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The big dilemma !! Insulin Carcinogenicity By: Eman Rushdy.

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Presentation on theme: "The big dilemma !! Insulin Carcinogenicity By: Eman Rushdy."— Presentation transcript:

1 The big dilemma !! Insulin Carcinogenicity By: Eman Rushdy

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3 Once upon a time there was a lady in faded gingham dress with her husband who dressed a home made suit directly passed to the office of the president of Harvard. Once upon a time there was a lady in faded gingham dress with her husband who dressed a home made suit directly passed to the office of the president of Harvard. The secretary could see that the people were not from Boston, and probably didn't even deserve to be in Cambridge. The secretary could see that the people were not from Boston, and probably didn't even deserve to be in Cambridge. We want to see the president", the man said softly. We want to see the president", the man said softly. Someone of his importance obviously didn't have the time to spend with them Someone of his importance obviously didn't have the time to spend with them

4 May be if they just see you for a few minutes, they'll leave.May be if they just see you for a few minutes, they'll leave. The lady told him, "We had a son that attended Harvard for one year. He loved Harvard. But about a year ago, he was accidentally killed. And my husband and I would like to erect a memorial to him.The lady told him, "We had a son that attended Harvard for one year. He loved Harvard. But about a year ago, he was accidentally killed. And my husband and I would like to erect a memorial to him. "Madam," he said gruffly, "we can't put up a statue for every person who attended Harvard and died."Madam," he said gruffly, "we can't put up a statue for every person who attended Harvard and died.

5 "We don't want to erect a statue. We thought we would like to give a building to Harvard. "We don't want to erect a statue. We thought we would like to give a building to Harvard. The president glanced at the gingham dress, then exclaimed, "A building! Do you have any earthly idea how much a building costs? The president glanced at the gingham dress, then exclaimed, "A building! Do you have any earthly idea how much a building costs? We have over seven and a half million dollars in the physical plant at Harvard". For a moment the lady was silent. The president was pleased. He could get rid of them now. We have over seven and a half million dollars in the physical plant at Harvard". For a moment the lady was silent. The president was pleased. He could get rid of them now. And the lady turned to her husband and said quietly, "Is that all it costs to start a University? And the lady turned to her husband and said quietly, "Is that all it costs to start a University? Mr. and Mrs. Leland Stanford established the University that bears their son name, Mr. and Mrs. Leland Stanford established the University that bears their son name, You can't judge a book by the cover....

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8 We have to evaluate the issue; Type 2 DM ( insulin resistance and obese ) taking insulin ( form, dose and duration)

9 Certainly everyone has to die of something, but death does not need to be slow and painful deaths deaths deaths deaths deaths deaths HIV/AIDS TB Malaria Cardiovascular Disease Cancer Diabetes 1 Adapted from Preventing CHRONIC DISEASES a vital investment, WHO report people will die in the next 10 years of a chronic diseases

10 Cardiovascular Chronic Respiratory Disease Type 2 Diabetes Cancer Chronic Diseases result in percent of deaths Chronic Diseases result in percent of deaths 4 52

11 Obesity means having too much body fat (adipose tissue). A BMI of 30 or higher is considered obese in adults—you are at a higher risk for certain health problems than those with a lower BMI.

12 LEPTIN FFA RESISTIN TNFa IL6 PAI RENIN ANGIOTENSINOGEN ESTROGEN dyslipidemia HTN IH D DMIR cancer

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15 Is there a link between obesity and cancer?

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18 Pathogenesis: Few controlled clinical trials, only observational studies, So the definite mechanism is unknown Few controlled clinical trials, only observational studies, So the definite mechanism is unknown

19 1- Genetic link: 1- Genetic link:  The agouti protein is a paracrine factor that is normally present in the skin of many species of mammals  Agouti regulates the switch between black and yellow hair pigmentation.  Mutations in the mouse agouti gene that cause the wild-type protein to be produced at abnormally high levels throughout the body.→ syndrome characterized by yellow coat color, obesity, hyperglycemia,hyperinsulinemia, and increased susceptibility to hyperplasia and carcinogenesis.

20 2-Metabolic and hormonal changes with obesity:  ↑ Leptin → + haemopoeisis + GMCF + GMCF + Angiogenesis + Angiogenesis  ↑ Insulin → cell proliferation  Hyperinsulinemia →↓ IGF-1 binding protein →↑ free IGF-1  ↑ Estrogen → cell proliferation  ↓ Sex hormone binding globulin →↑ free sex hormone

21 3-low physical activity: * E xercise prevents the buildup of fat tissue and regulates the levels of mediators in the blood. *Physical activity speeds the passage of dietary and environmental carcinogens from the body and reduces the amount of time these substances spend in contact with colorectal tissues. *Intense exercise before and during adolescence can also delay the start of menstruation and thus decrease the total number of ovulations that occur over a lifetime.

