MESBAH SAYED KAMEL

MD

Mesbah Sayed kamel

MD

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

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.

•Cancer and

Diabetes: Two

Epidemics or One?

DIABETES..

AN EPIDEMIC

IDF DIABETES ATLAS 2015 7th edition 14

November2015

Egypt Cancer statistics suggest:

Journal of Cancer Epidemiology

Volume 2014 (2014), Article ID 437971

DIABETES AND CANCER ARE TWO OF THE TOP THREE KILLERS IN

THE UNITED STATES

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)

CANCERThe 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

IS THERE REALLY A LINK BETWEEN DIABETES AND

CANCER?

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

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 Risk0.9 1.0 1.90.6

1.30

1.24

2.10

1.20

0.84

(Courtesy of J Johnson)

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

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

Cancer

Lipids

GlucoseAtheroma

BP

The Affluent Phenotype

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.

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)

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

Mitogenesis

Mutagenesis

Growth

Rapid cell division

Inherited factors

Growth promoters

Abnormal cell proliferation

Environmental agents

Growth inhibitors

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>Y Y

Metabolism Growth

INS-A IGF-1-R

YINS-B

YHybrids

Altered signalling in tumors

HYPERGLYCEMIA CAUSES INCREASED RISK FOR INFECTION, AND HIGHER

RATES OF CANCER RECURRENCE AND MORTALITY

BUTHYPERGLYCEMIA

IS NOT A MAJOR INDEPENDENT RISK FACTOR

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.

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)

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)

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%)

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

DIABETES THERAPY AND CANCER

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

AMP Kinase – the energy sensor

AMP ATP

AMP Kinase – the energy sensor

An increase in the AMP/ATP ratio activates AMPKand puts the cell into energy-saving mode

AMP Kinase – the energy sensor

Metformin activates AMPK

Metformin

Fay J.R. et al. Cancer Prev Res 2(4):301-309, 2009

AMPK

AMP/ATP

LKB1CaMKKß

Other kinases (TAK-1?)

Protein synthesis

Protein synthesis/ Cell survivalCell cycle arrest

Sterol synthesis

Fatty acid oxidation

Fatty acid synthesis

Fay J.R. et al. Cancer Prev Res 2(4):301-309, 2009

AMPK

AMP/ATP

LKB1CaMKKß

Other kinases (TAK-1?)

Protein synthesis

Protein synthesis/ Cell survivalCell cycle arrest

Sterol synthesis

Fatty acid oxidation

Fatty acid synthesis

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 Care2010;33:1304-8*

• Consistent reductions in cancer risks observed,RELATIVE to other diabetes therapies

0.63

0.99

0.4 0.6 0.8 1 1.2Adjusted* HR:

Reduced Risk Increased Risk

Metformin & Cancer Risk

Any exposure – Cancer Incidence

Metformin Exposure

Maximum Dose – Cancer IncidenceLow vs None

Medium vs None

High vs None0.28

0.51

Libby et al., Diabetes Care, 2009;32:1620

0.63

Cohort StudyTayside, Scotland, 1994-2003

*age, sex, smoking, deprivation, BMI, A1C, insulin and sulfonylurea use.

Any exposure – Cancer Mortality

Metformin Exposure

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

CANCER RISK VS INSULIN DOSE

0

0.5

1

1.5

2

2.5

3

Q1 Q2 Q3 Q4

Insulin + MF

Insulin

insulin dose

Adju

sted H

R

Currie et al submitted

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

Diabetes and Cancer, Endocr Pract. 2013;19(No. 4) 685

AACE/ACE Consensus Statement

Thank

you

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