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ORIGINAL ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 4  |  Page : 341-349  

Impact of structured exercise therapy on impaired cognitive function among young adults diagnosed newly with type 2 diabetes mellitus – A randomized controlled trial


1 Department of Physiology, JN Medical College, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India
2 Department of Medicine, JN Medical College, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India

Date of Submission28-Jun-2019
Date of Decision15-Aug-2019
Date of Acceptance20-Sep-2019
Date of Web Publication20-Jul-2020

Correspondence Address:
Harpreet Kour
Department of Physiology, JN Medical College, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_185_19

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  Abstract 


Background: Diabetes mellitus is the most common endocrine disorder associated with cognitive dysfunction. Battery of papers has revealed that diabetes causes detrimental effects on range of cognitive functions. Therefore, the present study has been undertaken to assess, in a randomized manner, the impact of structured exercise therapy on various domains of cognition in young adults newly diagnosed with type 2 diabetes mellitus (T2DM) in the age group of 20–45 years. Materials and Methods: This randomized controlled trial was conducted in the Research Laboratory, Department of Physiology, JN Medical College attached to Dr. Prabhakar Kore Hospital and MRC, Belagavi. As per eligibility criteria, a total of 148 newly diagnosed T2DM patients in the age group of 20–45 years were enrolled from the outpatient department, department of medicine, after obtaining institutional ethical clearance and informed consent from the patients. The patients were then divided randomly into diabetic controls and interventional group. The interventional group was asked to perform structured exercise therapy. Sociodemographic and cognitive functions (by PGI Battery of Brain Dysfunction) and glycated hemoglobin were evaluated at baseline and the end of 6 months for the study groups. Socio-demographic and cognitive functions (by PGI Battery of Brain Dysfunction) and glycated hemoglobin were evaluated at baseline and the end of 6 months for both of the study groups. Whereas, additionally in the interventional group, various parameters were studied for the four times i.e at the baseline, end of the 2nd, 4th, and 6th months. IBM SPSS Statistics for Windows, version 20.0 (Armonk, NY, IBM Corp., USA) was used for appropriate statistical analysis. Results: A significant improvement was observed in cognitive functions in the interventional group at the end of 6 months with structured exercise therapy.P < 0.05 was considered statistically significant. Conclusions: Exercise therapy along with dietary control and antidiabetic medications has a positive influence on cognitive functions.

Keywords: Cognitive functions, PGI Battery of Brain Dysfunction, PGIMS, structured exercise therapy, type 2 diabetes mellitus


How to cite this article:
Kour H, Kothiwale V A, Goudar SS. Impact of structured exercise therapy on impaired cognitive function among young adults diagnosed newly with type 2 diabetes mellitus – A randomized controlled trial. Med J DY Patil Vidyapeeth 2020;13:341-9

How to cite this URL:
Kour H, Kothiwale V A, Goudar SS. Impact of structured exercise therapy on impaired cognitive function among young adults diagnosed newly with type 2 diabetes mellitus – A randomized controlled trial. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Dec 2];13:341-9. Available from: https://www.mjdrdypv.org/text.asp?2020/13/4/341/290162