22 Cancer breast:  ↑ E strogen  ↑ Duration of exposure to excess estrogen. (Adulthood weight and regular physical activity are important)  Detected at a later stage, because the detection of it is more difficult in obese versus lean women stage ovary FAT breas t fat breast ER

23 Cancer colon: *Male: Men with high BMI *Females: Estrogen with normal gynecoid fat distribution appears to be protective for colon cancer Obese females (central obesity) have higher risk than those females with lean weight, So measurements for abdominal obesity as waist circumference and waist hip ratio are better predictors than BMI alone. *↑ insulin and other growth factors. *Diet: Diets containing substantial amounts of red meat and low fibers *Low physical activity

24 Cancer esophagus: Increased incidence of gastric reflux in obese patients Increased incidence of gastric reflux in obese patients

25 Cancer liver: Cirrhosis with NASH Cirrhosis with NASH Hyperinsulinemia → altered Hyperinsulinemia → altered proliferation/apoptosis with hyperproliferation and dysplasia many years before cirrhosis develop proliferation/apoptosis with hyperproliferation and dysplasia many years before cirrhosis develop

26 CANCER GALL BLADDER: Increased incidence of gall bladder stones Increased incidence of gall bladder stones

27 Cancer prostate Aggressive tumour, with high mortality rate. Aggressive tumour, with high mortality rate. Might be due to : Might be due to : difficult and late diagnosis. difficult and late diagnosis. difficult surgical total resection difficult surgical total resection low PSA level in obese patients low PSA level in obese patients

28 Does insulin resistance and glycemic load make a difference in cancer risk ?

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30 8-18% of cancer patients also have diabetes All types of cancer particularly: –Breast Cancer –Endometrial Cancer –Pancreatic Cancer –Liver Cancer –Kidney Cancer –Colon Cancer

31 Colorectal Colorectal –Keku TO et al. Insulin resistance, apoptosis, and colorectal adenoma risk Cancer Epidemiol Biomarkers Prev;14(9): –Higginbotham S et al. Dietary glycemic load and risk of colorectal cancer in the Women's Health Study J Natl Cancer Inst;96(3): Breast Breast –Borugian MJ et al. Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer? Cancer Epidemiol Biomarkers Prev;13(7): –Bozcuk H et al. Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy Cytokine;27(2-3): Ovarian Ovarian –Augustin LS et al. Dietary glycemic index, glycemic load and ovarian cancer risk: a case-control study in Italy Ann Oncol;14(1): Prostate Prostate –Hsing AW et al. Insulin resistance and prostate cancer risk J Natl Cancer Inst;95(1): Insulin Resistance & Cancer Risk & Survival

32 Insulin problem !!!

33 Insulin Insulin receptor Insulin receptor tyrosine kinase Downstream targets Metabolic effects Mitogenic effects IGF- I receptor Supra-physiological insulin concentration IGF binding Pr. Free IGF

34 Glycemic Load (GL) Effects of Diet on Apoptotic Markers in Tumors High glycemic load decreased apoptosis

35 The normal human pancreas has a basal insulin secretory rate of 1-2 U per hour, with post prandial rates increasing to 4-6 U / hr. in two phases (early & Late phase). The normal human pancreas has a basal insulin secretory rate of 1-2 U per hour, with post prandial rates increasing to 4-6 U / hr. in two phases (early & Late phase). Normal daily total amounts of secreted insulin range from U. Normal daily total amounts of secreted insulin range from U. In patients with insulin resistance there will be hyperinsulinemia In patients with insulin resistance there will be hyperinsulinemia In patients with type 2 DM there is insulin deficiency (treatment supposed to compensate for the deficient amount of insulin) In patients with type 2 DM there is insulin deficiency (treatment supposed to compensate for the deficient amount of insulin)

36 Cancer risk is related to dose of insulin Cancer risk is related to dose of insulin What about the form??? What about the form???

