Health-related quality of life and insulin resistance over a 10-year follow-up

The aim of the study was to investigate the association between insulin resistance (IR) and health-related quality of life (HRQoL) among citizens of Palanga in a 10-year follow-up. A randomized epidemiological study was performed with 835 subjects. The following data were examined using questionnaires: sociodemographic characteristics, behavioural factors, HRQoL and self-perceived health. Fasting blood samples were drawn from all participants, and biochemical tests were performed for glucose and insulin. IR was evaluated by the homeostasis model assessment of IR (HOMA-IR). In subjects with IR, after adjusting for various factors, logistic regression analysis showed that within 10 years, there was a significantly higher chance of deteriorating HRQoL in the areas of physical functioning (odds ratio [OR] = 1.15, p < 0.001), emotional role limitations (OR = 1.07, p = 0.034), social functioning (OR = 1.26, p = 0.004), pain (OR = 1.09, p = 0.005) and general health perception (OR = 1.07, p = 0.022). People with IR have a worse HRQoL, and as they age, they are significantly more likely to have a deterioration in their HRQoL than people without IR in the areas of physical functioning, emotional role limitations, social functioning, pain and general health perception.

Insulin, through its various effects on insulin target cells, plays an important role in regulating physiological blood glucose levels. Insulin resistance (IR) is a condition in which insulin-responsive cells do not respond to insulin as well as they should 1 . IR is one of the primary cause of metabolic syndrome [2][3][4][5] , which in turn reflects a real variety of closely linked risk factors. The aetiology of metabolic syndromes is complex and multifactorial. The key causes are obesity, physical inactivity, sedentary lifestyle and aging population [6][7][8] . The metabolic effects of IR, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased blood pressure to promote vascular injury which can exacerbate the hypertension and the damage it causes to the cardiovascular system 9,10 .
IR occurs as part of a cluster of cardiovascular-metabolic abnormalities. A strong relationship exists between diabetes mellitus (DM) and cardiovascular disease. Cardiovascular disease is the most prevalent cause of mortality and morbidity in diabetic populations 11 . Given the seriousness of cardiovascular disease data, diabetes is becoming a greater burden 12 . IR precedes the development of diabetes, cardiovascular disease, and Alzheimer's disease 13 . DM and impaired glucose tolerance have been associated not only with increased morbidity and mortality but also with poor quality of life 14,15 .
The assessment of IR indicators in everyday clinical practice is based on fasting glucose and insulin concentrations. The homeostasis model assessment of IR (HOMA-IR) is one of the most often used indirect indicators for characterizing this condition in the 'steady-state' 16,17 . Using the HOMA-IR and the SF-36 health survey, crosssectional data from 1212 participants in the Hertfordshire Cohort Study revealed that IR was associated with poor health-related quality of life (HRQoL) in domains of physical health but not in domains of mental health 18 .
IR was found be strongly correlated with an estimated measure of quality of life in patients with coronary heart disease but without known DM 19 .
HRQoL is a multidimensional term that relates to overall satisfaction with life and describes a patient's level of functioning across physical, emotional, and social domains. It represents the patient's perception of the impact of a disease and its treatment. Many variables influence HRQoL, including disease-related disability 20 .
To date, a correlation between IR and HRQoL has received little attention in the medical literature; therefore, it is still controversial and is not well understood. It is important to examine the association with worse HRQoL in this population. HRQoL reflects how an individual views and adapts to their symptom burden, mental distress, functional limitations, as well as how patients perceive their overall health. Thus, we aimed to investigate the association between HRQoL and IR among citizens of Palanga in a 10-year follow-up. Measures. WHO-5 wellbeing test. The WHO-5 Well-being Index 22 consisted of 5 questions reflecting the well-being of a person during the last 2 weeks: I feel cheerful and in good spirits; I feel calm and relaxed; I feel active and vigorous; I wake up feeling fresh and rested; my daily life is filled with things that interest me. The raw score is calculated by totalling the scores of the five items. The raw score ranges from 0 to 25; 0 represents the worst possible quality of life, and 25 represents the best possible quality of life. To obtain a standardized percentage score ranging from 0 to 100, the raw score is multiplied by 4. A standardized score of 0 represents the worst possible quality of life, whereas a score of 100 represents the best possible quality of life. Cronbach α = 0.876. The respondents who scored 50 or more were classified as not having depressive moods. Respondents who scored less than 50 were classified as having depressive moods, and they were considered to have an increased risk of depression.
Questionnaire on general data, behavioural factors and self-perceived health. The questionnaire on general data 23 was used to collect information about the marital status, education, employment and income of respondents. The questionnaire assessing behavioural factors 23 consisted of questions about smoking, alcohol consumption, and physical activity during the last year. The self-perceived health questionnaire 23 consisted of questions about complaints and diagnosed diseases, medications used during the last year, frequency of stress events, and visits to any doctor.
Objective investigation. Arterial blood pressure (mmHg) was measured twice with a quicksilver sphygmomanometer (Riester 660/306, DIPLOMAT Presameter, Germany) on the right hand while a person was sitting, with a precision of 2 mm according to the methodological guidelines 24 . The average of two measurements was used for the analysis. If the participants' systolic blood pressure was greater than 140 mmHg and/or their diastolic arterial blood pressure was greater than 90 mmHg in the previous two weeks, they were considered hypertensive. Body height was measured in stocking feet (without shoes) with a medical height rod. Body weight was measured without shoes using a medical scale (SECA 778, SECA Corporation, Hamburg, Germany) with a stadiometer. Body mass index (BMI) was calculated according to the following formula: BMI = body mass (kg)/height (m) 2 using the height and weight measurement data. Overweight was diagnosed when BMI was 25.0-29.9 kg/ m 2 , and obesity was diagnosed when BMI was 30.0 kg/m 2 or more. . The 36-item Short Form Medical Outcome Questionnaire (SF-36) consists of 8 multi-item subscales that assess HRQoL on 8 domains: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy/vitality, pain, and general health perception. Each of the 8 SF-36 domains is scored on scales from 0 to 100, with higher scores indicating better HRQoL 25 . The internal reliability (ɑ coefficients) of the 8 subscales was found to range between 0.71 and 0.85.