  Introduction Top


Over the past three decades, there is a change in the status of diabetes, from being considered as a mild disease of the aged individuals to one of the main causes of morbidity and mortality which is affecting the young population.[1] Diabetes mellitus is a multifaceted, slowly progressive, and complex metabolic disorder and can have catastrophic effects on all the systems of the body leading to end-organ damage in the brain. It is also associated with a plethora of microvascular and macrovascular complications.[2],[3] Impairment in cognitive functions is less known, not addressed extensively, and even not well-recognized complication of diabetes mellitus. Research shows that diabetics are found to have cognitive deficits which are attributing to their disease.[4] Impaired memory, executive functions, processing speed, intelligence, attention, and concentration are known to be associated with diabetes mellitus. There is no clear evidence available explaining that how and when, over time cognitive impairment develops in diabetics. The majority of studies have focused on known diabetic patients with long-standing diabetes mellitus. However, type 2 diabetes develops very slowly, and most of the time remains to be undiagnosed in its early stages. Therefore, impairment in cognitive functions may start developing before the definite diagnosis, even in the prediabetic stage. Before the patients are diagnosed as diabetic, they undergo prediabetic state in which there is evidence of glucose intolerance with bouts of hyper- and hypoglycemia which can cause cognitive dysfunctions.[5],[6],[7] Both hypoglycemia and hyperglycemia are suggested as causes of cognitive dysfunction in diabetes mellitus. Mildtomoderate impairments of cognitive functioning have been reported in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM).[8] The frontal lobe mediates the decrements of cognitive function which includes a large number of multifarious behaviors in diabetics, for example, problem-solving, planning, organization, insight, reasoning, and attention.[9] The primary substrate for brain energy metabolism is only glucose as neurons can neither store nor synthesize glucose. Therefore, through systemic circulation, glucose is obtained and consequently transported across the blood–brain barrier. In diabetes mellitus, the insulin signals are not taken up by the cells, and thus, the brain may not get a sufficient amount of glucose energy as required, especially for memory. Hence, loss of brain cells and impaired memory function result especially in the hippocampal region. Hippocampus is the region of the brain which is involved in learning and memory. The transportation of insulin across the blood–brain barrier occurs by its specific receptors. The improper function of insulin may inhibit synaptic activities in the brain. Insulin also reduces the cholinergic activity of striatal neurons and increases monoamines in the brain. Even though much research has been done in this field, still the pathophysiology of cognitive dysfunction is not clear, and suitable methods to diagnose, treat, and prevent cognitive dysfunction in diabetes mellitus are not defined so far.[10],[11],[12],[13],[14]

The large proportion of India's population belongs to the younger age group. Before being diagnosed as diabetic, the person goes through prediabetic period or impaired glucose tolerance phase which includes acute episodes of hyperglycemia and hypoglycemia. These acute episodes may lead to microvascular diseases and result in cognitive deficits.

Therefore, the present study has assessed, in a randomized manner, the effects of 6-month structured exercise therapy on various cognitive functions in young adults with newly diagnosed T2DM on dietary control and antidiabetic drug in the age group of 20–45 years. Cognitive functions evaluated included remote memory, recent memory, mental balance, attention and concentration, delayed recall, immediate recall, verbal retention for similar pairs, verbal retention for dissimilar pairs, visual retention and recognition by PGI Memory Analysis Scale (PGIMS), intelligence by Bhatia's Battery of Performance Test of Intelligence (BBI) and Verbal Adult Intelligence Scale (VAIS), organic brain pathology by Nahor–Benson test (NBT) and visual acuity and motor functioning by Bender VisualMotor Gestalt Test (BGT). These tests are part of PGI Battery of Brain Dysfunction (PGIBBD).[15],[16] Exercise has been considered as one among the cornerstone of diabetes management and the other two being diet and medication. The advantages of exercising regularly to prevent and treat diabetes are now extensively recognized. Exercise helps to improve glycemic control, body composition, cardiorespiratory endurance, insulin resistance, physical functioning, and well-being of diabetics,[14] but its effect on neurocognitive behavior is still not clear.

Objective of the study

To study the effects of six months structured exercise therapy on various cognitive functions and Glycated Hemoglobin in young adults with newly diagnosed T2DM on dietary control and anti-diabetic drug of age group 20-45 years.


  Materials and Methods Top


The present randomized controlled study was conducted in the Research Laboratory, Department of Physiology, Jawaharlal Nehru Medical College attached to KLES Dr. Prabhakar Kore Hospital and MRC, Belgaum. All patients diagnosed newly with T2DM from April 2017 to October 2018, from Medicine Outpatient Department of Dr. Prabhakar Kore Hospital and Research Centre form the study material after obtaining written informed consent from the patients. Ethical approval was obtained from the Institutional Ethics Committee through reference number KLEU/Ethic2012-13/D-4570. The study is registered with the Clinical Trial Registry of India through reference number CTRI/2018/07/014705

Inclusion criteria

All the patients diagnosed newly with T2DM (April 2017–October 2018) in the age group of 20–45 years were enrolled. The patients were treated with only diet and oral antidiabetics.

