Diabetes and certain cancers are linked by shared risk factors like obesity and age. People with diabetes have higher risks of cancers of the liver, pancreas, endometrium, and colon and breast cancers. The biological mechanisms linking the diseases involve insulin and insulin-like growth factors stimulating cancer cell growth. While hyperglycemia is not an independent risk factor, it can worsen cancer outcomes. Metformin may reduce cancer risk compared to other diabetes medications by activating AMPK, an energy sensor that puts cells in energy-saving mode and inhibits cancer cell growth. Further research is still needed to fully understand the diabetes-cancer relationship and its implications for treatment and management.

1. MESBAH SAYED KAMEL
MD
Mesbah Sayed kamel
MD

2. TO BE DISCUSSED:
Overview of diabetes, cancer, and
interactions between the two
Increased risk of certain cancers
with the comorbid condition of
diabetes
Glucose control in the
management of diabetes in patients
with cancer

3. INTRODUCTION
• Diabetes 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.

6. •Cancer and
Diabetes: Two
Epidemics or One?

7. DIABETES..
AN EPIDEMIC

9. IDF DIABETES ATLAS 2015 7th edition 14
November2015

11. Egypt Cancer statistics suggest:
Journal of Cancer Epidemiology
Volume 2014 (2014), Article ID 437971

12. DIABETES AND CANCER
ARE TWO OF THE TOP THREE KILLERS IN
THE UNITED STATES

13. Cancer: The “Big Five”
Lung 18%
Breast 10%
Bowel 9%
Stomach 9%
Prostate 6%
M Prostate 19% Lung 16%
Lung 18% Stomach 13%
Bowel 9% Liver 12%
Source: World Cancer Research Fund
F Breast 27% Breast 19%
Bowel 14% Cervix 15%
Lung 8% Stomach 8%
(Developed) (Underdeveloped)

14. CANCER
The GOOD NEWS: the number
of people becoming long-term
survivors is increasing
The BAD NEWS: a greater
number of patients will have to
face the challenge of living with
both cancer and diabetes

15. IS THERE REALLY A LINK
BETWEEN DIABETES AND
CANCER?

17. RISK FACTORS IN CANCER
AND DIABETES
• Age
• Race/ethnicity
• Sex (men have a higher risk for both cancer and diabetes)
• Obesity
• Physical activity
• Diet
• Alcohol
• Smoking

18. DIABETES & CANCER RISK
Meta-analyses, 2005-2007
Breast (Larsson, Int J Can, 2007); N=20
Pancreas (Huxley, Br J Cancer, 2005); N=36
Bladder (Larsson, Diabetologia 2006); N=16
Colorectal (Larsson, J Natl Can Inst 2005); N=15
Endometrial (Friberg, Diabetologia 2007); N=16
Prostate (Kasper. Cancer Epi 2006); N=19
1.82
1.3 1.6 2.1 3.0 3.5OR:
Reduced Risk Increased Risk
0.9 1.0 1.90.6
1.30
1.24
2.10
1.20
0.84
(Courtesy of J Johnson)

19. RELATIVE RISKS: OBESITY VS DM
Neoplasm BMI >30 DM
Colorectal 1.5-2.0 1.3
Breast (post-M) 1.5 1.2
Endometrial 2.0 2.1
Pancreatic 1.7 1.8
Nature Reviews Cancer 2004:579-591

20. RELATIVE RISKS: OBESITY VS DM
Neoplasm BMI >30 DM
Colorectal 1.5-2.0 1.3
Breast (post-M) 1.5 1.2
Endometrial 2.0 2.1
Pancreatic 1.7 1.8
Nature Reviews Cancer 2004:579-591
Obesity and diabetes confer similar risks
of cancer, suggesting that hyperglycemia
is not a major independent risk factor

21. Cancer
Lipids
GlucoseAtheroma
BP
The Affluent Phenotype

23. DIABETES CAUSES CANCER?
Many cells in the body have surface receptors for
insulin and insulin-like growth factors that have been
shown in lab tests to stimulate the growth and
metastasis of cancer cells.
About half of Type 2 diabetes and all Type 1's take
insulin daily, and their blood-insulin levels spike
higher than normal.
Diabetic patients also have episodes of higher than
normal blood sugar, which may promote cell cancer
growth.

24. QUICK SUMMARY:
INSULIN/IGFS WORK TOGETHER AS
A SYSTEM, WHICH CAN SWITCH
BETWEEN METABOLIC AND GROWTH-
PROMOTING EFFECTS
INSULIN RESISTANCE PROMOTES
THE GROWTH EFFECTS OF INSULIN
(DIRECT EFFECT)
AND PROMOTES RELEASE OF IGF-2
FROM ITS BINDING PROTEIN
(INDIRECT EFFECT)

25. QUICK SUMMARY
(CONTINUED):
INSULIN IS MITOGENIC BUT NOT
MUTAGENIC.
TUMORS ASSOCIATED WITH
DIABETES/OBESITY TYPICALLY
OVEREXPRESS RECEPTORS OF THE
INSULIN/IGF SYSTEM
AND GROW FASTER IN VITRO IN THE
PRESENCE OF INSULIN

26. Mitogenesis
Mutagenesis
Growth
Rapid cell division
Inherited factors
Growth
promoters
Abnormal cell
proliferation
Environmental
agents
Growth
inhibitors

27. >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>Y Y
Metabolism Growth
INS-A IGF-1-R
Y
INS-B
Y
Hybrids
Altered signalling in tumors

28. HYPERGLYCEMIA CAUSES INCREASED
RISK FOR INFECTION, AND HIGHER
RATES OF CANCER RECURRENCE AND
MORTALITY
BUT
HYPERGLYCEMIA
IS NOT A MAJOR INDEPENDENT RISK
FACTOR

29. Diabetics are twice as likely to get cancer of the
liver, pancreas and uterine lining. Their risk of
colon, breast, and bladder cancer is 20 to 50
percent higher than non-diabetics'.
There doesn't seem to be any higher risk for other
cancers, such as lung cancer.
The risk of prostate cancer is actually lower
among diabetics.

