Diabetes and Cancer
Mathew John, MD, DM, DNB
Providence Endocrine & Diabetes Specialty Centre
Trivandrum, India
www.endocrinologydiabetes.com
http://www.guardian.co.uk/society/2008/oct/06/health.cancer
Agenda
Diabetes and Cancer
Insulin, its receptor , IGF-1 and cancer pathogenesis
Diabetes therapies and cancer Diabetes therapies and cancer
Insulin and Analogs
Metformin
Glitazones
ARB
Introduction
Worldwide cancer is the 2nd and diabetes in the 12 th common cause of death
Cancer and diabetes are diagnosed within the same Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age
Causes of CancerEstimate percentage of total cancer deaths attributable to established causes of cancer
Dileep G. Bal, M.D., Diet and Cancer
Diabetes and CancerA Metaanalysis
Vigneri et al . Endocrine-related Cancer. E pub ahead of print 2009. Source: http://erc.endocrinology-journals.org, Accessed 4th September 2009
Risk factors for diabetes and cancer
Non modifiable
Age
Sex
Race/Ethnicity
Modifiable
Diet
Overweight/Obesity
Physical activity
Smoking Smoking
Alcohol
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010
Risk factors for Diabetes & Cancer
D
I
A
B
E
T
E
S
Non modifiable
Age
Sex
Race/Ethnicity
Modifiable
Diet
Overweight/Obesity
Physical activity
Smoking
C
A
N
C
E
R
D
I
A
B
E
T
E
S
Smoking
Alcohol
Made by data from GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010
Obesity and Cancer
The cancers most consistently associated with overweight and obesity are those of the
Breast
Colon/rectum
Endometrium
Liver
Growing body of evidence suggests that weight gain is associated with an increased risk of some cancers, breast cancer in particular
Endometrium
Pancreas
Esophagus,
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010
Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies
Summary risk estimates by cancer sites in men Summary risk estimates by cancer sites in women
Lancet 2008; 371: 56978
Diet and Cancer
Picture removed Picture removed
Fruits and vegetables Red meat
Meat and colorectal cancer
Processed meat Red meat
Sandhu MS et al. CEBP 2001;10:439- 446
Vegetables and Colorectal CancerProspective Cohort Studies
Dileep G. Bal, M.D., Diet and Cancer
Whole grains & cancerProspective cohort studies
Dileep G. Bal, M.D., Diet and Cancer
Epidemiological studies of physical activity and colon and colorectal cancer risk
Prospective studies
CM. Friedenreich Physical Activity and Cancer Prevention: From Observational to Intervention Research Cancer Epidemiology, Biomarkers & Prevention Vol. 10, 287301, April 2001
Tobacco Smoking
Tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths
Smoking is also an Smoking is also an independent risk factor for the development of diabetes
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010
Alcohol
Moderate alcohol consumption increases the risk of many types of cancer including those of the oral cavity, pharynx, larynx, esophagus, liver, colon/rectum, and female breastand female breast
Excess alcohol consumption is also a risk factor for diabetes
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010
Diabetes & CancerInterpreting associations
Many risk factors for CANCER are also risk factors for
DIABETES
Exercise caution in interpreting associations between
DIABETES and CANCER DIABETES and CANCER
Pathogenesis of Cancer
Dileep G. Bal, M.D., Diet and Cancer
The link
The most plausible hypothesis linking diabetes and
diabetes therapies to cancer is via the
Insulin and IGF-1 receptor
M. Pollak, D. Russell-Jones Insulin analogues and cancer risk: cause for concern or cause ce le` bre?Int J Clin Pract, April 2010, 64, 5, 628636
Insulin IGF-1
Cancer cells express Insulin receptor isoform A and IGF-1 receptors
Insulin, IGF-1
Insulin Receptor
IGF-1 Receptor
Metabolic effectsGlucose transport Glycogen synthesis Protein synthesis
Growth effectsRNA & DNA synthesisCell proliferation Cell survival
and IGF-1 receptors
Insulin receptor can induce Mitogeneis
Insulin receptor, IGF-1 receptors and hybrid receptors
Diabetes therapies and cancer
Insulin & Insulin Analogs
Metformin
Thiazolidinediones
Secreatgogues
GLP-1 associated agents GLP-1 associated agents
Angiotensin receptor blockers
Differences between insulins in receptor binding properties.