Statistical analysis.
The clinical and sociodemographic characteristics were reported by frequencies and percentages for the categorical variables and with means and standard deviations for the continuous variables. Informed consent. Informed consent was obtained from all individual participants included in the study.

Results
Baseline characteristics.   Table 2. HRQoL according to the physical functioning subscale was significantly lower in the first study and after 10 years in subjects with IR than in subjects without IR. Additionally, after 10 years, HRQoL in the physical function subscale decreased significantly in both study groups according to the presence of IR, but the decrease in HRQoL was statistically significantly greater in the IR group. Physical role limitations subscale scores did not differ between groups in the first study, but 10 years later, the difference was significant. Significantly lower physical role limitations were found in IR individuals, although this dimension of HRQoL decreased significantly with age in both groups. Social function subscale scores were the same in both the IR and without IR groups in the first study; these scores did not change after 10 years in the group without IR and decreased significantly in the IR group, so the difference in the social function dimension of HRQoL was significantly worse in subjects with IR. Scores on the mental health subscale increased significantly with age in both groups, but we did not find a significant difference in the groups according to the presence of IR. Scores on the pain subscale did not significantly change with age in either group, but after 10 years, the difference in HRQoL between groups became statistically significantly different, with worse HRQoL being observed in the IR group. No differences were found in the energy vitality and emotional role limitations subscales when evaluating the data in the groups according to IR over 10 years. The general health perception dimension of HRQoL did not change with age in the IR group; in the group without IR, it improved significantly, and after 10 years, the differences between the groups became significant.
In the IR group, the HRQoL became significantly worse than that in the group without IR.
The change in health-related quality of life at the 10-year follow-up. www.nature.com/scientificreports/ After adjusting for year, sex, age, IR, marital status, education, employment, self-perceived health, frequent stressful events, depressed mood, alcohol use, smoking, illness during the past 12 months, and body mass index, subjects with IR had a significantly higher chance of deteriorating HRQoL in the dimensions of physical functioning (OR 1.15, p < 0.001), emotional role limitations (OR 1.07, p = 0.034), social functioning (OR 1.26, p = 0.004), pain (OR 1.09, p = 0.005) and general health perception (OR 1.07, p = 0.022) after a 10-year period, as seen in Model 2 (Table 4).

