Diabetes, Obesity and Cancer Is Hyperinsulinemia a Culprit?

1
Diabetes, Obesity and CancerIs Hyperinsulinemia
a Culprit?

• Emily Jane Gallagher
• Mount Sinai Medical Center
• New York, NY

2
Diabetes, Obesity and Cancer Outline

• Epidemiological Data linking diabetes, obesity
  and cancer
• Mechanisms that contribute to increased risk of
  cancer in type 2 diabetes (T2DM) and obesity
• Diabetes therapies and cancer risk
• Insulin Analogs
• Metformin
• Thiazoledinediones

3
Diabetes and Cancer
1910
A Statistical Study in Cancer Death-Rates Cancer
and Diabetes, Both diseases have very much the
same age distribution. They stand almost alone as
being on the increase, while other causes of
death show declining rates. The aetiology of
both diseases is obscure. Both being diseases of
old age If there were a common factor in
the causation of the dual increase a correlation
between these diseases might be discovered.
Maynard GD. Biometrika 1910 7 276-304
4
American Diabetes Association / American
Cancer Society Consensus Report2010
Type 2 diabetes and cancer share many risk
factors, but potential biologic links between the
two diseases are incompletely understood.
Cancer and diabetes are diagnosed within the
same individual more frequently than would be
expected by chance, even after adjusting for age.
Giovannucci E et al. Diabetes Care
201033(7)1674-85.
5
Diabetes and Cancer Incidence
Noto H et al. Endocr Pract 2011 17(4) 616-628
6
Diabetes and Cancer Mortality
Noto H et al. Endocr Pract 2011 17(4) 616-628
7
T2DM is associated with an increased risk of
cancer at specific sites
8
Obesity is associated with increased cancer
mortality
Calle E et al. N Engl J Med 2003 348(17)
1625-1638
9
Does Bariatric Surgery Affect Mortality?
University of Utah 2007

• Retrospective cohort study
• 9949 gastric bypass patents
• 9628 severely obese drivers license applicants
  (BMI 35 kg/m2)

Adams TD et al. N Engl J Med 2007357753-761.
10
Does Bariatric Surgery Affect Mortality?
Adams TD et al. N Engl J Med 2007357753-761.
11
Diabetes, Obesity and Cancer Outline

• Epidemiological Data linking diabetes, obesity
  and cancer
• Mechanisms that contribute to increased risk of
  cancer in type 2 diabetes (T2DM) and obesity
• Diabetes therapies and cancer risk
• Insulin Analogs
• Metformin
• Thiazoledinediones

12
What factors may be increasing the risk of cancer
in type 2 diabetes and obesity?
Diabetes
Hyperinsulinemia
Hyperglycemia
Dyslipidemia
Cancer
Inflammation
IGF-1
Adipokines
Obesity
13
Insulin, IGF-1 and Cancer
14
Higher insulin levels are linked to lower
recurrence free survival in women with breast
cancer
Goodwin et al. J Clin Oncol 2002 20 (1) 42-51
15
Higher insulin receptor content is associated
with lower disease free survival
Mathieu et al. Proc Assoc Am Physicians. 1997
109(6)565-71
16
IGF-1 Receptor and Insulin Receptors
IGF-I
Insulin
Cell Survival, Growth, Proliferation
Metabolic Effects
17
Type 2 Diabetes and Cancer
Hyperinsulinemia
Hyperinsulinemia
Obesity
Hyperglycemia
Cancer
Dyslipidemia
Inflammation
Female MKR mouse
18
Orthograft Model of Breast Cancer
Hyperinsulinemic MKR Mouse
Novosyadlyy R et al. Cancer Res 2010 70(2)
741-751
19
Strategies to Reduce Tumor-Promoting Activity in
T2DM
? Insulin
Insulin resistance
IR / IGF-IR
PI3K
IRS
Akt

• ? Apoptosis
• Proliferation
• Migration
• Invasion

? Tumor progression
20
Strategies to Reduce Tumor-Promoting Activity in
T2DM
? Insulin
Insulin resistance
IR / IGF-IR
PI3K
IRS
Akt

• ? Apoptosis
• Proliferation
• Migration
• Invasion

? Tumor progression
21
Compounds Targeting IR / IGF-IR Signaling in
Breast Cancer Clinical Trials
22
Incomplete Response to IGF-IR Blockade
Insulin
IGF-II
IR-A
IGF-IR
PI3K
IRS
Akt

• ? Apoptosis
• Proliferation
• Migration
• Invasion

? Tumor progression
23
Summary

• Epidemiological studies suggest that obesity and
  type 2 diabetes are associated with an increased
  risk of many cancers
• Hyperglycemia and hyperinsulinemia may contribute
  to the increased risk of cancer
• Other factors including IGF-1, inflammation,
  dyslipidemia and adipokines may also contribute
  to the increased risk
• Mice with hyperinsulinemia demonstrate increased
  breast cancer growth
• Therapies that lower insulin levels or block
  insulin / IGF-1 receptor signaling may reduce
  tumor development and growth

24
Diabetes, Obesity and Cancer Outline

• Epidemiological Data linking diabetes, obesity
  and cancer
• Mechanisms that contribute to increased risk of
  cancer in type 2 diabetes (T2DM) and obesity
• Diabetes therapies and cancer risk
• Insulin Analogs
• Metformin
• Thiazoledinediones

