Minimal Effective Dose of Resistance Training for Glycaemic Control in Type 2 Diabetes Mellitus
A Three-Phase Evidence Synthesis, Protocol Validation, and Randomised Controlled Trial
Candidate: Muhamad Faiz bin Alias, Faculty of Sports Science and Recreation, Universiti Teknologi MARA (UiTM)
Main supervisor: Prof Dr. Hashbullah bin Ismail, Faculty of Sports Science and Recreation, UiTM
Co-supervisors: Dr. Mazlifah binti Omar, Faculty of Medicine; Prof. Dr. Sazzli Shahlan Bin Kasim, Cardiovascular Advancement and Research Excellence Institute (CARE)
4sets per muscle group per week
60-80%of 1RM
1-3repetitions in reserve
2sessions per week
12weeks
The intervention arm of the Phase 3 trial in one line (Sections 2.4 and 3.4.5). Test your own prescription against it on the minimal effective dose page.
Why this question
Scientific gapThe RT dose-response relationship for glycaemic outcomes has not been characterised, unlike aerobic exercise.
Translational gapClinicians have no evidence-based, low-burden RT prescription defined by a minimal effective dose.
Type 2 diabetes mellitus (T2DM) affects an estimated 537 million adults worldwide and 18.3% of Malaysian adults, with physical inactivity compounding cardiovascular mortality risk despite optimal pharmacological management. Resistance training (RT) offers a mechanistically distinct, insulin-independent pathway to glycaemic control through contraction-mediated GLUT4 translocation, yet no minimal effective dose (MED) has been established for T2DM populations, and current clinical practice guidelines recommend RT without operationalised volume, intensity, or frequency parameters. This doctoral research programme addresses this translational gap through a three-phase, evidence-to-trial research architecture. The exploration phase comprises two evidence-synthesis studies: a systematic review and meta-analysis of structured exercise programming for cardiorespiratory fitness and inflammatory outcomes in T2DM (Study 1a), and a systematic review isolating RT dose parameters - training volume, intensity, session frequency, and proximity to muscular failure - as predictors of glycaemic control and body composition outcomes (Study 1b). The validation phase appraises the methodological quality of existing exercise guidelines using the AGREE II instrument (Study 2a) and develops a SPIRIT-compliant randomised controlled trial (RCT) protocol (Study 2b). The final phase is a 12-week, two-arm, parallel-group RCT (target n = 70) conducted at Hospital Sultan Al-Abdullah (HASA), Puncak Alam - a UiTM-affiliated hospital and health centre - comparing a novel MED-informed RT programme - four sets per muscle group weekly at 60–80% one-repetition maximum, one-to-three repetitions in reserve, delivered across two weekly sessions - against usual care, with glycated haemoglobin (HbA1c) as the primary outcome and muscle thickness, body composition, functional exercise capacity, and patient-reported outcomes as secondary endpoints. The programme is designed to resolve a scientific gap (the absence of an established RT dose-response relationship for glycaemic outcomes, in contrast to aerobic exercise), a translational gap (the lack of an implementable, evidence-based prescription for clinicians), and an equity gap (the mismatch between resource-constrained Malaysian primary care delivery and conventional high-volume RT protocols). Findings are anticipated to inform revision of the Malaysian Clinical Practice Guidelines for T2DM management and to provide a scalable, physiotherapist-assistant-deliverable exercise model for resource-limited primary care settings in Malaysia and comparable middle-income contexts.
type 2 diabetes mellitusresistance trainingminimal effective dosedose-responseglycaemic controlrandomised controlled trial
Using this site
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Chapter 1 · Sections 1.1 - 1.2
Background and Problem
The epidemiological case and the problem statement behind the programme.
