document: the associations between diabetes and cancer have been the subject of debate for over a century . 
   the length of this debate suggests , perhaps , that any such associations are relatively weak , and it is safe to say that most practicing diabetologists do not view cancer as a specific , diabetes - associated risk in day - to - day practice . that diabetes is not more clearly associated with cancer 
   is surprising , since diabetes may be viewed as a disease of increased intracellular oxidative stress , as well as accelerated  biochemical aging caused by the accumulation of  advanced glycation end - products ( ages ) on proteins and other macromolecules ( reviewed in ) . 
   an additional concern is the role of insulin , which , in various forms , is increasingly used in the management of type 2 diabetes , a condition that is now epidemic worldwide . 
   specifically , the ability of insulin to bind and activate the insulin - like growth factor-1 ( igf-1 ) receptor has raised concerns that it may promote the growth of nascent malignancies and even the establishment of new ones . 
   , there has been a recent surge in interest in the role of diabetes , insulin therapy , and specifically the effects of newer forms of insulin in promoting cancer . 
   recent rigorous epidemiologic studies have confirmed that type 2 diabetes does indeed confer increased risk for certain types of malignancies , in particular breast , colon , and pancreatic   tumors . 
   many patients with type 2 diabetes eventually require insulin , and the long - acting insulin analogue , glargine , is one of the most commonly used agents . 
   several recent studies have demonstrated the potential mitogenic and anti - apoptotic effects of glargine on cultured cancer cells , and have implicated activation of the igf-1 pathway . 
   however , the clinical implications remain controversial , particularly when studies pertaining to untransformed cells did not support any mitogenic potential . in addition , according to some authors , glargine compared with human insulin does not seem to display increased mitogenic effects , despite its higher affinity for the igf-1 receptor ; rather , any type of insulin has the potential to promote growth in cancer cells , especially if administered at sufficiently high , supra - physiologic doses . 
   the question now is whether glargine is associated with increased cancer risk compared with other commonly used forms of insulin . 
   this question has come to the fore with the publication of several studies in diabetologia [ 12 - 15 ] , which will be reviewed briefly here . 
   the epidemiologic study that initiated the recent debate was performed in germany   and suggested a specific cancer risk associated with glargine . based upon the mixed opinions of six reviewers , the editors of diabetologia , the journal to which it was submitted , commissioned three additional studies [ 13 - 15 ] , aiming to confirm or refute its findings . in the initial study , hemkens et al 
   .   followed 127,031 german patients who were being treated with human insulin and human insulin analogues ( aspart , lispro , or glargine ) over a mean of 1.6 years between january 1998 and june 2005 . 
   those on two insulin analogues or a combination of human insulin and an analogue were excluded from the analysis . 
   patients with known or suspected malignant disease within 3 years prior to study start were also excluded . 
   the primary outcome was occurrence of a malignant neoplasm , and the secondary outcome was all - cause mortality . the gross malignancy incidence rates for human insulin , aspart , lispro , and glargine were 2.50 , 2.16 , 2.13 , and 2.14 per 100 patient - years , respectively , in the unadjusted analysis . 
   however , when the data were adjusted for daily insulin dose , glargine was found to be associated with a greater risk of malignancy , and the risk was incremental with higher glargine doses when compared with human insulin { adjusted hazard ratio [ hr ] of 1.09 for a daily dose of 10 iu [ 95% confidence interval ( ci ) 1.00 - 1.19 ] , 1.19 for a daily dose of 30 iu [ 95% ci 1.10 - 1.30 ] , and 1.31 for a daily dose of 50 iu [ 95% ci 1.20 - 1.42]}. aspart and lispro were not associated with an increased risk for cancer compared with human insulin . 
   in addition , regardless of the type of insulin , higher doses and longer duration of exposure increased the risk of malignancy . 
   finally , the mean insulin dose until occurrence of a neoplasm ( cumulative dose divided by time until an event ) was significantly lower for glargine ( 25.9 iu / day ) than for human insulin , aspart , and lispro ( 43.8 , 38.9 , and 36.2 iu / day , respectively ) . the major weaknesses of the study included the fact that patients were not allocated to treatment groups in a prospective manner and that insulin dose was calculated during follow - up from mean values , and not determined at baseline . 