AnalogueInsulin receptor
affinity (%)Insulin receptor
off-rate (%)Metabolic potency
(lipogenesis) (%)IGF-I receptor
affinity (%)Mitogenic
potency (%)
Human insulin 100 100 100 100 100
B10Asp 205 20 14 1* 207 14 287 50 975 173B10Asp 205 20 14 1* 207 14 287 50 975 173
Aspart 92 6 81 8* 101 2 81 9 58 22
Lispro 84 6 100 11 82 3 156 16 66 10Glargine 86 3 152 13 60 3 641 51 783 132
A21Gly 78 10 162 11 88 3 42 11 34 12
B31B32diArg 120 4 75 8 75 5 2049 202 2180 390
Detemir 46 5/18 2 204 9 ca 27 16 1 ca 11
Kurtzhals P, Schffer L, Srensen A et al. Correlations of receptor binding and metabolic and mitogenicpotencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 9991005
Insulin-Receptor Interaction
Insulin/ Insulin Analog
IGF-1 Receptor
InsulinReceptor(IR)
Different insulin analogs have different affinities to insulin
receptor and IGF-1 receptor
Mitogenic potential of insulin
Increased duration at IR
Increased affinity at IGF-1 R
Other experimental data
Pancreatic cancer cell line responded similarly to HI and Glargine
Erbel S, Diabetes Care 2008, 31: 1105
Colorectal, breast and prostate cell lines showed proliferative changes and resistance to apoptosis with proliferative changes and resistance to apoptosis with Glargine, Detemir,Lispro but not Human Insulin
Weinstein D, Diabetes Metab Res Rev 25: 41-49
Growth of malignant cell line MCF7 was strongly promoted by insulin Glargine , but not other insulins
Shukla A, Endocr Rel Cancer 2009 16: 429
Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/ s00125-009-1441-5.
EASD requests investigators in Sweden, Scotland & UK to conduct similar population based studies
A cohort study from Germany shows dose dependent cancer risk with Lantus
(N=127031)
Significant increase in incidence of Ca. Breast
in women usingGlargine monotherapy
(N=114841)
Significant increase in incidence of all cancers
in people usingGlargine monotherapy
(N=49197)
No increased risk of cancer with
insulin analogues(N=10067)
Sweden Scotland UK
EASD communicates possible link between glargine and cancer
Criticism to studies
Observational study
Biological implausibility : short duration 1.31 years
Unexplained improvement of Glargine on all cause mortality
No difference between cancer risk in crude analysis
Different tumors : unlikely that one agent will produce different tumors
Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/ s00125-009-1441-5.
Glargine : metaanalysis of
randomised controlled trials
31 studies, 12 in type 1 diabetes and 19 in type 2 diabetes. Twenty compared insulin Glargine with NPH insulin
Studies were generally of 6 months duration, except for trial Studies were generally of 6 months duration, except for trial reference number 4016 (n=1,017), which had a duration of 5 years.
Insulin Glargine was not associated with an increased incidence of cancer, including breast cancer, compared with the comparator group
P. D. Home & P. Lagarenne. Published online: 15 September 2009
Insulin glargine & malignancy : prospective studies
Ehninger G, Schmidt AH Putting Insulin Glargine and Malignancies into PerspectiveThe Oncologist 2009;14:11691174
Current recommendation
FDA
FDA recommends that patients should not stop taking their insulin
therapy without consulting a physician
American Association of Clinical EndocrinologistsAmerican Association of Clinical Endocrinologists
The AACE does not recommend that the use of any insulin be
changed.
