Metabolic, Inflammatory, Cognitive Risk Stratification, and Intensive Aerobic and Resistance Exercise Intervention for Middle-aged and Older Adults With Type 2 Diabetes Mellitus
Phase: NA
Conditions: Type 2 Diabetes Mellitus, Cognitive Impairment, Non-insulin-dependent Diabetes Mellitus, Cognitive Dysfunction
Sponsor: National University of Singapore

 
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Metabolic, Inflammatory, Cognitive Risk Stratification, Aerobic and Resistant Exercise 
and e-Health Intervention for patients with Type 2 Diabetes Mellitus 
Specific Aims & Hypothesis 
    The overall objective of this study is to develop a risk stratification score for the sensitive identification of 
type 2 diabetes (T2DM) middle-aged and older adults with high risk for metabolic health and cognitive 
impairment (CI), and subsequently conduct and evaluate an Intensive Aerobic and Resistant Exercise 
Program. The hypothesis of this study is that T2DM patients with high risk for metabolic health and CI can 
be detected by cognitive tests, biomarkers and self-care assessment, and the identified patients can be 
managed effectively at primary care settings through an Intensive Aerobic and Resistant Exercise program. 
Specifically, we aim to: 
1. develop a risk stratification score based on metabolic, inflammatory, and cognitive markers to 
identify high risk T2DM patients for poor metabolic health (glycemic control) and CI; 
2. deliver customized Intensive Aerobic and Resistant Exercise Program (IAREP) to high-risk patients 
and perform preliminary assessment for these patients in improving glycemic control, cognition, 
muscle strength, and self-care ability. 
 
Background  
T2DM is a leading cause of morbidity and mortality among adults worldwide [1], with approximately 5 
million diabetes‐related deaths which account for 12.8% of all‐cause mortality in 2015 [2]. In Asia, T2DM is 
on the rise, with anticipated patients to increase from 78 million in 2015 to 140 million by 2040 [2]. Asia is 
emerging as the “diabetes epicenter” due to rapid economic development, urbanization and nutrition 
transition [3]. T2DM is a complex disease with environmental and genetic contributions that causes many 
severe complications in middle-aged and older adults, including higher susceptibility for mild cognitive 
impairment (MCI) and dementia [4]. Given so, the World Health Organization has identified dementia control 
as a global health priority. In many healthcare systems around the world, dementia and cognitive 
impairment (CI) is usually underdiagnosed and assumed to be unrelated to other medical problems in 
patients [5]. Especially for patients living in the community, not much emphasis is placed on cognitive 
health. Lifestyle interventions including exercise and diet are effective in alleviating diabetes but there are 
psychological barriers for T2DM patients to commit to regular exercise and diet controls, e.g., fatigue, fear 
of hypoglycemia, and the lack of measurable biomarkers to indicate the effectiveness or efficiency of such 
efforts [6, 7]. In this context, identifying and understanding molecular pathogenesis is instrumental in 
developing scientifically sound lifestyle intervention. 
   Metabolic, Inflammatory and Neurological mechanism Skeletal muscles are a major organ in glucose 
uptake and consumption which is regulated by insulins. In T2DM, these muscle cells develop elevated 
inflammatory status which decreases muscle sensitivity to insulins. It was found that differentiated cultured 
monocytes isolated from T2DM subjects with insulin resistance secreted more inflammatory cytokines such 
as Tumour Necrosis Factor alpha (TNF-α), which can induce insulin resistance and mitochondrial 
dysfunction in muscle cells [8]. TNF-α has been hypothesised to be one of the main activators for the 
IKK/NF-κB pathway, and this pathway has been postulated to play a role in insulin resistance through higher 
rates of IKK-mediated serine phosphorylation of insulin receptor substrate 1 (IRS-1) or insulin receptor (IR) 
[19]. This results in impairment of insulin-induced tyrosine phosphorylation and subsequent inhibition of 
downstream insulin signalling suppressed expression of molecules such as GLUT4 glucose transporters in 
the insulin signalling cascade. However, there are currently no reliable serum biomarkers specifically 
associated with skeletal muscle inflammation [8]. The biomarkers included in this study are to be 
determined for their specificity in muscle inflammation. Aside from skeletal muscles, insulin resistance has 
also been found to be an independent risk factor for MCI and may be linked to sporadic Alzheimer’s disease 
(AD) in the brain [9].  Acting as a long-term neuroprotectant, insulin reduces Amyloid β protein (Aβ) 
generation and aggregation [10]. Aβ aggregation in the brain results in neurofibrillary tangles and senile 

 
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plaques being formed. Insulin resistance thus results in neuronal loss and contributes to the progression of 
AD. (Figure 1) 
 