1.1Background of the Study
Type 2 diabetes mellitus (T2DM) ranks among the most consequential non-communicable diseases of the twenty-first century, imposing an inequitable clinical, economic, and mortality burden across both high-income and low-to-middle-income countries. The International Diabetes Federation reported that more than 537 million adults were living with diabetes worldwide in 2021, a figure projected to reach 783 million by 2045, with the steepest rises concentrated in Southeast Asia and the Western Pacific regions (Magliano & Boyko, 2021).
Malaysia currently has a very worrying destiny in this global destiny. According to the National Health and Morbidity Survey (NHMS) 2019, Malaysia had an age-standardised prevalence of diabetes at 18.3% amongst adults aged 18 years and above, and is one of the countries with the highest prevalence of diabetes in the Southeast Asian region (Ganapathy et al., 2019). Diabetes and its associated comorbidities, including hypertension and hypercholesterolaemia, remain the predominant non-communicable disease burden among Malaysian adults, a pattern that has persisted across successive national surveillance cycles (Ganapathy et al., 2019). The burden is not limited to the general population; the prevalence of diabetes among the adult indigenous Orang Asli in Peninsular Malaysia was 16.1% (95% CI: 14.3-17.9%), and was significantly higher among the elderly age group (60 years and above), urban population (21.1%) and persons with concurrent hypertension (24.2%) in the Orang Asli Health Survey 2022 (Ismail et al., 2026).
The high prevalence of undiagnosed T2DM cases, sub-optimal glycemic control among identified cases and increasing physical inactivity rate (a modifiable primary risk factor) further exacerbate the epidemiological burden of T2DM in Malaysia. Physical inactivity is disproportionately prevalent among older Malaysian adults, and T2DM has been independently associated with elevated odds of physical inactivity in this age group. This vicious circle is bidirectional, with T2DM driving physical inactivity and physical inactivity driving glycaemic deterioration, and with direct disease progression and macrovascular implications.
In Malaysia, cardiovascular disease (CVD) stands out as a leading contributor to mortality among people with T2DM. Data from a large Asian cohort of 103,958 patients with T2DM, drawn from the Joint Asia Diabetes Evaluation (JADE) Register at University of Malaya and including Malaysian participants, showed a CVD incidence of 61.60 per 1000 person-years among those with prior CVD compared with 11.65 per 1000 person-years among those without, while only 1.5% and 5.1% of the two groups respectively had achieved all three cardiometabolic targets at baseline (Lim et al., 2023). The data highlight the massive treatment failure rate of current drug treatments in preventing downstream mortality and confirms the importance of non-pharmacological, adjunctive therapies, most notably structured exercise.
Despite a substantial international evidence base establishing exercise as an effective insulin-sensitising therapeutic modality in T2DM, its uptake into clinical practice within Malaysia remains limited. One of the most important and unresolved challenges is the lack of clear operationalized and evidence-based dosing parameters for resistance training (RT), the most direct modality to target skeletal muscle, the site of the largest postprandial glucose disposal. The present research proposal is specifically geared toward resolving this translational gap with a three-phase research architecture of evidence to trial. The exploration phase involves four evidence synthesis studies: systematic reviews and meta-analysis of different exercise intervention for T2DM population, and a systematic review of RT dose-response. The validation stage involves a methodological quality assessment of current clinical practice guidelines and protocol development and registration of the trial. The final stage involves a randomized controlled trial to compare the novel MED-informed RT programme with usual care delivered in the primary health care system in Malaysia. The evidence base for exercise and resistance training, underpinning this programme, is summarized in a comprehensive review in Chapter 2.
1.2Problem Statement
Type 2 diabetes mellitus constitutes a public health emergency of epidemic scale, driven not only by rising prevalence and mortality but also by the absence of consensus regarding which non-pharmacological interventions are effective and how they translate into practice. This is a critical scenario in Malaysia, with a prevalence of diabetes of 18.3% in adults, and a significant proportion of older adults with T2DM who are physically inactive, while a majority of them are dying due to CVD, and current pharmacological treatments do not adequately address this situation (Ganapathy et al., 2019; Lim et al., 2023). Resistance training is the exercise modality most mechanistically suited for this population, given its ability to induce insulin-independent GLUT4 translocation pathways which form the main glucose disposal site in that tissue, and which are not impaired by advanced insulin resistance. However, over the past decades, although some RT efficacy research has been conducted in T2DM, there is no consensus on the minimum training dose necessary to induce clinically relevant metabolic improvements.
