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.
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
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
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
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
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
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
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
