as reduced testosterone levels, may be involved”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Diabetes and Cancer

    Possible mechanisms for a direct link between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation.

    “Possible mechanisms for a direct link between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A positive association between diabetes and pancreatic cancer risk has been found when restricted to diabetes that precedes the diagnosis of pancreatic cancer by at least 5 years, so reverse causation does not likely account for the entirety of the association.

    “However, a positive association between diabetes and pancreatic cancer risk has been found when restricted to diabetes that precedes the diagnosis of pancreatic cancer by at least 5 years, so reverse causation does not likely account for the entirety of the association.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Circulating testosterone levels have not been consistently associated with prostate cancer incidence.

    “although circulating testosterone levels have not been consistently associated with prostate cancer incidence”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other cancers (e.g., lung) do not appear to be associated with an increased risk in diabetes, and the evidence for others (e.g., kidney, non-Hodgkin lymphoma) is inconclusive.

    “Other cancers (e.g., lung) do not appear to be associated with an increased risk in diabetes, and the evidence for others (e.g., kidney, non-Hodgkin lymphoma) is inconclusive.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Vigneri, 2009, Diabetes and cancer, Endocr Relat Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age.

    “Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The relative risks imparted by diabetes are greatest (about twofold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder.

    “The relative risks imparted by diabetes are greatest (about twofold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2–1.5 fold) for cancers of the colon and rectum, breast, and bladder.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Vigneri, 2009, Diabetes and cancer, Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Diabetes and Cancer

    Healthful diets, physical activity, and weight management reduce risk and improve outcomes of type 2 diabetes and some forms of cancer.

    “Healthful diets, physical activity, and weight management reduce risk and improve outcomes of type 2 diabetes and some forms of cancer and should be promoted for all.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In diabetes, numerous studies have shown that weight loss decreases diabetes incidence and restores euglycemia in a significant fraction of individuals with type 2 diabetes.

    “In the case of diabetes, numerous studies have shown that weight loss decreases diabetes incidence and restores euglycemia in a significant fraction of individuals with type 2 diabetes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Men have slightly higher age-adjusted risk of diabetes than women.

    “Men have slightly higher age-adjusted risk of diabetes than women (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2007 [article online], 2008. Atlanta, Georgia, Centers for Disease Control and Prevention. Available from http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed 1 April 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies over decades have consistently shown a strong association between obesity and both insulin resistance and type 2 diabetes incidence.

    “Studies over decades have consistently shown a strong association between obesity and both insulin resistance and type 2 diabetes incidence (18)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Schienkiewitz, 2006, Body mass index history and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, Am J Clin Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In economically developed countries, 78% of all newly diagnosed cancer occurs among individuals aged 55 years and older.

    “In economically developed countries, 78% of all newly diagnosed cancer occurs among individuals aged 55 years and older (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Garcia, 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Potential risk factors common to both cancer and diabetes include aging, sex, obesity, physical activity, diet, alcohol, and smoking.

    “Potential risk factors (modifiable and nonmodifiable) common to both cancer and diabetes include aging, sex, obesity, physical activity, diet, alcohol, and smoking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Factors that may contribute to variability in cancer and diabetes incidence among populations include differences in the prevalence of major risk factors, genetic factors, medical practices such as screening, and completeness of reporting.

    “Factors that may contribute to this variability include differences in the prevalence of major risk factors, genetic factors, medical practices such as screening, and completeness of reporting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Higher pre-diagnosis C-peptide levels have been associated with a poorer disease-specific survival for prostate cancer and colorectal cancer.

    “higher pre-diagnosis C-peptide levels (an indirect marker of insulin resistance) have been associated with a poorer disease-specific survival for prostate cancer (7) and colorectal cancer (10).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Ma, 2008, Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis, Lancet Oncol source

      Not checked in the free run.

    • cites [10] Wolpin, 2009, Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following African Americans are non-Hispanic whites, with Hispanics, Native Americans, and Asian Americans/Pacific Islanders having lower cancer incidence and mortality.

    “Following African Americans are non-Hispanic whites, with Hispanics, Native Americans, and Asian Americans/Pacific Islanders having lower cancer incidence and mortality (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Jemal, 2009, Cancer statistics, 2009, CA Cancer J Clin source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Genetic, socioeconomic, lifestyle, and other environmental factors are thought to contribute to disparities in type 2 diabetes.