30. COLORECTAL CANCER
Elevated postprandial insulin have shown to
increase colorectal cancer risk (Meyerhardt et al,
2003)
Several studies show that patients with diabetes and
stage II and III colon cancer had significantly higher
rates of overall mortality
Patients with diabetes often have delayed stool
transit and gastrointestinal abnormalities, which are
associated with colorectal cancer (Will et al, 1998)

31. BREAST CANCER
•Women with the highest fasting insulin
levels had two-fold increased risk of
distant cancer recurrence and three-fold
increased risk of death compared to those
with lower insulin levels (Coughlin et al,
2004, Goodwin et al, 2002)

32. In a study (Weiser, et al 2004), the complete
remission duration, survival, and treatment-
related complications were compared in
patients with and without hyperglycemia
•Patients with hyperglycemia had shorter
complete remission (24 versus 52 months)
•Shorter median survival (29 versus 88
months)
•More likely to develop a complicated
infection (39% versus 25%)

33. SO IS THERE A LINK BETWEEN
CANCER AND DIABETES?
Yes and No
Studies remain inconclusive on the
connection
A link appears to be more prevalent
between diabetes and certain cancers, i.e.
breast and colon
There appears to be enough of a connection
to warrant consideration when treating a
patient with this dual diagnosis

34. DIABETES THERAPY AND
CANCER

35. Copyright © 2013 AACE.
May not be reprinted in any form without express written permission from AACE.

36. AMP Kinase – the energy sensor
AMP ATP

37. AMP Kinase – the energy sensor
An increase in the AMP/ATP ratio activates AMPK
and puts the cell into energy-saving mode

38. AMP Kinase – the energy sensor
Metformin activates AMPK
Metformin

39. Fay J.R. et al. Cancer Prev Res 2(4):301-309, 2009
AMPK
AMP/ATP
LKB1
CaMKKß
Other kinases (TAK-1?)
Protein synthesis
Protein synthesis/
Cell survivalCell cycle arrest
Sterol synthesis
Fatty acid
oxidation
Fatty acid
synthesis

40. Fay J.R. et al. Cancer Prev Res 2(4):301-309, 2009
AMPK
AMP/ATP
LKB1
CaMKKß
Other kinases (TAK-1?)
Protein synthesis
Protein synthesis/
Cell survivalCell cycle arrest
Sterol synthesis
Fatty acid
oxidation
Fatty acid
synthesis

41. Metformin and reduced risk of cancer in
diabetic patients. BMJ 2005;330:1304-5
… 6 other observational studies …
Long-term metformin use is associated with
decreased risk of breast cancer. Diabetes Care
2010;33:1304-8*
• Consistent reductions in cancer risks observed,
RELATIVE to other diabetes therapies

42. 0.63
0.99
0.4 0.6 0.8 1 1.2
Adjusted* HR:
Reduced Risk Increased Risk
Metformin & Cancer Risk
Any exposure – Cancer Incidence
Metformin Exposure
Maximum Dose – Cancer Incidence
Low vs None
Medium vs None
High vs None
0.28
0.51
Libby et al., Diabetes Care, 2009;32:1620
0.63
Cohort Study
Tayside, Scotland, 1994-2003
*age, sex, smoking, deprivation, BMI, A1C, insulin and sulfonylurea use.
Any exposure – Cancer Mortality
Metformin Exposure

43. Metformin selectively targets cancer stem
cells and acts together with chemotherapy
to block tumor growth and prolong remission
“Low doses of metformin … inhibit cellular
transformation and selectively kill cancer stem
cells in 4 genetically different types of breast
cancer…”
Cancer Res: 14 Sept 2009

44. CANCER RISK VS INSULIN DOSE
0
0.5
1
1.5
2
2.5
3
Q1 Q2 Q3 Q4
Insulin + MF
Insulin
insulin dose
AdjustedHR
Currie et al
submitted

45. QUICK SUMMARY
1.PATIENTS ON METFORMIN ARE LESS
LIKELY TO BE DIAGNOSED WITH CERTAIN
CANCERS THAN THOSE ON INSULIN
2.HIGHER DOSES OF INSULIN ARE
ASSOCIATED WITH A HIGHER RISK OF
CANCERS
3.THE EXCESS OF CANCERS OBSERVED WITH
INSULIN SEEMS TO BE CONCENTRATED
WITHIN THE FIRST FEW YEARS OF
THERAPY

46. Diabetes and Cancer, Endocr Pract. 2013;19(No. 4) 685
AACE/ACE Consensus Statement

49. Thank
you

50. Center for Disease Control and Prevention [CDC], 2011
December 2011, Volume 15, Number 6, Clinical Journal of
Oncology Nursing
Clinical Journal of Oncology Nursing, Volume 13, Number 2,
Diabetes Management and Self-Care Education
Diabetes and Cancer: A Consensus Report: 2010: American
Diabetes Association and the American Cancer Society
Diabetes Spectrum, Volume 19, Number 3, 2006: Clinical
Challenges in Caring for Patients with Diabetes and Cancer