The European Association for the Study of Diabetes(EASD)
Patients with diabetes taking Lantus should continue to do so, although
some might wish to consider alternative types of insulin
Accessed from FDA/AACE/EASD websites on 5/12/2009
Metformin
In laboratory models
Inhibit cell proliferation,
Reduce colony formation
Partial cell cycle arrest in cancer cell lines
Metformin and cancer prevention Mechanism
Activation of AMP kinase
Inhibits genes involved in gluconeogenesis
Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:11781181
AMPK has role in tumor suppression
Metformin reduces cancer risk in type 2 diabetes
Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:11781181
Metformin & Cancer Mortality
Adjusted HR of Metformin use for cancer mortality was 0.43 (0.230.80)
The hazard for cancer The hazard for cancer mortality decreased by 42% for every 1-g increase in the Metformin dose.
Landman GWD et al. Metformin Associated With Lower Cancer Mortality in Type 2 DiabetesZODIAC-16 Diabetes Care. 2010 Feb;33(2):322-6.
Thiazoliinediones and Cancer
In vitro studies
Inhibiting growth
Inducing apoptosis and cell differentiation
Rodent studies
PPAR gamma agonists have tumorogenic properties
differentiation
Inhibits invasion
Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T. J Clin Endocrinol Metab 2001;86:21702177Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Biochim Biophys Acta 2007;1771:10651081Liu H, Zang C, Fenner MH. et al. PPAR gamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitro. Breast Cancer Res Treat 2003; 79: 6374.Govindarajan R, Ratnasinghe L, Simmons DL. et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007; 12: 14761481.
They have found 33% reduction in lung cancer risk among TZD users (RR 0.67; 95%; CI: 0.510.87)
Pioglitazone and bladder tumors
Bladder tumors were seen in male rats receiving a dose of pioglitazone
Ten-year, observational cohort study as well as a nested case-control study
No statistically significant association between any No statistically significant association between any Pioglitazone exposure and increased bladder cancer risk in the study (HR= 1.2, 95% CI: 0.9-1.5)
Risk of bladder cancer increased with increasing dose and duration of Pioglitazone use, reaching statistical significance after 24 months of exposure
http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm
Insulin secretagogues
Limited studies linking secreatgogue use to malignancy
Very few cancer cases among users
GLP-1 associated agents
Liraglutide increased risk of medullary thyroid cancer in rats and mice in preclinical tests
In transgenic rodent model, the DPP-4 inhibitor sitagliptin was demonstrated to increase pancreatic sitagliptin was demonstrated to increase pancreatic ductal hyperplasia
No increase in human cancer incidence with these agents
Pathogenesis of CancerInsulin and Analogs
Dileep G. Bal, M.D., Diet and Cancer
Insulin is unlikely to be Mutagenic Insulin is likely to be
mitogenic ( IR A and IGF1 Receptor
ARB and Cancer
Cancer occurrence reported in all included trials of Angiotensin-receptor blockers
Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials Lancet Oncol 2010; 11: 62736
ARB and Cancer
ARBs are associated with a modestly increased risk of new cancer occurrence
RAAS is involved in regulation of cell proliferation, tumour growth, angiogenesis, and metastasistumour growth, angiogenesis, and metastasis
AT1R blockade with an ARB (which is associated
with unopposed AT2R stimulation) and direct stimulation
of AT2R are capable of stimulating tumour angiogenesis
in vivo.
Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials Lancet Oncol 2010; 11: 62736
Messages
Diabetes, obesity and insulin resistance are independently associated with cancer
The association between diabetes and cancer is confounded by different agentsconfounded by different agents
Insulin interaction with Insulin receptor and IGF-1 receptor forms the basis
Insulin analogs are likely to be mitogenic (not mutagenic)
Thank you
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Disclaimer
The material for these slides were derived from various sources including picturesand cartoons from the world wide web. I have tried my best to acknowledge allpossible sources and references. However, if I have overlooked any particularreference, it is not done intentionally. Anyone reproducing materials from thispresentations should acknowledge the author of the original work. The case given isimaginary and is given only to support the purpose of this talk. Any similarity topublished case report/ patient is unintentional.
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