    “While incompletely understood, genetic, socioeconomic, lifestyle, and other environmental factors are thought to contribute to these disparities.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Diabetes becomes increasingly common with age: prevalence is 2.6% in U.S. adults 20-39 years, 10.8% in those 40-59 years, and 23.8% in those 60 years or older.

    “Diabetes also becomes increasingly common with age: Prevalence is 2.6% in U.S. adults 20–39 years of age, 10.8% in those 40–59 years of age, and increases to 23.8% in those 60 years of age or older (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2007 [article online], 2008. Atlanta, Georgia, Centers for Disease Control and Prevention. Available from http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed 1 April 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Overall cancer occurs more frequently in men.

    “overall cancer occurs more frequently in men.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Risk of diabetes and earlier age at onset are directly linked to obesity severity.

    “with risk of diabetes and earlier age at onset directly linked to obesity severity (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Abdul-Ghani, 2005, High frequency of pre-diabetes, undiagnosed diabetes and metabolic syndrome among overweight Arabs in Israel, Isr Med Assoc J

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    U.S. race/ethnic variability in cancer incidence is attributed, at least in part, to socioeconomic and other disparities, but biological factors, such as levels of hormones that vary by race, may also play a role.

    “As with the worldwide situation, the U.S. race/ethnic variability in cancer incidence is attributed, at least in part, to socioeconomic and other disparities, but biological factors, such as levels of hormones that vary by race (15), may also play a role.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Pinheiro, 2005, Racial differences in premenopausal endogenous hormones, Cancer Epidemiol Biomarkers Prev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The incidence of most cancers increases with age.

    “the incidence of most cancers increases with age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Most evidence on weight loss and cancer risk has been derived from breast cancer studies, where weak or null associations were observed.

    “Most evidence has been derived from breast cancer studies, where weak or null associations were observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increases in body weight during adulthood largely reflect increases in adipose tissue rather than lean mass, so total body fat may be a better measure of cancer risk than BMI.

    “Increases in body weight during adulthood largely reflect increases in adipose tissue rather than lean mass, so total body fat may be a better measure of the risk for cancer than BMI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Physical activity may also help prevent other cancers, including lung and aggressive prostate cancer, but a clear link has not been established.

    “Physical activity may also help prevent other cancers, including lung and aggressive prostate cancer, but a clear link has not been established.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the Diabetes Prevention Program, those who did not reach weight loss goals still significantly reduced their risk of diabetes if they reached exercise goals, although weight loss was the only component independently associated with diabetes prevention in multivariate analyses.

    “Analyses of the effects of different components of the intensive lifestyle intervention in the Diabetes Prevention Program suggested that those who did not reach weight loss goals still significantly reduced their risk of diabetes if they reached the exercise goals, although weight loss was the only component independently associated with diabetes prevention in multivariate analyses (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Hamman, 2006, Effect of weight loss with lifestyle intervention on risk of diabetes, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Worldwide, tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths.

    “It is estimated that worldwide, tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Mackay, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Low-carbohydrate diets have been associated with weight loss and improvements in insulin sensitivity and glycemic control.

    “Low-carbohydrate diets (which often include greater consumption of red meats and fat) have also been associated with weight loss and improvements in insulin sensitivity and glycemic control.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Lower levels of adiposity, healthy diets, and regular physical activity are associated with reduced risk for type 2 diabetes and for several common types of cancer.

    “While it is clear that lower levels of adiposity, healthy diets, and regular physical activity are associated with reduced risk for type 2 diabetes and for several common types of cancer”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Other cancers strongly associated with smoking are larynx, upper digestive, bladder, kidney, pancreas, leukemia, liver, stomach, and uterine cervix.

    “Other cancers strongly associated with smoking are larynx, upper digestive, bladder, kidney, pancreas, leukemia, liver, stomach, and uterine cervix.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bariatric surgery is a very effective treatment for type 2 diabetes, with a meta-analysis showing that type 2 diabetes resolved in 78% and resolved or improved in 87% of patients after bariatric surgery.

    “Bariatric surgery is a very effective treatment for type 2 diabetes, with a meta-analysis showing that type 2 diabetes resolved in 78% and resolved or improved in 87% of patients after bariatric surgery (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Buchwald, 2009, Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis, Am J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Reduced sex hormone binding globulin leads to increased bioavailable testosterone in women but not in men.