Current clinical practice guidelines for T2DM (Malaysian Clinical Practice Guidelines for T2DM) and for the Standards of Care by the ADA (ADA Standards of Care) recommend RT in general terms, based on the frequency of the sessions, and the extent of major muscle groups covered, but do not define the minimal volume (per week), intensity (threshold) or proximity-to-failure (criteria) that would mean a prescription is either therapeutically effective or ineffective. The recommendations are based on information from general population strength training literature, and not on dose-response evidence in T2DM, which leads to an empirically unsupported prescription framework for the clinical population they aim to serve. This leads to either over-prescription (prescription is too complicated and involves too much exercise for someone to maintain and so they drop out and exercise fails to have an effect on glycaemia) or under-prescription (exercise is not enough in terms of intensity or frequency to achieve any measurable glycaemic effect, and therefore may reinforce clinical scepticism towards exercise as a therapeutic intervention).
In addition to the previously mentioned dose-response issue, the dose-response evidence presented in Chapter 2 highlights another fundamental problem with RT: whereas the volume-dependent dose-response relationship for aerobic exercise has been clearly established with HbA1c, such a relationship has not been established for RT alone. The meta-regression of 26 RCTs (Umpierre et al., 2013), and the individual-participant analysis of the DARE trial (Benham et al., 2020), both reported a lack of any association between RT volume, frequency or adherence and glycaemic response. However, short training durations (one set per exercise) and relatively high intensities (specifically to or near the point of muscular failure) have been shown to yield clinically relevant and persistent reductions in HbA1c levels, body composition, and insulin sensitivity in T2DM patient cohorts(Giessing et al., 2022; Piralaiy et al., 2025). It is a paradox that, despite the lack of evidence that volume predicts glycaemic benefit, low-volume protocols are still able to achieve glycaemic benefit, a question that has not yet been investigated systematically, and which has not been the primary focus of a systematic review or meta-analysis to date.
A systematic review of the minimal dose of RT required to elicit clinically meaningful glycaemic and body composition benefits (Study 1b of the exploration phase of the current research) returned no results in a targeted search of the three databases PubMed, Scopus and Web of Science. Study 1a will explore the evidence base further, using a systematic review and meta-analysis of exercise programming for T2DM. The two outputs of the exploration phase will create both the content and the context of the evidence gap. The validation phase will then evaluate the methodological quality of the existing clinical practice guidelines, applying the AGREE II instrument, and create the registered trial protocol, thus forming the methodological groundwork for the subsequent phase of the RCT.
The research question is therefore defined as follows: What is the minimum safe and effective dose of resistance training, as measured by the dose parameters of volume, intensity, frequency and time, needed to produce clinically meaningful improvements in glycaemic control and body composition in non-insulin-dependent adults with T2DM has yet to be determined by prospectively designed, adequately powered clinical trial. There are three dimensions to this gap. The dose-response relationship for RT-specific metabolic adaptation in T2DM is structurally different from that of aerobic exercise, and has not been characterised by the existing literature, which is a scientific gap. Second, it's a translational gap: Clinicians are unable to make evidence-based exercise prescriptions that are minimally burdened and maximally effective without a defined MED. Third, it is also an equity gap as in a Malaysian clinical context, with limited physiotherapy resources, patient time and mobility and limited patient motivation, the lack of a MED-informed prescription protocol is directly affecting the reach and the impact of exercise as a diabetes management tool. The three phase research programme proposed in this proposal (the exploration phase including 4 evidence synthesis studies, the validation phase including guideline quality appraisal, protocol development, and a randomised controlled trial) is proposed to address this gap in a systematic, evidence-based and contextually relevant way.
