1. Introduction

2. Incidence of Diabetes in Cancer Patients

The incidence of new-onset diabetes in general was higher in cancer patients compared with the cancer-free population. Although there is currently no clear explanation on the underlying mechanism for the association between cancer and diabetes, there are still some clues to be tracked. According to previous studies, most cancer treatment modalities could be positively associated with new-onset diabetes. When our body is not able to produce sufficient insulin or cannot use it effectively, diabetes occurs ^[25]. Interestingly, varying mechanisms for diabetes can be observed in different therapeutic methods according to cancer type. Surgery and radiotherapy involving the pancreas can result in pancreatic insufficiency, which is one of the important reasons for diabetes development ^[12]. Cranial irradiation and total body irradiation can influence the hypothalamic–pituitary axis, leading to changes in the body composition (e.g., overweight) and insulin resistance ^[13][14]. Although no evidence has been found that chemotherapeutic drugs could directly impinge on glucose metabolism, in classical chemotherapy regimens, they are often used in conjunction with glucocorticoids. Glucocorticoids can enhance the efficacy of chemotherapy, treat swelling, intracranial hypertension, pain, nausea, or be used as antitumor drugs in hematological malignancies ^[15]. Glucocorticoids affect several insulin-signaling pathways, leading to reduced insulin sensitivity, inducing insulin resistance, and increasing the risk of diabetes ^[15]. Targeted therapy drugs are also often used alone or in combination with chemotherapy. Some inhibitors block the pathways that are also involved in glucose regulation, such as the tyrosine kinase receptors insulin growth factor receptor 1 (IGF-1R) which could lead to insulin resistance ^[16]. Patients with hematologic malignancies are at high risk of exposure to glucocorticoids. They are also likely to receive HCT. HCT can contribute to the release of several proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) ^[17][18], and previous studies have shown that the latter could contribute to insulin resistance by influencing the insulin signaling pathway ^[19]. ADT is widely used in prostate cancer ^[26]. A reduction in testosterone levels can be observed during the application of ADT drugs, however, decreased testosterone is directly associated with insulin resistance in men ^[27]. As for hormone therapy for breast cancer patients, it observed no significant association in a subgroup analysis involving only patients having received hormone therapy. This might be due to the favorable changes on the lipid profile by aromatase inhibitors (AIs) and tamoxifen ^[28][29].

The incidence of diabetes may be higher in the first year after cancer diagnosis. Closer contact between care providers and patients and a potential higher risk of detection bias in the initial years after cancer diagnosis might be possible explanations for this observation. Furthermore, some limitations in the underlying studies such as information bias regarding the correct assessment of the timing of the diabetes diagnosis and the potential survival bias during long-term follow-up could also explain these results. Moreover, since there is an age-related increase in diabetes risk in both cancer patients and controls ^[30], a reduced relative risk might be observed with the passing of time.

However, a statistically significant positive association was also observed during years one to ten. Several reasons could partly explain the fact that incident diabetes was still positively associated with cancer five or more years post diagnosis, when the effects of most treatments would most likely have subsided. First, in cancer patients, particularly those who suffer from cancer cachexia, insulin resistance often occurs as a result of the secretion and activation of several proinflammatory cytokines induced by cancer itself, such as TNF-α ^[31][32][33]. Some psychological consequences of cancer, such as depression, may also make the survivors more vulnerable to diabetes due to integrated mechanisms such as hypothalamic abnormality and an unhealthy lifestyle ^[34]. Moreover, the alteration of the glucose metabolism can start to appear more than ten years before the diagnosis of diabetes ^[35]. Furthermore, cancer and diabetes share a number of common risk factors, such as obesity, tobacco abuse, and alcohol consumption ^[9] and cancer survivors are more likely to be physically inactive compared with the general population ^[36]. A positive association was also observed ten or more years post diagnosis. Although this result was not statistically significant, the potential positive association should not be ignored, and future studies with sufficient power and a sufficiently long follow-up post cancer diagnosis are recommended. Furthermore, extension of surveillance for incident diabetes to beyond ten years post diagnosis could be of clinical relevance.

The association between cancer and new-onset diabetes varied by cancer type. The highest relative risk of diabetes was found in pancreatic cancer, which was not surprising. This association in patients of hematologic malignancies was also strong, which was comparable with another study ^[37], possibly due to intensive and comprehensive therapy such as total body irradiation, chemotherapy with glucocorticoids, and HCT. However, there is a statistically significant inverse association in the head and neck cancer patients. One possible explanation could be that cancer patients whose salivary glands and oral cavity were included in the treatment field, whether surgery or radiotherapy, could experience an unpleasant dietary intake thus would be less likely to become obese ^[38]. Furthermore, increased glucose-disposal rates were found in head and neck cancer patients indicating that the cancer cells played the role of a glucose drain ^[39].

In summary, new-onset diabetes was positively associated with cancer. This association was stronger during the first years after cancer diagnosis and varied according to cancer type. In this context, integration and coordination of healthcare should be applied for cancer patients. More prospective studies with large sample sizes and longer follow-up times (over ten years post diagnosis) are advocated to further examine the association and the underlying mechanisms.