25
Diabetes Therapy and Cancer - Insulin
26
The affinity of insulin analogs for the IGF-IR
and duration of interaction is a possible
mechanism for increasing tumor progression
27
Insulin Glargine Compared to other Insulin Use
Suissa S et al. Diabetologia 2011 54 2254-2262
28
Insulin Glargine and Other Insulin Analogs
Ruiter R et al. Diabetologia 2012 55 51-62
29
Insulin Glargine and Breast Cancer
Ljung et al. Acta Oncol 2012
30
Insulin Analogs
Lys
Glu
Asp
AspB10
Regan FM, Dunger DB. Arch Dis Child Educ Pract Ed
2006
31
Jorgensen LN et al. Diabetologia 1992 Suppl A3
(OP4)
32
The affinity of insulin analogs for the IGF-IR
and duration of interaction is a possible
mechanism for increasing tumor progression
Kurtzhals P et al. Diabetes 2000 49(6) 999-1005
33

• Mitogenic action of insulin and insulin analogs
  in vitro can be linked to
• Enhanced affinity/ potency towards the IGF-I
  receptor
• Altered affinity/ potency towards insulin
  receptor (IR-A/B)
• action of hybrid receptors (IR-IGF1-R)
• Occupancy time of the insulin receptor / IGF-1R
• Altered time action profile of signaling cascades

34
Insulin Glargine
Bio- transformation
GlyA21 insulin M1
Sommerfeld MR et al, PLoS One 2010 5(3) e9540
35
Insulin Glargine Metabolites have a lower IGFR
activity compared to insulin
400
300
200
100
IC50 63.2 nM
10
8
IGF1R affinity
relative to insulin
6
4
2
0
1
Glargine
Insulin
Glargine
Glargine
AspB10
IGF-1
M2
M1
Sommerfeld MR et al, PLoS One 2010 5(3) e9540
36
Summary Insulin Analogs and Cancer

• Epidemiological studies have conflicting results
  regarding the risk of cancer with specific
  analogs
• In vitro studies should be interpreted with
  caution as they are of questionable physiological
  relevance
• There is no definitive data suggesting that any
  of the insulin analogs in current use increase
  the risk of cancer over human insulin

37
Diabetes Treatment and Cancer
Metformin
Sulfonylurea metformin
No diabetes treatment
Sulphonylurea
38

• Metformin is not FDA approved for the prevention
  or treatment of cancer
• FDA Indication for Metformin
• Metformin hydrochloride tablets are indicated as
  an adjunct to diet and exercise to improve
  glycemic control in adults and children with type
  2 diabetes mellitus.

39
Diabetes Treatment and Cancer
40
Cancer Mortality and Diabetes Treatment
Bowker SL et al. Diabetes Care 2006 29 254-258
41
Meta-Analysis of Metformin and Cancer
Decensi A et al. Cancer Prev Res 2010 3(11)
1451-61
42
Metformin and Breast Cancer Survival
43
Metformin reduces insulin levels in breast cancer
patients
Goodwin PJ et al. Clin Breast Ca 2008 8(6)
501-505
Goodwin PJ et al. JCO 2002 20(1) 42-51
44
Metformin Improved Pathological Complete Response
to Neoadjuvant Chemotherapy in Breast Cancer
Jiralerspong S et al. JCO 2009 27(20) 3297-3306
45
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46
Metformin reduces proliferation of human breast
cancer cells
Zakikhani M et al. Cancer Res 2006 6610269
47
Limitations of Animal and In vitro Studies
O Dowling RJ et al. J Mol Endocrinol 2012 48
R31-R43
48
Clinical Trials studying Metformin and Cancer
49
SummaryMetformin and Cancer

• 1. Epidemiological studies suggest that metformin
  decreases the risk of certain cancers and
  improves response to chemotherapy
• 2. Metformin may reduce tumor growth by
• Indirect mechanisms
• Reducing glucose levels
• Decreasing insulin levels
• Direct mechanisms
• Activating AMPK in the tumor cells
• 3. Randomized control trials are underway to
  determine whether - Metformin improves response
  to chemotherapy in patients and improves
  survival
• - Metformin has direct actions on tumors in
  humans

50
Thiazoledinediones and Cancer

• In vitro studies demonstrate that rosiglitazone
  has antiproliferative effects
• Animal studies have suggested that rosiglitazone
  may prevent the progression of lung cancer
• However, a meta-analysis of randomized clinical
  trials reported no significant modification in
  cancer risk with rosiglitazone treatment
• In women with breast cancer, no effect was seen
  in breast tumor cell proliferation

Yee LD et al. Clin Cancer Res 2007 13
247. Monami M et al. Diabetes Care 2008
311455-1460 Lyon CM et al. Carcinogenesis 2009
30(12) 2095-2099.
51
Pioglitazone has been associated with an
increased risk of bladder cancer

• Withdrawn from French and German markets June
  2011
• FDA recommendations
• Healthcare professionals should
• Not use pioglitazone in patients with active
  bladder cancer.
• Use pioglitazone with caution in patients with a
  prior history of bladder cancer.
• The benefits of blood sugar control with
  pioglitazone should be weighed against the
  unknown risks for cancer recurrence.

52
Conclusions

• T2DM is associated with an increased risk of
  cancer at certain sites
• Hyperinsulinemia, hyperglycemia and inflammation
  may contribute to the increased risk of cancer in
  T2DM
• Some studies have reported that insulin therapy
  may increase the risk of certain cancers, while
  others have reported the opposite
• Metformin may have a protective role in breast
  cancer development and progression
• RCT are currently underway
• Pioglitazone may be associated with an increased
  risk of bladder cancer

53
Acknowledgements

• Derek LeRoith
• Shoshana Yakar
• Ruslan Novosyadlyy
• Yvonne Fierz
• Archana Vijayakumar
• Hui Sun
• Rosalyn Ferguson
• Nyosha Alikhani
• Aviva Tobin-Hess
• Dara Cannata