    “Increased circulating insulin has a number of indirect effects including a reduction in the hepatic synthesis and blood levels of sex hormone binding globulin, leading to increases in bioavailable estrogen in both men and women and increased levels of bioavailable testosterone in women but not in men (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Calle, 2004, Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms, Nat Rev Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Because most glucose uptake in cancer cells is constitutively high and independent of insulin binding to its receptor, the effects of insulin receptor activation on neoplastic cells may relate more to cell survival and mitogenesis than to enhanced glucose uptake.

    “Because most glucose uptake in cancer cells is constitutively high and independent of insulin binding to its receptor (51), the effects of insulin receptor activation on neoplastic cells may relate more to cell survival and mitogenesis than to enhanced glucose uptake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Zhang, 2007, Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin and IGF receptors form a complex network of cell surface receptors; homodimers and heterodimers have been described, and all function to mediate insulin and IGF responses.

    “Insulin and insulin-like growth factor (IGF) receptors form a complex network of cell surface receptors; homodimers and heterodimers have been described, and all function to mediate insulin and IGF responses (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Pollak, 2008, Insulin and insulin-like growth factor signalling in neoplasia, Nat Rev Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Insulin receptor may be a marker of breast cancer cell differentiation and identify cells with a potentially less aggressive phenotype.

    “Just like ER, insulin receptor may be a marker of breast cancer cell differentiation and identify cells with a potentially less aggressive phenotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms and therefore may not derive a further growth advantage from hyperglycemia.

    “Direct data concerning dose-response characteristics of cancers to glucose are sparse, but it is relevant that most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms (67) and therefore may not derive a further growth advantage from hyperglycemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Yun, 2009, Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Once activated, these signaling pathways may stimulate multiple cancer phenotypes including proliferation, protection from apoptotic stimuli, invasion, and metastasis, potentially enhancing promotion and progression of many types of cancer cells.

    “Once activated, these signaling pathways may stimulate multiple cancer phenotypes including proliferation, protection from apoptotic stimuli, invasion, and metastasis, potentially enhancing promotion and progression of many types of cancer cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    These factors (adiposity, diet, physical activity) are generally interrelated, making the contribution of each factor difficult to assess.

    “these factors are generally interrelated, making the contribution of each factor difficult to assess.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Since growth factors may downregulate the expression of their cognate receptors, tumors with low insulin receptor levels may be the most insulin-stimulated.

    “Since growth factors may downregulate the expression of their cognate receptors, it is possible that tumors with low insulin receptor levels are the most insulin-stimulated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human tumors commonly over-express insulin, IGF-I, and hybrid receptors.

    “Human tumors commonly over-express these receptors, and many cancer cell lines have been shown to be responsive to the mitogenic action of physiological concentrations of IGF-I.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Pollak, 2008, Insulin and insulin-like growth factor signalling in neoplasia, Nat Rev Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The resulting relative insulin deficiency gives rise to both fasting and postmeal hyperglycemia.

    “The resulting relative insulin deficiency gives rise to both fasting and postmeal hyperglycemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted.

    “Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted (72–74).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] Kalaany, 2009, Tumours with PI3K activation are resistant to dietary restriction, Nature source

      Not checked in the free run.

    • cites [73] Park, 2010, Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression, Cell source

      Not checked in the free run.

    • cites [74] Algire, 2008, Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth, Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of STAT signaling via cytokines such as IL-6 enhances cancer cell proliferation, survival, and invasion while suppressing host anti-tumor immunity.

    “Activation of signal transducer and activator of transcription protein (STAT) signaling, via cytokines such as IL-6, is known to enhance cancer cell proliferation, survival, and invasion while also suppressing host anti-tumor immunity (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat Rev Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Studies relating hyperglycemia to cancer do not necessarily indicate that glucose mediates the relationship; hyperglycemia may serve as a surrogate for a causative factor such as hyperinsulinemia.

    “Studies relating hyperglycemia to cancer do not necessarily indicate that glucose mediates the relationship; rather, hyperglycemia may serve as a surrogate for a causative factor such as hyperinsulinemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The insulin-lowering action of metformin may contribute to its anti-neoplastic activity, and it may have less impact on cancers in less hyperinsulinemic patients.

    “This suggests that the insulin-lowering action of metformin may contribute to its anti-neoplastic activity, and that it may have less impact on cancers in less hyperinsulinemic patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Most large studies have only fasting levels; postprandial (area under the curve) insulin levels have not been adequately examined.