Chapter 1 · Section 1.3
Aim, Objectives and Questions
One aim, five objectives and eight research questions, mapped to each other.
1.3Research Aim, Objectives, and Questions
1.3.1Research Aim
This research programme's central aim is to establish the minimal effective dose (MED) of resistance training needed to achieve clinically meaningful gains in glycaemic control and body composition among non-insulin-dependent adults with type 2 diabetes mellitus, using a three-phase, evidence-to-trial research architecture comprising an exploration phase (two evidence synthesis studies), a validation phase (guideline quality appraisal and trial protocol development), and a randomised controlled trial comparing the novel MED-informed RT programme against usual care in the Malaysian primary care setting.
1.3.2Research Objectives
These objectives are sequenced across the programme's three phases. The exploration phase maps the structural landscape of the existing literature by means of a systematic review and meta-analysis; the programme then proceeds to develop and validate the exercise programme alongside the study protocol, after which the intervention is ready for clinical testing.
Objective 1a (Exploration Phase - Exercise Programming SR and MA): To conduct a systematic review and meta-analysis of randomised controlled trials examining the effects of structured exercise programming on cardiorespiratory fitness and inflammation marker in T2DM population.
Objective 1b (Exploration Phase - Minimal Effective Dose Systematic Review): To conduct a systematic review of published and registered studies that isolate resistance training dose parameters, specifically training volume, exercise intensity, session frequency, and proximity to muscular failure, as predictors of glycaemic control and body composition outcomes in adults with T2DM.
Objective 2a (Validation Phase - Guideline Appraisal): To appraise the methodological quality of current exercise guidelines that incorporate resistance training recommendations for adults with T2DM using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument.
Objective 2b (Validation Phase - Trial Protocol Development): To develop, register, and publish the methodological protocol for the randomised controlled trial evaluating the novel MED-informed RT programme in T2DM in the Malaysian primary care setting.
Objective 3 (RCT Phase): To evaluate the clinical efficacy of the novel MED-informed RT programme, compared with usual care, on glycaemic control (HbA1c), muscle thickness, body composition, functional exercise capacity, cardiometabolic risk markers, exercise self-efficacy and health-related quality of life in non-insulin-dependent adults with T2DM over a 12-week intervention period conducted within the Malaysian primary care setting.
1.3.3Research Questions
Each research question below maps onto its corresponding objective across the programme's three phases and is framed so that it can be answered directly by the methods set out in the relevant study protocol.
Research Question 1a: What is the aggregate effect of structured exercise programming on cardiorespiratory fitness and inflammation markers in adults with T2DM, and does exercise modality (aerobic, resistance, or concurrent training) significantly moderate the magnitude of this effect?
Research Question 1b: Is there an identifiable minimal effective resistance training dose, characterised by its volume, intensity, frequency, and proximity-to-failure parameters, that has been demonstrated to produce clinically meaningful improvements in glycaemic control and body composition in adults with T2DM, and if so, what are its defining parameters?
Research Question 2a: What is the methodological quality of current exercise guidelines incorporating resistance training recommendations for adults with T2DM, as assessed by the AGREE II instrument across its six domains?
Research Question 2b: Does the RCT protocol for the novel MED-informed RT programme satisfy pre-specified methodological criteria, including trial registration, peer-reviewed protocol publication, and allocation concealment integrity, sufficient to proceed to full-scale implementation?
Research Question 3a: Does the novel MED-informed RT programme produce a clinically meaningful absolute reduction in HbA1c (minimum threshold: 1.0 percentage point) compared with usual care at 12 weeks in non-insulin-dependent adults with T2DM in the Malaysian primary care setting?
