Patients with both cognitive impairment and solid cancer present increased insulin resistance

Objective In an aging population, an increase in elderly cancer patients with cognitive impairment is to be expected. Because cognitive impairment has a serious impact on quality of life of cancer patients, it is important to elucidate the possible association between cancer and cognitive impairment. Here, we focused on glucose metabolism as a factor that links cancer and cognitive impairment. Results A homeostasis model assessment was used to assess insulin resistance (HOMA-IR) and β-cell function (HOMA-B). HOMA-B showed no difference among patients with cancer, with dementia, and with both. However, there was a signicant difference in HOMA-IR. In comparison with patients with only solid cancer, patients with only cognitive impairment and those with both cancer and cognitive impairment showed increased HOMA-IR value. Insulin resistance was increased in patients with cognitive impairment only and those with both cognitive impairment and solid cancer compared to cancer patients without cognitive impairment; however, β-cell function was not affected. The present data indicate that elderly cancer patients with a high HOMA-IR score may be in higher risk of developing cognitive impairment. Furthermore, early treatment to reduce insulin sensitivity may become the prevention of cognitive impairment.


Background
An increase in elderly patients with cancer, cognitive impairment or both, is inevitable in an aging population. It has recently been shown that up to 30% of patients with cancer exhibit cognitive impairment [1][2][3][4][5], which can have a serious impact on quality of life for both patients and families. However, the association between cognitive impairment and cancer remains unknown, and there is no effective treatment for such patients. Recent studies have indicated that diabetes contributes to the development of cognitive impairment such as Alzheimer's disease [6]. A number of reports have also indicated that hyperglycaemia is a contributing factor to the progression of cancer [7]. Therefore, hyperglycaemia or glucose intolerance may be the key factor that links the development of cognitive impairment and cancer [8]. Hyperglycaemia can be induced by two different mechanisms. One is the reduction of insulin secretion from pancreatic β-cells and another is the increase in insulin resistance in target organs. It is well known that the majority of diabetes cases in Asia are caused by reduction of insulin secretion; whereas, those in the US and Europe are due to insulin resistance. However, little is known regarding the contribution of hyperglycaemia to cognitive impairment and cancer. As the number of elderly cancer patients with cognitive impairment is expected to increase, it is important to understand the underlying mechanism that links both diseases. In this study, we focused on the aspect in which hyperglycemia may link cognitive impairment and cancer. We applied a homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and β-cell function (HOMA-B) in elderly patients with solid cancer (patients with cancers of the esophagus, gastric area, colon, bile duct, prostate, mammalian, lung and ovary) and those with cognitive impairment, as well as in patients with both cancer and cognitive impairment.

Patient information
Thirteen subjects (7 males and 6 females, with average age of 85) with solid cancers and cognitive impairment were recruited (Table). As a control, 14 subjects (6 males, 8 females, with average age of 86) with only cognitive impairment were recruited and 8 subjects (5 males, 3 females, with average age of 88) with only cancer were recruited.

Research methods
For cognitive assessments, the patients underwent both Mini-Mental State Examination (MMSE) [9][10][11] and Revised Hasegawa's dementia scale (HDS-R) tests [12]. Eight subjects (5 males, 3 females, with average age of 88) with cancer only were recruited. Blood samples were collected at 07:00 A.M. after overnight fasting to measure fasting plasma glucose and fasting insulin levels.

Comparison of insulin resistance
Insulin resistance assessed by HOMA-IR showed a signi cant difference among the groups. HOMA-IR was signi cantly increased in patients with cognitive impairment only (1.307±0.673) and those with both cognitive impairment and cancer (1.896±0.435), compared to patients with only cancer (0.645±0.196) (Fig. B).

Clinical features of the patients and the relationship between BS and IRI level
Blood sugar (BS) and immunoreactive insulin (IRI) levels of patients with both cognitiveimpairment and cancer are higher than those of patients with cognitive impairment only (P < 0.05) (Table).

Discussion
In the present study, we have shown that insulin resistance (as assessed by HOMA-IR) is increased in patients with cognitive impairment regardless of the presence of solid cancer, compared to that in cancer patients without cognitive impairment. HOMA-IR showed no signi cant differences between patients with cognitive impairment only and those with both cognitive impairment and cancer, therefore it is possible to consider that the existence of solid cancer itself may have no contribution to the development of insulin resistance in cancer patients.
To date, there have been many studies indicating the relationship between insulin resistance and development/progression of cancer [13]. However, in the present study, HOMA-IR of patients with cancer only was signi cantly lower compared to those with cognitive impairment only. Therefore, the contribution of insulin resistance to the development and progression of cancer was not indicated and further studies are required. On the other hand, recent epidemiological and basic scienti c investigations have suggested an association and common pathological mechanisms between hyperglycaemia and cognitive impairment including Alzheimer's disease [7]. As for the mechanisms for the development of cognitive impairment in diabetic patients, interference of insulin signal processing in the brain has been indicated. Wan et al. reported that insulin induces functional postsynaptic GABA receptors in the brain [14]. Furthermore, low insulin sensitivity is reported to contribute to the decrease in acetylcholine synthesis, which leads to Alzheimer's disease [15]. Our present data con rms that cancer patients are no exception to develop hyperglycaemia due to low insulin sensitivity which induces cognitive impairment.
However, because HOMA-IR showed no signi cant difference between patients with cognitive impairment only and patients with both cancer and cognitive impairment, insulin resistance may not contribute solely to the development of cognitive impairment in patients with solid cancers. Interestingly, the majority of Japanese diabetic patients are known to have insulin secretion de ciency but not insulin resistance [16]. Our present data may also indicate the importance of HOMA-IR measurement in elderly cancer patients since those with high HOMA-IR scores may be in higher risk of developing cognitive impairment. Early treatment to reduce insulin sensitivity, such as with the use of biganides, in patients with high HOMA-IR scores, is important. However, further studies are required to investigate the effects of biganides on the development of cognitive impairment in elderly cancer patients.

Conclusions
In summary, our results suggest that insulin resistance was increased in patients with cognitive impairment only and those with both cognitive impairment and solid cancer compared to cancer patients without cognitive impairment; however, β-cell function was not affected. The present data indicate that elderly cancer patients with insulin resistance may be in higher risk of developing cognitive impairment.
Early treatment to reduce insulin sensitivity may be able to the prevention of cognitive impairment.

Limitations
The study cannot show cause-effect relationship. Social desirability and recall bias were also possible limitations. MMSE average score of thirteen subjects with solid cancers and cognitive impairment was 22.6, and 14 subjects with only cognitive impairment was 21.4. The score of the MMSE study of the patients are 23 points or less. It may be said that the patients are cognitive decline. We reviewed the consent form that submitted to the Ethical Review Board in reference to the background and the design of the LASA study. I obtained the quali cation of the specialist in intractable disease designation from Governor Fukushima.
For example, an intractable disease is frontal head form dementia or young people dementia appointed by Japanese Ministry of Health, Labor and Welfare. Written informed consent was obtained from the legal guardians or representative of thirteen subjects with solid cancers and cognitive impairment and 14 subjects with only cognitive impairment these participants provided consent on their behalf included in the study.

Consent for publication
Not applicable.

Availability of data and materials
The dataset in the current study is available from the corresponding author upon request.  Tables   Figures  Figure 1 Results of HOMA-B evaluation HOMA-B of patients with cancer, with cognitive impairment, and with both showed no signi cant difference. Data represent mean ± SD. P values determined using Student's t test. *, P ≤ 0.001; **, P ≤ 0.05.