    “In addition, most of the large studies have only fasting levels; postprandial (area under the curve) insulin levels have not been adequately examined.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Type 2 diabetes commonly advances from a pre-diabetic state characterized by insulin resistance (hyperinsulinemia) to frank diabetes with sustained insulin resistance and progressive reduction in insulin secretion.

    “Type 2 diabetes is generally associated with overweight and obesity (in an estimated 80% of cases) and commonly advances from a pre-diabetic state characterized by insulin resistance (hyperinsulinemia) to frank diabetes with sustained insulin resistance accompanied by a progressive reduction in insulin secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin may selectively kill cancer stem cells and enhance effectiveness of breast cancer treatment regimens.

    “Other in vitro studies suggest that metformin may selectively kill cancer stem cells and enhance effectiveness of breast cancer treatment regimens (85–87).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] Vazquez-Martin, 2009, The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells, Cell Cycle source

      Not checked in the free run.

    • cites [86] Hirsch, 2009, Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission, Cancer Res source

      Not checked in the free run.

    • cites [87] Oliveras-Ferraros, 2009, Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells, Cell Cycle source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Type 2 diabetes is generally associated with overweight and obesity in an estimated 80% of cases.

    “Type 2 diabetes is generally associated with overweight and obesity (in an estimated 80% of cases) and commonly advances from a pre-diabetic state characterized by insulin resistance (hyperinsulinemia) to frank diabetes with sustained insulin resistance accompanied by a progressive reduction in insulin secretion.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    The risk of long-term exposure to high levels of insulin is relatively underexplored.

    “The risk of long-term exposure to high levels of insulin is relatively underexplored and has direct relevance to the cancer risk associated with diabetes duration and use of exogenous insulin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In laboratory studies, metformin inhibits cell proliferation, reduces colony formation, and causes partial cell cycle arrest in cancer cell lines.

    “In laboratory studies, metformin has been shown to inhibit cell proliferation, reduce colony formation, and cause partial cell cycle arrest in cancer cell lines (81–83).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Zakikhani, 2006, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells, Cancer Res source

      Not checked in the free run.

    • cites [82] Alimova, 2009, Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro, Cell Cycle source

      Not checked in the free run.

    • cites [83] Liu, 2009, Metformin induces unique biological and molecular responses in triple negative breast cancer cells, Cell Cycle source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin is the most commonly used therapy in patients with type 2 diabetes, often prescribed as initial or combination therapy.

    “The biguanide metformin is the most commonly used therapy in patients with type 2 diabetes, often prescribed as initial or combination therapy (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Nathan, 2009, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    The association between diabetes and cancer may not be causal; diabetes and cancer may be associated simply because they share common predisposing risk factors such as obesity.

    “It is recognized the association may not be causal; diabetes and cancer may be associated simply because they share common predisposing risk factors such as obesity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent in vitro studies indicate that the effects of PPARγ agonists on cell growth are often independent of the presence of PPARγ, so the clinical relevance of in vitro findings is unclear.

    “However, since recent in vitro studies indicate that the effects of PPARγ agonists on cell growth are often independent of the presence of PPARγ (100–102), the clinical relevance of findings of in vitro studies is unclear.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Clay, 2001, Magnitude of peroxisome proliferator-activated receptor-gamma activation is associated with important and seemingly opposite biological responses in breast cancer cells, J Investig Med source

      Not checked in the free run.

    • cites [101] Clay, 2002, 15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis does not require PPARgamma in breast cancer cells, J Lipid Res source

      Not checked in the free run.

    • cites [102] Palakurthi, 2001, Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation, Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rodent studies indicate that PPAR agonists can potentiate tumorigenesis, and they have been considered by some to be multi-species, multi-sex carcinogens.

    “Rodent studies also indicate that PPAR agonists can potentiate tumorigenesis, and they have been considered by some to be multi-species, multi-sex carcinogens (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Rubenstrunk, 2007, Safety issues and prospects for future generations of PPAR modulators, Biochim Biophys Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exenatide, liraglutide, and DPP-4 inhibitors increased β-cell proliferation in animal studies, and sitagliptin increased pancreatic ductal hyperplasia in one small transgenic rodent study.