Research Question 3b: Does the novel MED-informed RT programme produce superior improvements in muscle thickness and body composition (lean mass, fat mass, waist circumference), functional exercise capacity (Incremental Shuttle Walk Test), and cardiometabolic risk markers (blood pressure, resting heart rate) compared with usual care at 12 weeks?
Research Question 3c: What is the programme adherence rate, and do participants achieving the predefined compliance threshold of 70% or more of prescribed sessions demonstrate significantly greater improvements in primary and secondary outcomes relative to those below this threshold?
Research Question 3d: Does the novel MED-informed RT programme produce greater improvements in exercise self-efficacy, as measured by the Malay-validated version of the Exercise Self-Efficacy Scale, and health-related quality of life, as measured by the Malay-validated version of the 36-Item Short Form Health Survey (SF-36), compared with usual care at 12 weeks?
Chapter 1 · Sections 1.4 - 1.5
Significance and Scope
Who benefits, and where the programme stops.
1.4Significance of the Study
The research project has multiple implications including applied value in the patient level, healthcare level and policy making level as it relates to non-communicable disease management in Malaysia. The programme's structured evidence synthesis and then appraisal of guidelines and validation of protocols will be followed by a clinical trial that will ensure that the knowledge produced at each stage is put into action at a corresponding level of the health care system.
1.4.1Individual and Patient-Level Significance
In terms of individual and patient care, the key significance of this research is that adults with T2DM have access to a scientifically validated, low burden exercise prescription, based on T2DM-specific dose response evidence, not extrapolated from the general population. Concurrently, Malaysian T2DM patients are often overweight/obese, hypertensive and dyslipidaemia and often take multiple medications (pill burden) that are not adherent to (Ministry of Health Malaysia, 2020). In this population, the availability of an evidence-based RT programme with clearly defined minimum effective parameters has clear clinical benefit in that it eliminates the “how much is enough?” confusion, diminishes the weight of the time and effort barrier which is the most important obstacle to exercise participation and offers a credible, physiologically based alternative or adjunct route to glycaemic control. The individual patient will benefit from a clinically significant HbA1c reduction with a reduced pharmacological burden, improved body composition with maintenance of lean mass, improved functional exercise capacity (ISA) as assessed by the Incremental Shuttle Walk Test, and lower cardiometabolic risk profile if the RCT phase proves that the patients benefit from a clinically significant reduction of HbA1c after only a low volume of exercise per day, two sessions per week, but very high intensity. If the RCT phase confirms that the patients can gain a clinically significant reduction of HbA1c after a low volume of exercise per day, two sessions per week, but very high intensity, then they will benefit from a reduced pharmacological burden, improved body composition (maintenance of lean mass), improved functional exercise capacity (ISA) as assessed by the Incremental Shuttle Walk Test, and a lower cardiometabolic risk profile, and they will benefit at a time commitment that is much shorter than the conventional multi-set programmes. This is especially important for the aging population of Malaysia with T2DM because the combination of loss of muscle mass, decreased exercise tolerance and fear of exercise-induced hypoglycaemia are all barriers to exercise initiation that a precisely calibrated MED prescription will address.
1.4.2Institutional Significance
The impact of this research at an institutional level lies with hospitals, Primary Care clinics, physiotherapy departments, and university-based health science programmes involved in diabetes management and research. The physiotherapy workforce in Malaysian public healthcare institutions is well reported to be constrained with the ratio of physiotherapists to the population significantly lower than that recommended by WHO. A standardised MED-informed RT protocol which only needs two supervised sessions per week, can be delivered by trained physiotherapy assistants under qualified supervision and requires no specialist equipment other than traditional resistance training equipment, provides a scalable, cost-effective exercise-delivery model capable of straightforward adoption within the existing primary care physiotherapy service. The exploration phase's two outputs, namely the systematic review and meta-analysis of exercise programming together with the dose-response systematic review, will also serve as structured, peer-reviewed reference materials for clinical physiotherapy and exercise science academic departments, universities in Malaysia, for curriculum development, postgraduate research training and systematic evidence appraisal competency. The AGREE II guideline appraisal subscale of the validation process will produce standardized, domain-specific quality assessments of international and Malaysian CPGs, which will give institutional research programmes a replicable methodological template to follow for evaluations of CPGs in the future.