   in addition , the exclusion of patients on combination insulin therapy may not reflect common practice , in which patients are typically on basal / bolus regimens requiring the use of different types of insulin . 
   finally , the duration of diabetes , as well as smoking status , body mass index ( bmi ) , and other potential confounding factors were not taken into account . 
   the three additional , commissioned studies were published in the same issue of diabetologia . in sweden , jonasson and 
   colleagues   evaluated 114,842 patients with diabetes on insulin and noted that women on glargine alone , but not glargine combined with other types of insulin , had a higher risk of breast cancer than women on other types of insulin ( hr adjusted for age , smoking , bmi , and other confounding factors was 1.97 , 95% ci 1.29 - 3.00 ) . 
   however , this increased risk was not associated with an increased mortality rate ; instead , all - cause mortality was actually decreased in women on glargine alone versus women on other types of insulin ( relative risk [ rr ] 0.83 , 95% ci 0.71 - 0.96 ) . 
   the associations with other malignancies such as prostate and gastrointestinal tumors did not reach statistical significance . 
   no analysis taking into account insulin dose was possible in this study , and therefore the incremental risk conferred by higher doses as observed by hemkens et al . 
   the short duration of exposure and observation as well as the lack of data on how much insulin the patients were taking limit the strength of the conclusions . in a study in scotland , no increased risk of total or site - specific cancer associated with overall glargine use was found in a cohort of 12,852 patients followed for 4 years ; in particular , no increase in breast cancer risk ( hr 1.49 , 95% ci 0.79 - 2.83 ) was found . 
   however , exclusive use of glargine did seem to confer higher risk ( adjusted hr 3.39 , 95% ci 1.46 - 7.85 ) , but the number of cases was small ( six events ) . 
   in addition , glargine - only users tended to be older , were more likely to be women , and to have a higher bmi , reflecting a baseline imbalance . 
   finally , the restricted use of glargine in scotland may have contributed to a skewing of the results , since there were a limited number of patients taking this form of insulin . in a uk 
   studied 62,809 patients with diabetes on metformin , sulfonylurea monotherapy , a combination of both , or insulin therapy . 
   the latter were further divided into glargine - treated versus other human insulin - treated ( long - acting , biphasic , and biphasic analogue ) . the results indicated that any type of insulin therapy increased the risk of occurrence of solid tumors and that concomitant metformin therapy attenuated this effect . 
   indeed , the adjusted hrs relative to metformin monotherapy were 1.08 ( 95% ci 0.96 - 1.21 ) for the metformin / sulfonylurea combination , 1.36 ( 95% ci 1.19 - 1.54 ) for sulfonylurea alone , and 1.42 ( 95% ci 1.27 - 1.60 ) for insulin - based therapies . 
   concomitant metformin therapy decreased the risk of malignancy associated with insulin by 46% ( hr 0.54 , 95% ci 0.43 - 0.66 ) . when compared with glargine 
   , other human insulins displayed comparable rates , suggesting no added risk attributable to glargine ( adjusted hr 1.24 , 95% ci 0.90 - 1.17 for basal human insulin ; hr 0.88 , 95% ci 0.66 - 1.19 for biphasic human insulin ; and hr 1.02 , 95% ci 0.76 - 1.37 for analogue biphasic insulin ) . 
   malignancies that had the strongest association with insulin therapy compared with metformin were colorectal ( hr 1.69 , 95% ci 1.23 - 2.33 ) and pancreatic ( hr 4.63 , 95% ci 2.64 - 8.10 ) tumors . 
   breast and prostate cancer risks did not seem to be affected by treatment with insulin or insulin secretagogues , and a prior history of solid tumor strongly increased the overall risk ( hr 3.86 , 95% ci 3.46 - 4.31 ) . in a letter published in a subsequent issue of diabetologia , rosenstock et al . 
