From the point of shared pathophysiology, several types of cancer and NDs were considered as single cancer and ND group to investigate the epidemiologic association between T2D, cancer, and NDs in this study. As a result, the incidence rates of cancer and ND were significantly higher in the T2D group than in the control group. This study showed a 3.5% increase in the number of cancer patients in the T2D group compared to the control group and a 14.6% increase in the number of ND patients in the T2D group compared to the control group over a 10-year follow-up period. This study showed that T2D is positively associated with both cancer and ND, and these results support our assumption that these three diseases will have a common pathophysiology.
Diabetes and cancer often occur in the same patient. Up to 18% of cancer patients also have diabetes. Age, obesity and overweight, a lack of physical activity, and smoking are all risk factors for both diabetes and cancer [6]. T2D, on the other hand, is linked to an increased risk and mortality from various types of cancer, independent of obesity [12]. While several studies have found a consistent link between T2D and cancer, the findings in the incidence of other cancers are inconsistent. An important problem is whether the association of diabetes with different types of cancer is related to a common risk factor for both diseases or whether diabetes with insulin resistance and hyperinsulinemia is responsible for the increased risk of cancer. There are also many epidemiological studies that have reported an association between T2D and ND. In the Rotterdam Study, a prospective follow-up study of the elderly that began in 1990, the influence of T2D on the risk of dementia and AD in 6,370 elderly subjects was investigated, and the study results showed that T2D almost doubled the risk of dementia [13]. In longitudinal analyses on 1,488 subjects from a multiethnic cohort in northern Manhattan, Cheng et al. demonstrated that T2D was strongly associated with late-onset AD after adjustment for sex and age [14]. In addition to AD, studies have reported that T2D increases the incidence of PD and is a risk factor for PD [8, 15]. Many previous studies have reported a high incidence of several types of cancer and NDs in T2D patients, which is consistent with this study. Previous studies and this study show that T2D is a risk factor for cancer and ND, and these findings suggest that these three diseases are related by their shared pathophysiology.
Age-related diseases are closely related to problems with protein homeostasis (proteostasis) [5], and the accumulation of aggregated proteins is a hallmark of aging [16, 17]. Loss of proteostasis leads to protein aggregation that is responsible for dysregulation of the chaperone and co-chaperone levels. For protein homeostasis, chaperones are typically used to stabilize correctly folded proteins, and misfolded or damaged proteins are treated with scavenger proteins such as proteasomes or lysosomes [16]. Molecular chaperones, such as heat shock proteins, are involved in protein folding and stability. For example, damaged proteins resulting from free radical activity must be repaired or removed and replaced with functional proteins. The two main proteolytic systems that degrade and remove damaged proteins are the autophagy-lysosomal system and the ubiquitin-proteosome system. Both systems have been shown to decrease with age [18, 19]. Therefore, normal protein turnover is impaired with age, which can lead to the accumulation of damaged proteins that contribute to the pathophysiology of various age-related diseases.
T2D, cancer, and ND are typical age-related diseases, and these diseases are all known to be related to the impairment of proteostasis and cause aggregation of damaged proteins [20, 21]. NDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, or prion-like diseases have different clinical symptoms and courses, but they all share the accumulation of misfolded proteins and are classified as protein-misfolding diseases. Aggregation and deposition of misfolded proteins in the nervous system are common features of several NDs. Although the role of protein aggregation in ND pathology remains controversial [22], the association of protein misfolding and aggregation indicates that significant dysfunction of proteostasis occurs in these diseases [23, 24]. Another disease in which proteostasis failure is known to be an important factor in the pathogenesis is diabetes mellitus [25, 26]. T2D is now thought to be a proteostasis failure disease [27, 28]. Recently, proteotoxic stress is increased in cancer, and studies have been reported in which cancer cells are vulnerable to loss of proteostasis within the endoplasmic reticulum [29]. The links between proteostasis and cancer have long been identified [30], and there is a possibility that chaperones and proteostasis may play an important role in cancer formation. For this reason, research into therapeutic interventions for proteostasis control in anticancer therapy is being conducted [31−33]. Although proteostasis failure has been implicated in several age-related diseases, it remains poorly understood how it leads to pathological events in the intracellular network regulating proteostasis. Recent studies have reported a link between mitochondrial dysfunction and proteostasis failure [34, 35]. Mitochondrial dysfunction is associated with several age-related diseases, including T2D, cancer, cardiovascular disease, and neurodegenerative diseases [1−4]. Recently, studies on therapeutic interventions for age-related diseases have been conducted using shared pathophysiology. A typical example is the antidiabetic drug metformin. Recent studies have reported a positive effect of metformin on cancer, ND, and polycystic ovary syndrome [36].
This study has some limitations. First, this study was a retrospective observational design based on medical claims data, and the diagnoses for diseases were identified using KCD-6 codes in the claims database, which may have been inaccurate compared with diagnoses obtained from a medical chart, imaging tests, or laboratory tests. Second, although age, sex, and comorbidities were controlled in the calculation of HR, we did not control for other confounding factors, such as diet, exercise, alcohol drinking, and smoking, which also could influence the pathogenesis of the disease. Despite some limitations, this study has the strength of being a cohort study based on a large population with a 10-year follow-up period.