Exclusion criteria

Patients with a history of diabetes more than a year or with known vascular complication of diabetes, patients with any chronic diseases restricting physical activity, patients with prior regimen of physical exercise, and also patients who were on any other medication (e.g., antihypertensives, sedatives, antipsychotics, and systemic steroid medication) that are known to affect memory and cognitive functions were excluded from the study.

Sample size was calculated as per the below-mentioned formula:



where Z = standard for test = X̅−X̅/standard deviation (SD), Z1−α = at 95%, confidence interval = 1.96, Z1 − β = at 80%, power of the test = 1.64, mean and SD are taken from by review of literature for study, and control was taken as 29.3 + 0.84 and 28.7 + 1.69. X1 − X2 = expected impact size. Calculations: n = (1.64 + 1.96) 2 (0.8426152 + 1.6970562)/(29.3 + 28.7)2 = 130. Accounting dropout cases as 10%, then, the calculated sample size was 132/0.9 = 144.4 – rounded to 146.

After enrollment as per eligibility criteria, a total of 148 patients were enrolled and then were randomly divided into diabetic group and interventional group by computer-generated, randomized sequence numbers. This randomization allocation was placed in opaque sealed envelopes. Diabetic controls (n = 74) included patients who were on dietary control and antidiabetic drugs, whereas the interventional group (n = 74) included patients who were on dietary control, antidiabetic drug, and structured exercise therapy. A total of 74 sex, age, and mean education-level matched healthy individuals were enrolled in the study as normal controls to obtain the baseline data. At the beginning, the normal controls were compared with 148 enrolled diabetic patients for baseline data. Then, the randomization was done for diabetic population. Both the diabetic and interventional groups were evaluated at the end of 6 months. The interventional group was also evaluated at the end of the 2nd and 4th months to see the timeline changes in study variables [Figure 1].
Figure 1: Consent flow diagram

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Structured exercise therapy

The interventional therapy consists of 6 months of the regular exercise program including the combination of aerobic and resistance exercises. The aerobic exercise includes about 30 min of walking at least 5 days/week with an intensity of 70%–80% of their individualized maximum heart rate. Resistance exercise was asked to perform three times a week with three sets of 8–10 repetitions. It included the exercises for all major groups of muscles, namely dumbbell flyes, seated single-leg extension, dumbbell shoulder press, dumbbell bent-over row, standing leg curls, dumbbell bicep curls, dumbbell upright row, dumbbell tricep kickbacks, and abdominal curls. All the patients were provided with detailed instruction booklets describing each resistance training exercise and appropriate equipment (dumbbells) to perform resistance training.[17],[18]

Study parameters

  1. Demographic profile includes age in years and sex was noted [Table 1]
  2. Cognitive parameters were measured by PGI-BBD. It requires nearly 90–120 min for its complete administration. The battery is having overall dysfunction rating and includes five main tests including:


    1. PGI memory analysis scale (PGIMS) which has ten subtests was standardized on adult patients in the age range of 20–45 years including recent memory, remote memory, mental balance, attention and concentration, delayed recall, immediate recall, verbal pretension for similar pairs, verbal pretension for dissimilar pairs, visual retention, and recognition
    2. Revised Bhatia's Battery of Performance Test of Intelligence (BBI) for adults consists of two subtests: Kohs Block Design Test and Pass-A-Long Test. This short scale was standardized on adult patients in the age range of 20–59 years. Norms are developed for four age groups and three educational levels separately for males and females to increase the sensitivity of scores
    3. Verbal Adult Intelligence Scale (VAIS) is characterized by social interaction, experiences, and schooling, and hence, it continues to develop beyond the age of physiological maturity. It consists of four subtests, namely information, digit span test, arithmetic test, and comprehension test. This test administration takes about 20–30 min
    4. NBT consists of eight cards. Out of these, five cards contain a design and three cards contain the instructions to be followed. This is a quick and simple screening test for organic brain pathology
    5. BGT: It involves perceptuo-motor organization consisting of nine figures and tests perceptual and visual-motor functioning.


