This document discusses the relationship between diabetes mellitus and cancer. It notes that people with diabetes, both type 1 and type 2, are at higher risk of developing many types of cancers. Several mechanisms are proposed for this link, including obesity, inflammation, oxidative stress, and hyperinsulinemia. Some antidiabetic drugs like metformin may be protective against cancer, while insulin may increase cancer risk. Certain cancer therapies can also increase the risk of developing diabetes, such as steroids, mTOR inhibitors, and immunotherapy drugs. In summary, there appears to be a clear association between diabetes and higher cancer incidence, through various biological pathways.

1. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
‫الكلمة‬ ‫هذة‬ ‫فضل‬
‫كما‬ ‫إال‬ ‫األكبر‬ ‫هللا‬ ‫اسم‬ ‫وبين‬ ‫بينه‬ ‫وما‬ ‫هللا‬ ‫أسماء‬ ‫من‬ ‫اسم‬ ‫هو‬ ‫سواد‬ ‫بين‬
‫القرب‬ ‫من‬ ‫وبياضهما‬ ‫العينين‬
(
‫صحيح‬ ‫حديث‬
)
‫السالم‬ ‫علية‬ ‫عيسى‬ ‫قال‬
:
‫وهللا‬ ‫مملكته‬ ‫والميم‬ ‫سناؤه‬ ‫والسين‬ ‫هللا‬ ‫بهاء‬ ‫الباء‬
‫واآلخرة‬ ‫الدنيا‬ ‫رحمن‬ ‫والرحمن‬ ‫اآللهة‬ ‫إله‬ ‫اآلخرة‬ ‫رحيم‬ ‫والرحيم‬
«
‫كثير‬ ‫ابن‬ ‫تفسير‬

2. Relationship Between
Diabetes Mellitus and
Cancer
Abdelmoneim Ahmed
Ass.prof of internal medicine banha
university

3. Lecture outlines
 Relation between DM &cancer
 Mechanisms underlying the association between
diabetes mellitus and cancers
 Antidiabetics & cancer
 Cancer chemotherapy &DM
 Summary

4. Introduction
 Diabetes and cancer are common diseases with
tremendous impact on health worldwide.
 People with diabetes are at significantly higher risk for
many forms of cancer and the link between diabetes and
cancer has been proposed for more than 100 years
 The risk of cancers appears to be increased in both type 1
diabetes mellitus (T1DM) and type 2 diabetes mellitus
(T2DM)
 Cancer therapy may induce DM

5. CANCERS IN PATIENTS WITH DIABETES MELLITUS
T1DM
 A five-country study of cancers in patients with
T1DM has reported that T1DM was correlated
with the risk of several common cancers.
 Cancer incidence significantly increased for both
sexes with T1DM
- liver, pancreas, kidney,
- esophagus, stomach, lung, thyroid,
- squamous cell carcinoma, and leukaemia

7. CANCERS IN PATIENTS WITH DIABETES
MELLITUS T2DM
A comprehensive meta-analysis :the presence of
T2DM is associated with 10% increase of the risk
to develop cancer .
Includes :
hepatocellular, biliary tract, gallbladder,
pancreas, gastrointestinal,
kidney, bladder, lung, thyroid, breast, ovarian,
endometrial, oral, leukemia, glioma, and
melanoma

8.  Among them, the highest risks have been
demonstrated for colorectal cancer ,
hepatocellular cancer or pancreatic cancer.

9.  On the contrary, some cancers showed decreased
risk in diabetic patients including brain, buccal
cavity, esophageal, lung, breast, urinary bladder,
and laryngeal cancer
 Reduced risk of prostate cancer in patients with
T2DM (lower levels of testosterone & HNF1B
gene variants protect them from prostate
cancer)

10. MECHANISMS UNDERLYING THE
ASSOCIATION BETWEEN DIABETES
MELLITUS AND CANCERS

11. MECHANISMS UNDERLYING THE ASSOCIATION
BETWEEN DIABETES MELLITUS AND CANCERS

12. 1- Obesity
 A large cohort study which included 900,000
individuals reported that severe obesity was
associated with a significantly increased mortality
from cancers of the liver, pancreas, colon and
rectum, kidney, non-Hodjkins lymphoma,
esophagus, and multiple myeloma.

13. Obesity
 The greatest influences were observed in cancers of
liver, colon and rectum, and pancreas .
 Obesity associated with increased risk of cancers
probably by mechanisms that involve cellular
proliferation, inflammation, and hormonal balance .

14. 2- Inflammation and Oxidative Stress & hyperglycemia
 Inflammation is a key element in the link between diabetes mellitus and cancer
 T2DM is associated with insulin secretory defects related to inflammation
 advanced glycation end products (AGEs). Receptor AGEs, (RAGE)

15. 3- Hyperinsulinemia
 Increased risk for several cancers, including cancers of
the endometrium, ovarian, breast, colon, pancreas, and
kidney .
 The hepatic IGF-1 production increased due to the
upregulation of the growth hormone receptor (GHR) and
augment of GHR signaling
 Insulin, IGF-1 and IGF-2 could activate the PI3K/Akt/
mammalian target of rapamycin signaling pathway,.