    “Exenatide, liraglutide, and DPP-4 inhibitors increased β-cell proliferation in animal studies, and in one small study of a transgenic rodent model, the DPP-4 inhibitor sitagliptin was demonstrated to increase pancreatic ductal hyperplasia (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Butler, 2009, Insulin glargine controversy: a tribute to the editorial team at Diabetologia, Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Sulfonylureas can cause hypoglycemia and weight gain.

    “While this class of agents is one of the more effective in lowering A1C, these drugs can cause hypoglycemia and weight gain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Secretagogues stimulate β-cells to release insulin by binding to specific cell receptors, resulting in β-cell depolarization and release of insulin stores.

    “Secretagogues, including sulfonylureas and the rapid-acting glinides, stimulate β-cells to release insulin by binding to specific cell receptors, resulting in β-cell depolarization and release of insulin stores.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Three epidemiologic studies among patients with diabetes focused on all cancers combined or only on a limited number of cancer sites, and results were inconsistent.

    “Three epidemiologic studies conducted among patients with diabetes focused on all cancers combined or only on a limited number of cancer sites, and results were inconsistent (104–106).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Koro, 2007, Cancer risks in thiazolidinedione users compared to other anti-diabetic agents, Pharmacoepidemiol Drug Saf source

      Not checked in the free run.

    • cites [105] Govindarajan, 2007, Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes, J Clin Oncol source

      Not checked in the free run.

    • cites [106] Ramos-Nino, 2007, Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System, BMC Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Thiazolidinediones (TZDs) are insulin-sensitizing PPARγ agonists that do not increase insulin secretion directly or cause hypoglycemia when used alone.

    “Thiazolidinediones (TZDs) are insulin-sensitizing peroxisome proliferator–activated receptor (PPAR)γ agonists that do not increase insulin secretion directly or cause hypoglycemia when used alone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    TZDs may increase, decrease, or have a neutral effect on the risk of cancer or cancer progression in humans.

    “Therefore, it is possible that TZDs may increase, decrease, or have a neutral effect on the risk of cancer or cancer progression in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only a few clinical trials of TZDs for cancer treatment have been conducted, and results have largely been negative.

    “Only a few clinical trials of TZDs for cancer treatment have been conducted, and results have largely been negative (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Burstein, 2003, Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study, Breast Cancer Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide increased risk of medullary thyroid cancer in rats and mice in preclinical tests and was associated with slight increases in serum calcitonin in human trials.

    “Liraglutide increased risk of medullary thyroid cancer in rats and mice in preclinical tests and was associated with slight increases in serum calcitonin in human trials (U.S. Food and Drug Administration).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites U.S. Food and Drug Administration

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Most of these studies had very few cancer cases among users of sulfonylureas, so power was limited to examine associations with specific cancer sites.

    “However, most of these studies had very few cancer cases among users of sulfonylureas, and therefore power was limited to examine associations with specific cancer sites (91,111).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Currie, 2009, The influence of glucose-lowering therapies on cancer risk in type 2 diabetes, Diabetologia source

      Not checked in the free run.

    • cites [111] Currie, 2009, The longest ever randomised controlled trial of insulin glargine: study design and HbA(1c) findings, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The ongoing ORIGIN trial is much larger but was powered for cardiovascular outcomes and may still not provide definitive evidence regarding cancer incidence, especially for specific cancers.

    “The ongoing randomized ORIGIN trial (glargine versus placebo in patients with impaired fasting glucose or newly diagnosed type 2 diabetes) is much larger (∼12,000 patients randomized and followed for 6–7 years) (119). Importantly, this trial was powered for cardiovascular outcomes and may still not provide definitive evidence regarding cancer incidence, especially for specific cancers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention) [registered clinical trial], 2009. Clinical trial reg. no. NCT00069784, clinicaltrials.gov. Accessed 5 April 2010

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Classic subcutaneous therapy with human insulin involves transient exposures to very high insulin levels, while subcutaneous administration of some synthetic insulins results in longer-term exposure to higher insulin concentrations.

    “Classic subcutaneous therapy with subcutaneous human insulin involves transient exposures to very high insulin levels, while subcutaneous administration of some synthetic insulins results (by design) in longer-term exposure to higher insulin concentrations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Insulin glargine may have a disparate impact on cancer risk through its binding to IGF-1 receptors.

    “As noted below, insulin glargine may have a disparate impact on cancer risk through its binding to IGF-1 receptors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Many agents that affect carcinogenesis have long latencies or require a minimum exposure level, and risk associated with some agents may return to baseline after the exposure has been terminated for a period of time.