37 Insulin Insulin receptor Insulin receptor tyrosine kinase Downstream targets Metabolic effects Mitogenic effects IGF-I receptor Any insulin affinity is significantly lower than the affinity of endogenous IGF-1 for IGF-1R Preclinical Evidence :

38 To summarize: There is a strong link between Obesity, Diabetes Mellitus, Insulin Resistance and Carcinogenesis. There is a strong link between Obesity, Diabetes Mellitus, Insulin Resistance and Carcinogenesis. Insulin might be a contributing factor in pathogenesis (with many other pathogenic factors), But in which dose and which form ?! Insulin might be a contributing factor in pathogenesis (with many other pathogenic factors), But in which dose and which form ?!

39 ADA press release “Findings from these research papers are conflicting and inconclusive, and the American Diabetes Association cautions against over-reaction until more information is available.” “Findings from these research papers are conflicting and inconclusive, and the American Diabetes Association cautions against over-reaction until more information is available.” “Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it” “Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it” “Statement From the American Diabetes Association Related to Studies Published in Diabetologia Suggesting Possible Link Between Insulin Glargine and Cancer Research Conflicting and Inconclusive: Patients Should Not Stop Using Insulin and Should Talk to Their Doctor”

40 AACE Response to Insulin Glargine Articles in Diabetologia The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. AACE supports further research into the effectiveness and safety of all diabetes therapies AACE supports further research into the effectiveness and safety of all diabetes therapies

41 EASD 2009: It's also possible, however, that patients treated with insulins are at increased risk for cancer because of the underlying disease, not because of the drugs. It's also possible, however, that patients treated with insulins are at increased risk for cancer because of the underlying disease, not because of the drugs. Studies also show that insulin glargine was found to have no special risk over and above other insulin products. Studies also show that insulin glargine was found to have no special risk over and above other insulin products. At the core of the matter is this: is this due to high circulating insulin, or is it the basic defect associated with both obesity and type 2 diabetes ( insulin resistance?) At the core of the matter is this: is this due to high circulating insulin, or is it the basic defect associated with both obesity and type 2 diabetes ( insulin resistance?) EASD does not recommend that the use of any insulin to be changed. EASD does not recommend that the use of any insulin to be changed.

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44 The four registry analyses published in Diabetologia (June,26 th 2009)

45 45 The German study: Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues aspart, lispro, glargine Hemkens LG, Grouven U, Bender R, et al (2009). Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia DOI /s Increased risk of cancer was only seen when analysis was adjusted for insulin doses Potentially relevant factors such as insulin resistance, body mass index,smoking, social status and duration of diabetes, were not available and therefore could not be considered in the analyses”

46 46 The Scottish study Glargine vs. glargine + other insulin vs. other insulin (no glargine) October SDRN Epidemiology Group (2009). Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia in press. Available from journal.org/cancer_files/090818Colhounacceptedpaper.pdf. Accessed 29 June 2009http://www.diabetologia- journal.org/cancer_files/090818Colhounacceptedpaper.pdf Increased risk of cancer with glargine alone but not with glargine combined with other insulins The short period of time between exposure and events in these analyses also argues strongly against a causal relationship”

47 47 Studies conducted at request of EASD following Hemkens’s paper The Swedish study: Insulin glargine use and short-term incidence of malignancies: Jonasson JM, Ljung R, Talbäck B, Haglund S, Gudbjörnsdòttir S, Steineck G (2009) Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia in press. Available from journal.org/cancer_files/090776Jonassonacceptedpaper.pdf. Accessed 29 June 2009.http://www.diabetologia- journal.org/cancer_files/090776Jonassonacceptedpaper.pdf Increased risk of breast cancer associated with glargine use but not of other malignancies The short duration from the start of insulin glargine use (January 2006 to Dec. 2007) to the increased incidence rate for breast cancer suggests that our results could be due to random fluctuation”

48 The long-term Retinopathy study Five-year, open-label, multicenter, that randomized type 2 diabetes patients to insulin treatment with either once-daily insulin glargine or twice-daily NPH The primary objective was to assess the risk of progression of diabetic retinopathy Diabetic retinopathy is a proliferative complication of diabetes involving IGF-1 mediated activity No evidence of a greater risk of the development or progression of diabetic retinopathy with glargine vs NPH Rosenstock J, Fonseca V, McGill JB, et al (2009). Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia DOI /s

49 The long-term Retinopathy study: findings relative to cancer No statistically significant difference: J. Rosenstock & V. Fonseca & J. B. McGill & M. Riddle & J.-P. Hallé & I. Hramiak & P. Johnston & M. Davis. 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 Accepted: 29 June 2009 Glargine (514) NPH(503) All cancer 57 patients (11.1%) 62 patients (12.3%) Cancer breast 3 patients 5 patients


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