    Interpretation of PGI-BBD Battery: Total dysfunction rating score (TDRS) ranges from 0 to 57. The dysfunction rating score is above cutoff point 20 or more, suggesting that there is a significant cognitive dysfunction.
    Table 1: Sociodemographic parameters of study participants

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  3. Biochemical parameters: Hemoglobin A1c (HbA1c) was estimated by kit method (Ion-Exchange Resin Method).


Statistical analysis

Mean ± SD of normally distributed quantitative variables was compared using independent-samples t-test, and median and interquartile range (IQR) of nonnormally distributed quantitative variables were compared using Mann–Whitney U-test. Categorical variables were compared using Chi-square test. One-way repeated-measures analysis of variance was used to compute the statistical significance of differences in normally distributed quantitative variables at different follow-up periods.


  Results Top


Out of the subcomponents of memory, remote memory, recent memory, mental balance, verbal retention for similar pairs, and recognition components, the raw scores were comparable between healthy controls and diabetes patients (P > 0.05). A statistically significant difference was observed in raw scores obtained in tests included attention and concentration, delayed recall, immediate recall, verbal retention for dissimilar pairs, and visual retention (P < 0.001) [Table 1].

Performance quotient score of Bhatia battery of intelligence and test quotient score of the Verbal Adult Intelligence Scale were found significantly lesser in diabetic population as compared to normal controls (P < 0.005). Scores of NBT and BGT were comparable between diabetic population and controls. The cutoff point for total dysfunction score is 20. A score above 20 suggests cognitive dysfunction. The diabetics have a statistically significant high score as compared to normal controls (P < 0.001). The values of HbA1c are significantly higher in diabetics (P < 0.001) [Table 2].
Table 2: Comparison of cognitive functions and hemoglobin A1C between normal controls and diabetics

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The statistically significant improvement was observed in the raw scores obtained in attention and concentration, delayed recall, immediate recall, verbal retention for dissimilar pairs, and visual retention tests as compared to diabetic controls. A significant improvement was observed in total dysfunction score and HbA1c levels at the end of 6 months of interventional therapy (P < 0.001). There is a marginal difference between glycated hemoglobin in both the groups showing good blood glucose control in our population [Table 3].
Table 3: Scores of cognitive domains and hemoglobin A1C level at the end of 6th month

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A statistically significant improvement was observed in the above-mentioned cognitive domains and HbA1c levels at the end of the 2nd, 4th, and 6th months of structured exercise program in the interventional group (P < 0.001) [Table 4].
Table 4: Comparison of trend of various outcome parameters in the intervention group from baseline to postintervention

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  Discussion Top


The study population consisted of adult patients aged 20–45 years newly diagnosed with T2DM. In the current study, when compared to normal healthy controls, people with diabetes mellitus had shown poor memory and neurocognitive function. The components of the PGI Memory Analysis Scale, including median attention, delayed recall, immediate recall, verbal retention for dissimilar pairs, and visual retention were adversely affected among diabetic population. Overall performance quotient scores were also significantly lesser among the diabetic population, indicting poor overall memory. Among normal controls, the median test quotient on Verbal Adult Intelligence Scale (VAIS) was 128 (IQR: 116.175, 136.3), and it was 102.4 (IQR: 94.9, 113) among the diabetic group (P < 0.001). Among normal controls, the median TDRS was 15 (IQR: 14, 16), and it was 22 (IQR: 21, 22) among the diabetic population (P < 0.001). Scores in various domains of cognitive functions showed a significant improvement with structured exercise therapy.