    “Many agents that affect carcinogenesis have long latencies or require a minimum exposure level, and risk associated with some agents may return to baseline after the exposure has been terminated for a period of time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Insulin is required for all patients with type 1 diabetes.

    “Insulin is required for all patients with type 1 diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    If some medications increase risk while others decrease or have no effect, different comparator drugs will likely lead to different associations and may explain some observed inconsistencies across studies.

    “For example, if some medications increase risk, while other decrease or have no effect on risk, different comparator drugs will likely lead to different associations and may explain some of the observed inconsistencies across studies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    One concern is that insulin is more commonly prescribed in patients with longer duration of type 2 diabetes and is used more often in those with one or more comorbid conditions that preclude use of comparator medications.

    “For example, one concern is that insulin is more commonly prescribed in patients with longer duration of type 2 diabetes and is used more often in those with one or more comorbid conditions that preclude use of comparator medications.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Subcutaneous injection of insulin results in significantly higher levels of circulating insulin in the systemic circulation than endogenous insulin secretion, thereby possibly amplifying links between hyperinsulinemia and cancer risk.

    “Subcutaneous injection of insulin results in significantly higher levels of circulating insulin in the systemic circulation than endogenous insulin secretion, thereby possibly amplifying links between hyperinsulinemia and cancer risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Randomized clinical trial data from an open-label 5-year trial of insulin glargine versus NPH insulin did not find evidence of excess cancer risk (all sites combined) in the insulin glargine arm, although there was a very small number of cancer end points.

    “Randomized clinical trial data from an open-label 5-year trial of insulin glargine versus NPH insulin did not find evidence of excess cancer risk (all sites combined) in the insulin glargine arm (118), although among the ∼1,000 subjects randomized, there was a very small number of cancer end points (57 cancer cases in the glargine arm and 62 cases in the NPH arm).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Rosenstock, 2009, Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Insulin is necessary for many patients with type 2 diabetes to treat hyperglycemia, in part due to progressive loss of β-cell function over time.

    “It is also necessary for many patients with type 2 diabetes to treat hyperglycemia, in part due to the progressive loss of β-cell function over time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Substantial prior research has emphasized differences between human insulin and analog insulins with respect to binding affinity to the IGF-I receptor, including evidence that insulin glargine has much higher affinity and higher mitogenic potency than human insulin or other analogs.

    “Substantial prior research has emphasized differences between human insulin and analog insulins with respect to binding affinity to the IGF-I receptor, including evidence that insulin glargine has much higher affinity, and higher mitogenic potency, than human insulin or other analogs (120–122).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [120] Shukla, 2009, Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines, Endocr Relat Cancer source

      Not checked in the free run.

    • cites [121] Kurtzhals, 2000, Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use, Diabetes source

      Not checked in the free run.

    • cites [122] Liefvendahl, 2008, Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I, Horm Metab Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Few studies examined risk associated with dose, duration, or recency of medication use, which might inform the biologic plausibility of observed associations.

    “Few studies examined risk associated with dose, duration, or recency of medication use, which might inform the biologic plausibility of observed associations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Most diabetic patients are treated with one or more anti-hyperglycemic medications, adding complexity to studies of long-term outcomes such as cancer incidence.

    “Another limitation of observational studies is that most diabetic patients are treated with one or more anti-hyperglycemic medications. Indeed, the progressive nature of type 2 diabetes, requiring changes in pharmacotherapy over time, adds complexity to studies of a long-term outcome such as cancer incidence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Study design and conductreasoning

    Results of in vitro and preclinical studies should inform design considerations for observational studies but by themselves cannot be considered conclusive.

    “Results of in vitro and preclinical studies should inform design considerations for observational studies but by themselves cannot be considered conclusive.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    No impact of incretin-based agents on human cancer incidence has been reported, likely because these newer drugs have not been used in sufficient numbers or for long enough to fully assess effects on cancer risk.

    “No impact of incretin-based agents on human cancer incidence has been reported, likely due to the fact that these newer drugs have not been used in sufficient numbers of patients or for long enough periods of time to fully assess any possible effects on cancer risk.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Conducting studies with all sites combined might attenuate or even mask important associations with only specific cancer sites.

    “Conducting studies with all sites combined might attenuate or even mask important associations with only specific cancer sites.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Some diabetes medications have only recently come on the market, so studies of these agents will only assess cancer risk associated with relatively short-term use.