1.4.3Policy and Systemic Significance
The value of this research lies at the policy-making level, where its results can be expressed in its ability to fill a reported gap in the Malaysian Clinical Practice Guidelines (CPG) for the Management of Type 2 Diabetes Mellitus, similar to most clinical practice guidelines found in international literature, which suggest resistance training in general without operational actionable dose parameters. The independent instrument-validated assessment in the AGREE II appraisal in the validation phase will determine whether the resistance training recommendations that are included in current CPGs are based on well-established processes of evidence synthesis, especially in the Rigour of Development and the Applicability domains. The assessment will produce an accurate, quantitative evidence base that will be available for the CPG revision committees at the Ministry of Health Malaysia, enabling them to have the required methodological quality data to support their decision to update the diabetes CPG to include RT prescription parameters specific to MED. A systemic perspective is needed to consider the cost-effectiveness impact, directly relevant to the national health financing framework of the Ministry of Health, and the National Strategic Plan for Non-Communicable Diseases, if the RCT phase confirms that a minimal-dose RT programme is clinically meaningful in a Malaysian primary care context. Exercise referral pathways, community exercise programmes and the national diabetes register could all be modified to include MED-informed RT prescription, thus expanding the evidence-based exercise treatment to a population that is currently under-represented in either pharmacologic or nonpharmacologic treatment options.
1.5Scope and Limitations of the Study
This section identifies the boundaries within which the current research is conducted and the methodological and contextual limiting factors that impact on the generalisability and inferential power of the results of the current research.
1.5.1Scope
The research programme is designed for adults (aged over 18 years) with clinically established type 2 diabetes mellitus who are currently treated with oral hypoglycaemic drugs without insulin administration. Resistance training is the main therapeutic approach being explored. The aerobic training and concurrent training interventions are discussed as comparators in the exploration phase evidence syntheses, but are not interventions in the RCT phase. The major outcomes of interest are glycaemic control (glycated haemoglobin [HbA1c]) and body composition (lean mass and fat mass via bioelectrical impedance analysis). Other outcomes are functional exercise capacity and cardiometabolic risk markers. The geographical focus of the RCT phase is limited to the Malaysian primary care setting because the aim of the translational objective is to produce evidence that will be directly applicable in the Malaysian healthcare system.
The scope boundaries for each phase of the research programme are determined by the methodological needs of the study design for each phase. The exploration phase bibliometric analysis only works with literature indexed in Web of Science and Scopus databases; it has no way of accounting for literature that is not indexed in these databases (grey literature, conference proceedings, non-English publications). The two systematic evidence syntheses in the ‘exploration’ phase are limited by the inclusion criteria detailed in the registered protocol and only randomised controlled trials or controlled trials with clearly defined exercise dose parameters and glycaemic or body composition outcomes in T2DM populations are included. The validation phase is limited to appraisal of clinical practice guidelines with clear recommendations for resistance training that were published or updated in the last decade and development of the RCT methodology (not efficacy evidence). The RCT phase is a 12-week, two arm, parallel group design with only one primary care setting in Malaysia.
