Cancer predisposition in diabetics: risk factors considered for predictive diagnostics and targeted preventive measures

Abstract

Diabetes mellitus (DM) is a lifelong progressive disease with high morbidity and mortality worldwide. Whereas cardiovascular complications are well-known for DM, increasing evidence indicates that diabetics are predisposed to cancer. Understanding of molecular pathomechanisms of cancer in DM is of great importance. Dysregulation of glucose/insulin homeostasis leads to increased production of Reactive Oxygen/Nitrogen Species (ROS/RNS) and consequent damage to chromosomal/mitochondrial DNA, a frequent finding in DM. Long-term accumulation of modified/damaged DNA is well-acknowledged as triggering cancer. DNA-repair is a highly energy consuming process provoking increased mitochondrial activity. Particularly dangerous is a provoked activity of damaged mitochondria leading to a "vicious circle" lowering energy supply and potentiating ROS/RNS production. Mitochondrial dysfunction may be implicated in pathomechanisms of diabetes-related cancer. High risk for infectious disorders and induced viral proto-oncogenic activity may further contribute to cancer provocation. Much attention should be focused on preventive measures in diabetic healthcare, in order to restrict severe diabetes-related complications.

Fig. 1

General predisposition of diabetics to single cancer types: breast [2], endometrial [3], colorectal [4], pancreas [5], and liver [6] cancers

Fig. 2

Population studies in Japan as an example of cancer predisposition of diabetics in years 1990–2003 [7]

Fig. 3

Specific cancer incidence with respect to age in Swedish diabetics type 1 registered in years 1965–1999 [8]

Fig. 4

Cancer risk for type 2 diabetics in North Italy in years 1987–1996 [9]

Fig. 5

Mortality by cancer in diabetic versus non-diabetic patients registered in Netherlands in years 1995–2002 [11]

Fig. 6

Increased mortality of diabetics versus non-diabetics for single cancer types as documented for patients treated in USA in years 1982–1998 [12]

Fig. 7

Mitochondrial “vicious circle” causes a dangerous imbalance between highly increased production of ROS on one side and low energy production on the other side. Highly increased damage to chrDNA and mtDNA, remarkably decrease repair capacity as well as compromise cell-cycle control are direct consequences of stress-provoked mitochondrial dysfunction [22, 26, 28, 33, 36]

Fig. 8

Clue to viral etiology in DM-provoked cancer: “vicious circle” is the particularity of metabolic syndrome with high risk of cancer development [, , , , , –, –56]

Fig. 9

Particularities of metabolic syndrome and factors contributing to cancer development. Corresponding references are given