    “Some diabetes medications have only recently come on the market (e.g., TZDs, insulin analogs, incretin-based therapies). Therefore, studies of these agents will only assess cancer risk associated with relatively short-term use.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Potential mechanisms by which administration of insulin or insulin analogs might influence neoplastic disease include both direct and indirect actions.

    “Potential mechanisms by which administration of insulin or insulin analogs might influence neoplastic disease include both direct and indirect actions.”
    Quote in the paperNot a substantial claim
85 of 85

  • The paper relies on this without support.

    Insulin is produced by pancreatic β-cells and transported via the portal vein to the liver, so both the liver and the pancreas are exposed to high concentrations of endogenously produced insulin.

    “Since insulin is produced by pancreatic β-cells and then transported via the portal vein to the liver, both the liver and the pancreas are exposed to high concentrations of endogenously produced insulin.”

  • The paper relies on this without support.

    Normal cells must undergo multiple genetic “hits” before the full neoplastic phenotype of growth, invasion, and metastasis occurs.

    “Normal cells must undergo multiple genetic “hits” before the full neoplastic phenotype of growth, invasion, and metastasis occurs.”

  • The paper relies on this without support.

    Most cancer cells express insulin and IGF-I receptors; the A isoform of the insulin receptor is commonly expressed.

    “Most cancer cells express insulin and IGF-I receptors; the A isoform of the insulin receptor is commonly expressed.”

  • The paper relies on this without support.

    In addition to its metabolic functions, the insulin receptor is capable of stimulating cancer cell proliferation and metastasis.

    “In addition to its metabolic functions, the insulin receptor is also capable of stimulating cancer cell proliferation and metastasis.”

  • The paper relies on this without support.

    Multiple signaling pathways are activated after insulin receptors or IGF-I receptors interact with their ligands.

    “Multiple signaling pathways are activated after insulin receptors or IGF-I receptors interact with their ligands.”

  • The paper relies on this without support.

    Insulin/IGF may stimulate normal cells that are involved in cancer progression.

    “It is also clear that insulin/IGF may stimulate normal cells that are involved in cancer progression.”

  • The paper relies on this without support.

    Abnormal vasculature growth is a hallmark of cancer.

    “abnormal vasculature growth is also a hallmark of cancer.”

  • The authors state this as an assumption.

    In the setting of insulin resistance of classic insulin target organs (liver, muscle, adipose tissue), at least a subset of cancers remain insulin-sensitive, or insulin insensitivity to metabolic pathways does not extend to resistance to growth-promoting properties.

    “The assumption that in the setting of insulin resistance of classic insulin target organs (liver, muscle, adipose tissue) at least a subset of cancers remain insulin-sensitive, or that insulin insensitivity to metabolic pathways does not extend to resistance to growth-promoting properties, needs to be more closely examined.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Garcia, 2007, Global Cancer Facts & Figures 2007
  2. Mackay, 2006, The Cancer Atlas

Cited by

Sorted by citations

Related

Authors
Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G., & Yee, D.
Affiliations
  • Harvard University (US)
  • University of Massachusetts Chan Medical School (US)
  • University of Toronto (CA)
  • Park Nicollet Clinic (US)
  • American Cancer Society (US)
  • Kaiser Permanente (US)
  • Department of Oncology, McGill University, Montreal, Quebec, Canada;
  • University of Colorado Anschutz (US)
  • University of Minnesota (US)
Corresponding author
Giovannucci, Edward
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2010-07-01
Volume
33
Issue
7
Pages
1674-1685
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc10-0666
PMC
PMC2890380
OpenAlex
W2104195235
Cited by
2,366
References
144
Citations by year
2026: 77 · 2025: 110 · 2024: 150 · 2023: 134 · 2022: 149 · 2021: 189 · 2020: 211 · 2019: 145 · 2018: 156 · 2017: 160 · 2016: 157 · 2015: 144 · 2014: 167 · 2013: 162 · 2012: 141
FWCI
53.32
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes Care (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Oncology › Cancer Risks and Factors
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
diabetes mellitus, cancer, type 2 diabetes, cancer incidence, cancer prognosis, shared risk factors, cancer risk, biological mechanisms
MeSH terms
Diabetes Mellitus, Humans, Hypoglycemic Agents, Neoplasms, Prognosis, Risk Factors, Incidence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review