A recent meta-analysis by Sadanand et al. has reviewed the published evidence to compare the memory and executive functions between type 2 diabetic population and controls. As compared to controls, persons with T2DM showed decrements in episodic memory, logical memory, and other subdomains of executive functions (including phonemic fluency, cognitive flexibility, and speed of processing). Verbal short-term memory and working memory were found to be comparable with controls.[19]

Another meta-analysis demonstrated that T2DM was associated with poorer performance in six cognitive domains, with the largest effects on measures of speed of information processing and psychomotor efficiency, executive functions, and verbal learning. As per this meta-analysis, there was a variation across the studies on negative impact of diabetes on verbal memory, attributed to heterogeneity in tools used across the studies. Compared to individuals without diabetes, individuals with diabetes had worse overall performance on tests of the visual memory domain.Compared to individuals without diabetes, individuals with diabetes showed worse overall performance on tests of attention/concentration. The most frequently used tests were the Wechsler Adult Intelligence Scale-Digit Span Forward and Backward, Stroop Part I, Stroop Part II, and Wechsler Memory Scale (WMS)-Digit Span Backward. Executive function, as assessed by Trail Making Test (TMT) Part B, Stroop Part III Interference, and Wisconsin Card Sorting Test-Categories were also poorer among diabetic population, compared to healthy controls.[20] As per study by Avadhani et al., after adjusting for age, education, and cardiovascular covariates, HbA1c remained associated with cognitive function tests of Rey Auditory Verbal Learning Test (R[2] = 0.27, P < 0.0001), TMT (R[2] = 0.18, P < 0.0001), and categorical verbal fluency (R[2] = 0.20, P < 0.0001). This study had concluded that higher HbA1c is associated with lower cognitive function performance scores across multiple domain tests in men with metabolic syndrome and coronary artery disease.[21] A study by García-Casares et al. has assessed the neuropsychological performance of a group of middle-aged patients with well-controlled T2DM. As per this study, people with type 2 diabetes had significantly lower scores than healthy controls in the TMT B (P < 0.004), Color-Word Stroop Test (P < 0.005), semantic fluency (P < 0.006), Digit-Symbol Modalities Test (P < 0.02), Text Recall from the WMS (P < 0.0001), Rey–Osterrieth Complex Figure – copy (P < 0.004), and delayed reproduction (P < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex and temporal (middle gyrus, parahippocampus, and uncus) and cerebellum regions (P < 0.001).[22] Takeuchi et al. in their study have assessed the neuropsychological profile of inpatients with poorly controlled type 2 diabetes and assessed the effects of clinical factors on neuropsychological functions. As per these study findings, diabetic patients demonstrated mild cognitive deterioration in attention and working memory, processing speed, verbal memory, and executive function. In particular, the neuropsychological decline became prominent when tasks related to speed and verbal stimuli became unstructured and complex.[23] Roberts et al. in their case–control study of people aged between 70 and 89 years have explored the association between mild cognitive impairment and diabetes mellitus. As per these study findings, after adjusting for the effect of potential confounders, onset of diabetes before 65 years, duration of diabetes >10 years, and presence of diabetic complications were independent predictors of dementia.[24] Since then, numerous researchers across the globe have explored the ill effects of diabetes on the brain and resulting negative impact on memory, cognition, and other neurophysiological functions. It also highlights the mechanisms of diabetes-induced brain injury. It seems that the pathogenesis of hyperglycemia-induced brain injury is complex and includes combination of vascular disease, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, reduction of neurotrophic factors, acetylcholinesterase activation, neurotransmitters' changes, impairment of brain repair processes, impairment of brain lymphatic system, accumulation of amyloid-beta, and tau phosphorylation and neurodegeneration.[25] Poor cognition was, in turn, reported result in many untoward consequences among diabetic patients. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial which was a prospective cohort analysis of data of 2956 adults aged ≥55 years with type 2 diabetes had documented some interesting associations between poor cognitive function and risk of severe hypoglycemic episodes. This has concluded that poor baseline cognitive function at baseline is predictive of severe hypoglycemic episodes. The cognitive decline over 20 months further increased the risk of subsequent hypoglycemia among the people with poor cognitive function.[26]

In spite of the strong association and clinical implications of cognitive dysfunction, it is one of the least focused, underdiagnosed, and ignored aspects of diabetes care in developing nations such as India. Lack of adequate amount of literature documenting the extent of the problem and offering effective preventive and treatment options can be considered as the major reason for this phenomenon.