Methods & Approach 
Research Design - A two-phase study will be conducted. Phase 1 aims to develop a risk stratification 
score for the sensitive identification of T2DM middle-aged and older adults with poor metabolic health or 
CI. Phase 2 is a pilot randomised control trial (RCT) which aims to evaluate the Intensive Aerobic and 
Resistant Exercise Program (IAREP) on high-risk T2DM patients with poor metabolic health or cognitive 
functioning in improving glycemic control, cognition and self-care ability. A follow-up process evaluation will 
assess acceptability, strengths and limitations of Intensive Aerobic and Resistant Exercise Program.  
Setting - National University Polyclinics (NUP) provide one-stop medical facilities and healthcare services 
for patients and their families. A high proportion of patients with chronic diseases such as diabetes, 
hypertension, hyperlipidemia, stroke etc., is managed by polyclinics.  Among all the chronic diseases 
attended by Singapore polyclinics, diabetes is the third most prevalent chronic disease [34].  
Phase 1 - Developing a Risk Stratification Score (RSS) 
Eligibility and Recruitment – Convenience sampling will be recruited by NUS research assistants (RAs) 
at NUP. Recruitment posters will be displayed at NUP. Eligibility of the subjects will be checked. Participants 
are recruited according to the inclusion criteria: 1) aged 40 to 85; 2) living in the community; 3) 
diagnosed with T2DM; 4) literate in English or Mandarin; 5) Activities of Daily Living (ADL)-
independent; and 6) obtain at least a score of 5 in Short Physical Performance Battery (SPPB) test. 
Patients with the following exclusion criteria will be excluded from the study: 1) severe cognitive (e.g., 
dementia) or psychiatric disorders (e.g., schizophrenia or severe depression); 2) severe hearing or vision 
impairments; 3) terminally ill medical conditions (e.g., end stage cancer), severe cardiovascular, respiratory 
(e.g., respiratory failure), or orthopedic conditions (e.g., freeze shoulder); 4) absolute contraindications to 
aerobic exercise and resistance training programs (e.g., recent myocardial infarction or electrocardiography 
changes, complete heart block, acute congestive heart failure, unstable angina, uncontrolled hypertension); 
5) pregnant or breastfeeding women; 6) uncomfortable with video-recording of intervention sessions. 
Sample Size – The participants will be divided into 40-60 and > 60 age groups for cross-sectional analyses. 
The sample size is calculated using RStudio running R version 3.5.1 [35, 36], based on power of 0.8, effect 
size of 0.15, at significance level of p<0.05, considering the multiple independent variables we are analyzing 
in the regression models (demographics, diabetes self-care abilities), we need 91 participants for both age 
groups respectively. In consideration of 10% invalid data that might be excluded due to various reasons 
post-recruitment, and Phase 1 being the recruitment pool for Phase 2 RCT with possible declines towards 
participation, we propose to have a recruitment target of 300 participants in total. Based on the data from 
NUP, Jurong Polyclinic has a total of 14888 T2DM patients aged above 40. A daily number of 40-80 T2DM 
patients visits Jurong polyclinic. Hence, the target recruitment number of 300 participants is achievable.  
Risk Stratification Score - Possible risk factors, such as age, education, cognitive test scores, 
microvascular disease, cerebrovascular disease, acute metabolic event, diabetic foot, and 
depression/mood disorder will be obtained from the participants during data collection. Outcome measures 
consist of metabolic profile and cognitive diagnosis defined by formal neuropsychological assessments. 
Predictors to derive RSS include inflammatory, lipid, cognitive markers, self-care ability and social-
demographic. Logistic regression model will be applied to generate the RSS to predict poor metabolic health 
and CI in T2DM patients (high, medium, low risk).  
Outcome Measures for RSS 
1. Metabolic profile (HbA1c) 
2. Vascular Dementia Battery (VDB): Formal neuropsychological assessments validated for the local 
population will be conducted [37]. The neuropsychological assessment covers domains in attention, 