16. Hyperinsulinemia

17. MECHANISMS UNDERLYING THE ASSOCIATION
BETWEEN DIABETES MELLITUS AND CANCERS

18. Antidiabetics & cancer
Drugs Effect on cancer Mechanism
Insulin Increase incidence
(CRC,BC,HCC)
increased levels of IGF-1
Insulin analogue (long acting ) dose-dependent increased risk
of cancer
increased levels of IGF-1
large randomized controlled trial study cohort study , and systematic review concluded that
insulin (analog) treatment does not impact the risk of cancer
Metoformin Protective inhibits the mTOR in (AMP)-
activated protein kinase (AMPK)
(DPPIV) inhibitor and glucagon-
like peptide-1(GLP-1)
Increase incidence of
pancreatic cancer
replication and apoptosis of
beta-cell, pancreatic ductal
metaplasia, and a four-fold
increase in duct cell
proliferation
GLP1 Thyroid c cancer
meta-analysis suggested that there is no exact evidence that the risk of pancreatic cancer in
patients on incretin-based therapies .

19. Antidiabetics & cancer
Drugs Effect on cancer Mechanism
SU Controversy
Thiazolidinediones
(TZDs)
bladder cancer with
pioglitazone (2005, false
impression)
Protective : lower risk of
colorectal and breast cancer
anti-proliferative effects, TZDs
can also enhance cytotoxic effects
of some anticancer therapies as
cisplatin and oxaliplatin by
increasing the expression of
apoptosis-inducing factor (AIF) and
suppressing survivin

20. SGL2 inhibitors

21. SGL2 INHIBITORS &CANCER
 “SGLT2 and cancer,” “canagliflozin and cancer,” “dapagliflozin (gliflizino)
and cancer,” “empagliflozin and cancer,” “ipragliflozin and cancer,”
“tofogliflozin and cancer,” “luseogliflozin and cancer,”
Protective for cancer

22. Cancer Cells May Overexpress SGLT
 SGLT1 is overexpressed in many cancers Inhibition of
SGLT1 sensitizes prostate cancer cells to treatment with
EGFR (epidermal growth factor receptor) tyrosine kinase
inhibitor .
 High SGLT1 level combined with high MAP17 (membrane-
associated protein 17) is a marker for good prognosis in
patients with cervical cancer after chemotherapy and
radiotherapy [41].
 High SGLT1 expression in pancreatic adenocarcinomas was
significantly correlated with disease free survival,
especially in younger patients

23.  In a study of lung cancer, there were no
significant differences in the level of SGLT1 or
SGLT2 gene expression between the primary lung
cancers and the normal lung tissues .
 However, higher SGLT2 expression was found in
metastatic lesions of lung cancer compared to
primary tumor .

24.  Studies above imply that SGLT, especially SGLT1,
plays a role in glucose uptake in many cancers.
From this point of view, inhibition of SGLT1 and
SGLT2 might even be protective in certain cancer
types. If there was any positive link between
dapagliflozin and bladder cancer, mechanisms
other than inhibition of SGLT2 should be
considered.

26. CANCER TREATMENT DIABETES
 Chemotherapy
Chemotherapy such as Tegafur-uracil (UFT)
paclitaxel and interferon alpha developed fulminant
T1DM or autoimmune-mediated T1DM

27. Glucocorticoid
 Glucocorticoids are a commonly used treatment for
cancers of blood system & used to treat cancer pain,
chemotherapy-induced nausea and vomiting, and
cancer-related cachexia.
 Steroid-induced diabetes mellitus is a complication of
glucocorticoid use for over 50 years

28. Targeted Cancer Therapies
 Targeted cancer therapies attempt to treat cancer
by targeting the changed cellular pathways
(VEGF inhibitors & mTOR drugs)
 Mammalian target of rapamycin (mTOR)
inhibitors has been used for multiple types of
cancer (RCC, BC).
 mTOR inhibitors is associated with a high
incidence of hyperglycemia and new-onset
diabetes, ranging from 13% to 50%

29. Cancer Immunotherapy
 Manipulate the immune system to recognize and attack
cancer cells( like check point inhibitors).
 lead to toxicity profiles for endocrine system.
1- Insulin-dependent diabetes0.4%-0.9%(like antiprogrammed
cell death protein 1 (PD-1) drugs )
2- Thyroid dysfunction

30. Summary
 There is a link between DM &cancer
 Many mechanisms underlie this link( obesity
, hyperinsulinemia, oxidative stress)
 Metformin &TDZ are protective from
cancer
 Insulin increases incidence of cancer
 Cancer therapy (steroids , M-TOR inhibitors
, checkpoint inhibitors ) induce DM

31. ‫العالمين‬ ‫رب‬ ‫هلل‬ ‫الحمد‬
Thank you