Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer

Abstract

Diabetes is one of the most frequent diseases throughout the world and its incidence is predicted to exponentially progress in the future. This metabolic disorder is associated with major complications such as neuropathy, retinopathy, atherosclerosis, and diabetic nephropathy, the severity of which correlates with hyperglycemia, suggesting that they are triggered by high glucose condition. Reducing sugars and reactive carbonyl species such as methylglyoxal (MGO) lead to glycation of proteins, lipids and DNA and the gradual accumulation of advanced glycation end products (AGEs) in cells and tissues. While AGEs are clearly implicated in the pathogenesis of diabetes complications, their potential involvement during malignant tumor development, progression and resistance to therapy is an emerging concept. Meta-analysis studies established that patients with diabetes are at higher risk of developing cancer and show a higher mortality rate than cancer patients free of diabetes. In this review, we highlight the potential connection between hyperglycemia-associated AGEs formation on the one hand and the recent evidence of pro-tumoral effects of MGO stress on the other hand. We also discuss the marked interest in anti-glycation compounds in view of their strategic use to treat diabetic complications but also to protect against augmented cancer risk in patients with diabetes.

Introduction

Diabetes prevalence and associated mortality are continuously rising. The International Diabetes Federation recently published global estimates for the prevalence of diabetes over the coming 28 years period [1]. The number of people with diabetes worldwide is predicted to rise from 451 million in 2017 to 693 million by 2045. In 2017, approximately 5 million deaths worldwide were attributable to diabetes in the 20–99 years age range [1]. This new projection alerts us, as much necessary it might be, about the large social, financial and health system burden represented by diabetes across the world. Even more worrying for public health is the link established between diabetes and the other severe and multifactorial chronic disease that is cancer. Indeed, substantial evidence indicates that individuals with diabetes present with an increased risk of developing cancer. Common risk factors for both diabetes and cancer are evident, including age, overweight, obesity, lack of physical activity and poor diet.

Methodological aspects and study designs supporting the association between diabetes and cancer must be carefully examined. Two reviews of a group of experts from the Diabetes and Cancer Research Consortium recapitulate the potential biases, confounders and modifiers to consider when studying cancer incidence [2] and mortality [3] in patients with diabetes. A consensus report by the American Diabetes Association and American Cancer Society concluded that type 2 diabetes (T2D) is convincingly associated with an increased risk for several solid cancers (colorectal, breast, endometrial, liver, pancreatic, and bladder) (Fig. 1), while the evidence appears less conclusive for kidney and esophageal cancer [4]. A recent large cohort prospective study found that T2D was independently associated with a greater risk of renal cell carcinoma in women but not in men [5]. Interestingly, meta-analysis studies consistently reported an inverse relationship between diabetes and prostate cancer [6], [7]. It is remarkable that although men with diabetes have a significant lower risk of prostate cancer, they present with a higher mortality from it [8] suggesting that cancer cells develop unique characteristics under diabetic conditions. Indeed, a meta-analysis revealed that newly diagnosed cancer patients with pre-existing diabetes have an increased risk of mortality compared with those without diabetes [9]. Chronic diabetes leads to serious complications each of which may worsen or accelerate the others including microvascular disease, neuropathy, retinopathy, atherosclerosis and diabetic nephropathy.