 
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processing speed, language, visuo-spatial ability, memory and executive function.  It is the gold 
standard to establish the diagnosis of cognitive impairment. It also establishes specific cognitive domain 
difficulties that T2DM patients may have that could hinder their learning process, so as to customize 
the intervention delivery for cognitively impaired patients. 
Predictors to derive RSS:  
1. Inflammatory profile (CRP, TNF, IL-6, adiponectin) and Exerkines (PCSK9) 
2. Self-care of Diabetes Inventory (SCODI): SCODI was developed based on the Self-care of Chronic 
Illness theory [41]. There are 40 items (5 points Likert type) and 4 dimensions: self-care maintenance, 
self-care monitoring, self-care management and self-care confidence 
3. Self-rated abilities for Health Practices Scale (SRAHP): Developed by Becker and Stuifbergen, 
SRAHP is a 28-item, 5-point scale to measure self-perceived ability to implement health-promoting 
behaviors. It contains four subscales: Exercise, Nutrition, Responsible Health Practice, and 
Psychological Well Being. Each subscale has seven items. Rating of each item is from 0 (not at all) to 
4 (completely). Total scores range from 0-112. Higher scores indicate greater self-efficacy for health 
practices.  
4. Social-demographic Data includes age, gender, ethnicity, religion, marital status, employment status, 
education level, household type/ownership, living arrangement and number of children. Clinical data 
includes chronic conditions, blood pressure, height, weight, smoking and drinking status, exercise 
frequency, and Short physical performance battery (SPPB).  
 
Phase 2 – RCT  
Eligibility and Recruitment – Following identification of high-risk patients for poor metabolic health or 
cognitive functioning, a customized intervention is required to help T2DM patients to better cope with these 
issues. T2DM patients with poor metabolic health or CI have been reported to demonstrate poor self-care 
management and medication adherence [25]. High-risk T2DM patients for poor metabolic health or CI will 
be identified from Phase 1 screening and formal neuropsychological assessments [42], and invited to 
participate in Phase 2 intervention. A 2-arm/group RCT is adopted.  
Group 1:  IAREP Intervention A 12-week Intensive Aerobic and Resistant Exercise Program (IAREP) 
aims to train muscle strength, stability and muscle mass and provide health education on lifestyle for the 
middle-age and older adults with T2DM. Participants with high risk of cognitive impairment will be identified 
from Phase 1 screening (with the recommended cut-off score). IAREP will be conducted for middle-aged 
and older adults with T2DM. After 12-week of IAREP, the same panel of cognitive tests, psychosocial 
assessments and blood tests will be repeated for participants. 
  Group 2: Control Participants will receive usual care at NUP, and they will be evaluated with the same 
panel of cognitive tests, psychosocial survey and blood tests at the end of the study. 
 
Sample Size –For the pilot evaluation sample will choose for 80 subjects in total as Brown (1995) cites a 
general flat rule to ‘use at least 30 subjects or greater to estimate a parameter. Thus, 40 subjects for each 
independent variable for multiple regression and logistic regression in the pilot evaluation study. A 
purposive sample of 25-36 participants will be invited for process evaluation. 
  Randomisation – The participants will be randomly assigned to either e-health intervention or IAREP or 
wait-list control group with computer-generated random numbers. The intervention groups will engage in 
IAREP. Participants in the control will receive usual care at NUP. The researchers will engage the 
participants in the IAREP and follow up with them during the 12-week intervention period via face-to-face 
platform or telephone call to ensure compliance.  
Outcome Measures – include Metabolic profile (HbA1c, plasma insulin), Vascular Dementia Battery 
(VDB), Self-care of Diabetes Inventory, Self-rated abilities for Health Practices Scale, SPPB, Rapid 
Sarcopenia screening (SARC-F), and International Physical Activity Questionnaire – Short Form 
(IPAQ-SF) at baseline and post-intervention. People with T2DM experience more progressive skeletal 
muscle loss than individuals in the non-diabetic population. The SARC-F questionnaire has been 
developed as a possible rapid diagnostic test for sarcopenia which defined as an age-associated loss of 
muscle mass. There are 5 SARC-F components: Strength, Assistance with walking, Rise from a chair, 