Exercise has been proven to have a positive impact on memory, cognition, and other neurophysiological functions, among the healthy population and people affected by a wide range of medical conditions. Wilckens et al. conducted that a study on community-dwelling young (21–30) and old (55–80 years) healthy people had explored the role of exercise on cognitive function. This study concluded that exercise leads to improvement in the cognitive function, probably mediated through increasing sleep efficiency. This phenomenon was observed in both young and old people. Hence, exercise was reported to have age-independent beneficial effect on cognition.[27] A randomized controlled trial (RCT) by Rogge et al. on healthy participants aged 19–65 years had compared the efficacy of either balance-based training or relaxation training for 12 weeks on cardiorespiratory fitness, memory, spatial cognition, and executive functions. Cardiorespiratory fitness remained unchanged in both the groups. Memory and spatial cognition had shown a significant improvement in balance-training group.[28] Another RCT by Heisz et al. has compared the effect of 6 weeks of exercise training, combined exercise and cognitive training, or no training (control) on cognitive function. Both the exercise and combined training groups improved performance on a high-interference memory task, whereas the control group did not. In contrast, neither training group improved on general recognition performance, suggesting that exercise training selectively increases high-interference memory that may be linked to hippocampal function. Individuals who experienced greater fitness improvements from the exercise training (i. e., high responders to exercise) also had greater increases in the serum neurotrophic factors such as brain-derived neurotrophic factor and insulin-like growth factor-1. These high responders to exercise also had better high-interference memory performance as a result of the combined exercise and cognitive training compared with exercise alone, suggesting that potential synergistic effects might depend on the availability of neurotrophic factors. These findings are especially important, as memory benefits accrued from a relatively short-duration intervention in high-functioning young adults.[29] Espeland et al. in their study have reported that physical activity-based interventions had a positive impact on global cognitive function and delayed memory as compared with no exercise group. However, this beneficial effect was observed only among diabetic patients, not among the nondiabetic population. Based on the findings, they have proposed that probably different mechanisms are responsible for interaction of physical activity and cognitive function among the diabetic and nondiabetic population.[30] Zhao et al. have conducted as a systematic review to assess the impact of physical activity or exercise on cognitive function among adults with T2DM. As for the review, only three RCTs were available with variable quality, with the rest of the evidence coming from poor quality observational studies. As per the review, four studies which have tested impact of the addition of aerobic exercise to diet had reported significant effects on delayed memory, with no significant impact on overall memory. Low-intensity exercise and moderate-intensity treadmill exercise had no significant impact on memory. The same review has reported no significant impact of exercise on information processing speed, based on very limited data available, as only two trials have reported this outcome. As per this review, studies have reported contradictory findings on the impact of aerobic exercise or high physical activity on global cognitive function. Four studies have reported significantly better global cognition in people engaged in higher physical activity, but they are of variable methodological quality.[31]

In summary, we found impaired cognitive functions in newly diagnosed patients with T2DM. A significant improvement was observed with structured exercise therapy consisting of aerobic and resistance exercises when compared to diabetic controls. However, our findings require validation with molecular studies to establish underlying mechanisms.


  Conclusions Top


The results of this trial have provided evidence to indicate that exercise improves cognition in a vulnerable group of young adults. The low-cost, nonpharmacological nature of exercise enhances its therapeutic appeal. This may have an immense beneficial effect on health-care systems, especially of high-volume, resource-poor settings such as India. This also has set the stage for larger trials to further examine the potential protective and disease-modifying effects of exercise therapy.

Financial support and sponsorship

We are grateful to the Indian Council of Medical Research for funding this project.

Conflicts of interest

There are no conflicts of interest.



 
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Zhao RR, O'Sullivan AJ, Fiatarone Singh MA. Exercise or physical activity and cognitive function in adults with type 2 diabetes, insulin resistance or impaired glucose tolerance: A systematic review. Eur Rev Aging Phys Act 2018;15:1.  Back to cited text no. 31
    


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