1. 1. Relation of DM & Cancer BY Dr. HALAALY GAMAL EL DIN Professor of Internal Medicine Faculty of Medicine Cairo University
2. 2. Agenda Introduction Relationship of diabetes & cancer ( Cancer & DM two epidemics or one ?? ) Suggested mechanism of cancer development Summary C & DM
3. 3. DM & Cancer Introduction:- Glucose metabolism is a complex process and several components of the regulatory metabolic pathways serve as possible triggers for cancer development . Type 2 diabetes is characterized by insulin resistance (indicated by elevated insulin concentrations), inappropriate hepatic production of glucose, and aberrant growth hormone production. These aberrations in glucose metabolism might lead to abnormal cellular growth and regulation. Giovannucci E (2003) Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 35: 694-704 C & DM
4. 4. DM & Cancer Introduction:- Extensive epidemiological studies have revealed that the diabetic population is at higher risk of suffering cancers of the liver, pancreas, endometrium, colon and others (Shikata et al. 2013). Increased cancer risk in the diabetic population may be attributed to treatment for diabetes, to hormonal disorders, to the status of chronic inflammation and to metabolic alterations underlying the diseases Shikata K, Ninomiya T & Kiyohara Y 2013 Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer Science 104 914. (doi:10.1111/cas.12043) C & DM
5. 5. DM & Cancer Zendehdel K et al. (2003) Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Nat Cancer Inst 95: 1797-1800 Introduction:- Persons with type 1 diabetes also have a higher risk of developing cancer than non-diabetic persons. The overall risk is similar to type 2 diabetes but the cancers associated with type 1 diabetes occur in different sites, mainly of the cervix and stomach, which is in contrast to colon and breast cancer associated with type 2 diabetes. The differences are likely related to the underlying immunologic mechanism causing type 1 diabetes.These cancers also have an immunologic mechanism. C & DM
6. 6. Figure 1 Links between diabetes and cancer. Garca-Jimnez C et al. J Mol Endocrinol 2014;52:R51-R66 2014 Society for Endocrinology
7. 7. Figure 2 Gluco-addiction and recycling of glucose into macromolecules to feed proliferation. Garca-Jimnez C et al. J Mol Endocrinol 2014;52:R51-R66 2014 Society for Endocrinology
8. 8. Figure 3 The many mechanisms by which hyperglycemia may feed cancer cells. Garca-Jimnez C et al. J Mol Endocrinol 2014;52:R51-R66 2014 Society for Endocrinology
9. 9. Figure 4 Cancer cells ensure high glucose supply through enhanced hyperglycemia and hyperglycemia favors tumor growth: the strategy of a parasite. Garca-Jimnez C et al. J Mol Endocrinol 2014;52:R51-R66 2014 Society for Endocrinology
10. 10. Figure 5 High glucose enhances cancer-associated WNT/-catenin signaling: a new link between hyperglycemia and cancer. Garca-Jimnez C et al. J Mol Endocrinol 2014;52:R51-R66 2014 Society for Endocrinology
11. 11. C & DM
12. 12. Suggested mechanisms of cancer development in diabetics:- The most obvious change in diabetic patients is reduced insulin sensitivity with compensatory hyperinsulinemia and elevated levels of IGF-1, high glucose has been shown to be essential for WNT/b-catenin signaling, a key cancer-associated pathway (Anagnostou & Shepherd 2008, Chocarro-Calvo et al. 2013). Angnostou SH & Shephaerd PR 2008 Glucose induces an autocrin activation of the Wnt/b-catenin pathway in macrophage cell lines. Biochemical Journal 416 211218. (doi:10.1042/BJ20081426) Garcia-Martinez JM, Ardila-Gonzalez S, De la Vieja A & Garcia-Jimenez C 2013 Glucose-induced b-catenin acetylation enhances Wnt signaling in cancer. Molecular Cell 49 474486. (doi:10.1016/j.molcel.2012.11.022) C & DM
13. 13. Be alert to the increased risk of some cancers in the diabetic population Likely role for insulin & hyperinsulinemia There are still many unanswered questions. For example, which WNT signals are required for incretin expression, which WNT signals are released in cancer, and which cooperate with high glucose? When or where is the cancer-related WNT signal released? Are there other signals such as other nutrients, hormones, or cytokines that cooperate with high glucose to induce nuclear accumulation of b-catenin? Can we find natural metabolites, hormones, etc., that oppose the effects of high glucose on WNT signaling? And if so, would it be possible to direct these signals specifically toward cancer cells and not toward healthy cells? C & DM
14. 14. Early detection of hyperglycemia and policies that change life style may prevent T2D; perhaps also some cancers might be prevented through the same policies. High glucose amplification of WNT signaling is an example of how metabolism can remodel a cancer-associated signaling pathway. Identifying the molecules and understanding the processes underlying metabolic remodeling of cancer-associated signaling will empower new preventive, diagnostic, and therapeutic approaches toward curing cancer.