 
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Climb stairs and Falls. The scores range from 0 to 10, with 0 to 2 points for each component. A score 
equal to or greater than 4 is predictive of sarcopenia and poor outcomes. The IPAQ-SF questionnaire 
assesses daily physical activities by asking individuals about their engagement in vigorous activities (e.g., 
heavy lifting), moderate activities (e.g., carrying light loads), and walking over the past 7 days. 
Participants report how many days they performed these activities and the duration for each. It also 
includes questions about time spent sitting during weekdays. The IPAQ-SF provides valuable insights into 
physical activity levels, aiding in health risk assessments and lifestyle improvements. 
  Process Evaluation – The purpose of process evaluation is to assess the acceptability, strengths and 
limitations of the IAREP based on the participants’ perspectives. A qualitative approach with in-depth, focus 
group discussion (FGD) will be used. Participants from the intervention group will be invited. A semi-
structured interview guide will facilitate the questions asked in the FGD. The qualitative data will provide 
valuable information on the experience and perspectives of the participants. 
  Data Collection Procedure – Recruitment and data collection will start upon ethical approval. The data 
collection process, from recruitment to administration of questionnaires, cognitive tests, blood sampling will 
be done by the research team. Potential participants attending NUP will be screened by primary care 
nurses, in which participants will be recruited by NUS RAs. All enquiries pertaining to the study will be 
answered and the study shall commence after obtaining the consent. Confidentiality will be maintained. 
Self-reported questionnaires will be administered. To avoid study participant selection bias, for the older 
participants who have difficulty to read and understand the survey, the researchers will use conversational 
style to engage the participants. The data collection for each participant will take about 40-45 minutes. For 
process evaluation, the FGD will be conducted according to the participants’ preferred language in either 
English or Chinese. The research assistant will arrange appointments with participants for the FGD. Each 
FGD consists of 5-6 participants and lasts for 45-60 minutes. Four to five FGDs will be conducted. 
  Data Analysis – Descriptive statistics will be used to summarize the demographic and clinical data. 
Analyses will be conducted at a significance level of p<0.05 using IBM SPSS (Version 27). In Phase 1, 
multiple linear regressions will be conducted to examine associations among different measurements. 
Cognitive impairment based on formal neuropsychological assessments and serum biomarkers such as 
HbA1c levels will be considered as outcome variables, adjusted by subject demographics, physical 
measurements, brief cognitive tests (MoCA, SDMT), and self-care ability. Next, logistic regression will be 
adopted to derive the RSS. Subjects’ cognitive status (CI vs non-CI) determined by formal 
neuropsychological assessment will be its dichotomized outcomes. All risk factors of interest (e.g. 
sociodemographic, medical history, biomarkers, MoCA and SDMT scores) will be examined using Chi-
squared tests or independent t-test to assess association with cognitive status. Significant factors will then 
be included in the logistic regression model and risk scores will be derived from the respective β-
coefficients. The area under receiver operating characteristic (ROC) curve will be assessed to determine 
the optimal cutoff for the Risk Stratification Score (high, medium, low risk).   
   In Phase 2, outcome measures before and after intervention will be tested for mean differences by paired-
sample Student’s t-test. For the process evaluation, the audio-recorded FGDs will be transcribed into either 
English or Chinese verbatim scripts respectively. The transcripts will be analysed in its original language to 
capture the perspectives of the participants closely. Thematic analysis using Braun and Clarke’s [47] six 
steps of analysis will be applied to provide in-depth and rich analysis of the verbatim. All themes and sub-
themes will be translated to English during report writing by the bilingual research team members to ensure 
the meaning of the translated themes and sub-themes are congruent to the participants’ views.  
  Ethical Issues – Domain Specific Review Board approval will be obtained. The principal investigator and 
co-investigators will explain the purpose of the research to potential participants. Informed consent will be 
obtained from the participants prior to data collection. The participants will be reassured that participation 
in the study is voluntary, and withdrawal from the study will not result in any negative consequences to their 
usual care.  
 
Research Team 
Dr. Wu Xi Vivien is experienced with geriatric and community care, diabetes management and 
technology-enhanced interventions. Dr. Wu has experience in managing grants. As PI, Dr. Wu oversees 

 
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the project, e.g., ethical application, recruitment, intervention, data collection and analysis, report writing, 
and coordinating with various team members and stakeholders. Dr. Wu, A/P Lu and Dr. Dong have 
worked on a prior project (CeHP) and published a number of papers on high impact peer-reviewed 
journals.  
A/Prof. Lu Jinhua is an immunologist who contributes to the understanding of inflammatory status in 
T2DM patients. Adiponectin is a molecule closely related to C1q which is a key molecular target of 
research in his laboratory. For this project, all laboratory-based work will be conducted in his laboratory. 
Dr. Dong Yanhong Catherine has clinical research expertise in neuro-cognition, especially in cognitive 
screening instrument development and validation for the Singaporean population. She has also 
developed a brain health program for older adults attending memory clinics and community-dwelling 
stroke patients. Her role in this project is to train RA for cognitive assessments and analyze the cognitive 
data.  
A/Prof. Zhou Wentao is the Program Director for Master in Nursing, Advanced Practice Nurse (APN) at 
NUS. Her role is to assist with translating the research findings into practice by developing workshops for 
APNs and primary care nurses to adopt the Risk Stratification Score screening and IAREP.  
Dr. Yeo Hui Nan is an Associate Consultant, family physician at NUP, and specializes in treatment for 
T2DM patients. Dr Yeo advises on the feasibility of the study and supports the recruitment process.  
Ms. Wang Na is an APN at NUP. She is experienced in primary care for T2DM patients. She supports the 
recruitment process, logistic issues and the intervention. Dr. Yeo and APN Wang will ensure the 
continuity of the project by translating the RSS and IAREP into clinical practice at NUP. 
 
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