   , reported a study of glargine versus neutral protamine hagedorn ( nph ) insulin in type 2 diabetes patients randomly assigned to one insulin or the other for over 4 years . although malignancy risk was not a primary endpoint for the study , no increased cancer risk with glargine compared to nph was found ( rr 0.90 , 95% ci 0.64 - 1.26 ) . home and lagarenne , using the sanofi - aventis 
   pharmacovigilance database for all randomized company - sponsored clinical trials , published a systematic review of 31 trials comparing glargine to other agents ( nph for most studies ) . 
   no evidence for an increased risk of malignancy attributable to glargine was found ( rr 0.90 , 95% ci 0.60 - 1.36 ) . 
   all but one of these studies lasted less than 12 months ( on average , 6 months ) , so their major limitation was the short duration of exposure and follow - up . 
   indeed , the majority of reported cases of malignancy were derived from the study of rosenstock and colleagues , discussed above , in which follow - up exceeded 4 years . 
   finally , a meta - analysis comparing cancer risk associated with another new , long - acting insulin , insulin detemir , versus nph and glargine was performed . 
   it used data from randomized controlled trials sponsored by novo nordisk ( bagsvaerd , denmark ) and found comparable malignancy risks associated with detemir and glargine in the five trials that compared both drugs . 
   however , the number of events was very small ( n = 8 ; event rate per 100 exposure - years = 0.87 for detemir , and n = 8 ; event rate per 100 exposure - years = 1.27 for glargine ) . 
   the issues are highly emotive : cancer and diabetes eventually affect a large proportion of the world 's population . 
   in addition , there are enormous financial implications surrounding the controversy , and unfortunately , complex issues tend to be oversimplified and are often sensationalized . 
   either a diagnosis of cancer or the institution of insulin therapy for diabetes provokes great anxiety in many people . 
   criticism of the publication of the diabetologia papers came in the correspondence section of the lancet , where pocock and smeeth   raised concerns regarding the quality of the statistical analyses and contended that these analytical flaws , especially in the german paper , had raised unsubstantiated anxieties . 
   they criticized the swedish study for its finding of an association of insulin glargine with breast cancer , arguing that the latter was not a 
   pre - defined site for analysis but rather a secondary finding ultimately not  confirmed by the scottish study   ( the latter did find an increased risk of breast cancer associated with the exclusive use of glargine , but only affecting very few , older patients ) . 
   further criticism came in an editorial by garg , hirsch , and skyler   in diabetes technology and therapeutics , questioning the motivations behind the german study and raising concerns similar to those brought up by pocock and smeeth . 
   this paper also emphasized the lack of evidence of an increased overall cancer risk associated with glargine based on the swedish , scottish , and uk studies , concluding that  glargine use should not be discontinued based on unsubstantiated allegations. the letter of pocock and smeeth elicited a prompt response from the editor of diabetologia . 
   the editor , while acknowledging the imperfections of the studies ( which he had already discussed in detail in an accompanying editorial ) , argued that the epidemiologic data can not and should not be dismissed , especially when considered in the context of animal and cell culture work , but rather should generate further research to define risk . 
   indeed , in his initial editorial on the subject , he had earlier stated that 
   the evidence presented in this set of papers is sufficient to establish that there is a case to answer , but is entirely insufficient to bring a verdict. at least on the latter conclusion , all parties agreed . 
   these thought - provoking studies , although inconclusive , do raise concerns about the long - term effects of diabetes itself , insulin treatment , and specifically , glargine , on cancer development . 
   it must be remembered that the greatly increased mortality among patients with diabetes has little to do with cancer , but instead is related to vascular complications . 
   the overall benefit - to - risk ratio of good glycemic control is likely to support extensive use of insulin . 
   all are agreed that the current evidence does not warrant any change in clinical practice , specifically with regard to the use of glargine . 
   further research will need to address the relationship between diabetes , insulin , insulin analogues and secretagogues , and cancer . 
   it will also explore potentially protective effects of metformin and perhaps the most tantalizing question : why is diabetes not more strongly associated with cancer ? 
   
summary: diabetes , in particular type 2 , is associated with an increased incidence of cancer . 
   although the mortality attributable to cancer in type 2 diabetes is overshadowed by that due to cardiovascular disease , emerging data from epidemiologic studies suggest that insulin therapy may confer added risk for cancer , perhaps mediated by signaling through the igf-1 ( insulin - like growth factor-1 ) receptor . 
   co - administered metformin seems to mitigate the risk associated with insulin . 
   a recent series of publications in diabetologia addresses the possibility that glargine , the most widely used long - acting insulin analogue , may confer a greater risk than other insulin preparations , particularly for breast cancer . 
   this has led to a heated controversy . despite this 
   , there is a consensus that the currently available data are not conclusive and should not be the basis for any change in practice . 
   further studies and more thorough surveillance of cancer in diabetes are needed to address this important issue .