Discussion
This longitudinal study regarding HRQoL among individuals in the western part of Lithuania indicated that decreases in HRQoL were significantly related to IR, as evaluated by HOMA-IR. The major finding in the present study is that subjects both with IR and without IR reported lower SF-36 scores in the physical functioning and physical role limitation dimensions after 10 years. However, the SF-36 subscale of mental health scores increased significantly with age in both groups, indicating better HRQoL. Over the course of 10 years, significant changes were observed in domains of the SF-36 subscales of physical functioning, social functioning and general health perception, showing worse HRQoL in subjects with IR. Furthermore, the results of this study suggest that future research should continue to examine people who have IR. It is a cause for concern that within 10 years, subjects with IR have a significantly higher chance of deteriorating HRQoL in the areas of the five of the eight subscales: physical functioning, emotional role limitations, social functioning, pain and general health perception.
To our knowledge, our study is the first to assess the association between IR and HRQoL over a 10-year follow-up. IR is an important factor that needs to be investigated for to precisely identify which dimensions of Table 1. The sociodemographic characteristics of subject groups without and with insulin resistance in the survey in 2003 and 2013. BMI body mass index, IR insulin resistance, SBP systolic blood pressure, DBP diastolic blood pressure; p-value of probability for comparison between groups (bolded numbers indicate significant differences, p < 0.05); data presented as n (%), mean ± SD.  26 , so it is likely that IR affects physical disability. Better mental health status thus leads to more physical activity, which in return has a positive association with better mental health and physical health 27 . Furthermore, better past mental health is found to reduce cigarette consumption, which then has a positive effect on present health 28 . In addition, the study by Ohrnberger et al. 29 implies that health investments may be considered intervention channels through which mental and physical health can be improved at old age. According to the findings of Eddy et al. 30 , people who acquire IR have a roughly threefold higher risk of coronary artery disease than those who do not. In participants with IR, normalizing IR lowered cardiovascular risk by approximately 55%. The study by Agewall et al. showed that an estimated measure of quality of life was significantly and independently associated with IR in patients with coronary heart disease and without known DM 19 .
According to growing data, IR is thought to have a role in the pathophysiology of cognitive impairment and neurodegeneration. Insulin has a significant impact on cognitive performance 31 . Poorer HRQoL is an independent predictor of cognitive function, as established in the recent research of community-based older persons 32 .
Together, the data from these studies and our data suggest that IR seems to be one of the most important factors determining HRQoL in healthy people. This is a potentially modifiable situation that could be changed with dietary and lifestyle improvements. As a result, we suggest that more research on HRQoL is needed, especially in the area of sexuality 33 , to support and investigate the health problems related to ageing and HRQoL improvements.
There is a growing body of evidence that shows a connection between metabolic syndrome and deterioration in HRQoL 6,[34][35][36] . Unfortunately, there is still little research examining IR as the primary cause of metabolic syndrome in association with HRQoL.
The present study aimed to draw attention to the effects that IR can have on HRQoL, as IR is still an important public health issue that can accompany a variety of risk factors (Supplementary Information).

Conclusions
The results of this study suggest that people with IR have a worse HRQoL, and as they age, they are significantly more likely to have deterioration in their HRQoL compared to people without IR in the areas of physical functioning, emotional role limitations, social functioning, pain and general health perception after a 10-year period.

Data availability
The datasets analysed during the current study are available from the corresponding author upon request.