1.5.2Limitations
There are a number of methodological constraints on the exploration phase. Bibliometric analysis is also database dependent and citation indexing dependent, and the results can be influenced by the indexation of literature from Southeast Asian nations compared to that from high income countries. In the phase, systematic reviews or meta-analyses can be performed and may be subject to between-study heterogeneity (due to differences in variables of the participants, the exercise prescription parameters, measures to assess the outcomes and the follow-up period), which could reduce the precision and interpretability of the pooled effect estimates. When the number of studies is small, however, there is no single correction method that will completely address the publication bias; this publication bias can only be partially detected using a funnel plot inspection. The AGREE II validation phase domain score is a measure of the quality of the methodological process used to develop a resistance training guideline and does not demonstrate evidence support of the resistance training recommendations in the guideline; a high AGREE II domain score does not imply that the resistance training recommendations in the guideline are evidence-supported. The RCT phase may have limitations associated with the design and context of the RCT. Blinding of participants and exercise physiotherapists who deliver the intervention is not possible in exercise trials, and thus allows for the possibility of performance bias and expectation effects. The single-centre design decreases the external generalisability of the results to other Malaysian primary care settings and to the T2DM population in other Southeast Asian or international contexts. While a 12-week intervention is adequate to observe meaningful changes in HbA1c with resistance training (due to the 8-12-week lifespan of the erythrocytes), this period may not be enough to achieve the progressive hypertrophic gains that are usually seen following resistance training over 16-24 weeks. When performing body composition assessment by bioelectrical impedance analysis, there is some measurement error compared with the reference standard for lean and fat mass quantification, dual-energy X-ray absorptiometry, and it can be sensitive to hydration status and food consumption in the hours leading up to measurement. Recruitment only from one clinical centre could also lead to a non-representative sample in terms of ethnicity, socio-economic status and comorbidity burden among the Malaysian population with T2DM.
Chapter 1 · Sections 1.6 - 1.7
Operational Definitions
How key terms are used throughout the programme.
1.6Operational Definitions
The following operational definitions specify the precise meaning of key terms as used throughout this research programme. Definitions are grounded in consensus clinical criteria, validated measurement instruments, or established exercise science terminology.
1.7Conclusion
This chapter has established the foundations for the research programme. The epidemiological evidence indicates that type 2 diabetes mellitus represents a public health emergency of particular severity in Malaysia, reflected in its high adult prevalence (18.3%), the elevated rate of physical inactivity among those diagnosed, and the persistence of cardiovascular mortality despite current pharmacological management. Mechanically different from other forms of exercise, resistance training is the most physiologically relevant form of exercise for this population because it restores glucose uptake by insulin independent pathways which remain functional when insulin is advanced. However, the minimum dose that would result in clinically meaningful glycaemic benefit has not been empirically determined, and a systematic review of the evidence as part of this programme found no published reviews addressing the question of the minimal effective dose for RT.
The two evidence synthesis studies in the exploration phase, the guideline quality appraisal and protocol development in the validation phase, and the RCT phase in the third phase of the research architecture described in this chapter is a structured and methodologically rigorous pathway from evidence characterisation to a prospective clinical test. The aims, objectives and research questions outlined in Section 1.3, the multidimensional significance outlined in Section 1.4 and the scope and operational definitions outlined in Sections 1.5 and 1.6 are all interdependent in defining the investigative boundaries and expected scholarly contributions of this programme. The theoretical and empirical literature that informed the research is critically reviewed in Chapter 2, including the mechanisms of exercise-induced glycaemic adaptation in T2DM, the evidence in support of a dose-response relationship for resistance training, and the conceptual model for integration of the dose-response framework.
Chapter 2 · Sections 2.0 - 2.1
Exercise Modalities
Aerobic, resistance and concurrent training compared on the evidence the proposal cites.
2.0Introduction
This chapter critically synthesises the theoretical and empirical literature that underpins the present research programme, with the review organised thematically to mirror the sequential evidence architecture of the research questions.
2.1Exercise as a Therapeutic Modality in Type 2 Diabetes Mellitus
Exercise training is a well-established component of non-pharmacological management for T2DM. Major international clinical guidelines, including those of the American Diabetes Association (ADA) and the American College of Sports Medicine (ACSM), recommend a minimum of 150 minutes per week of moderate-to-vigorous physical activity for individuals with T2DM, incorporating both aerobic and resistance components. The evidence base underpinning these recommendations, however, is derived from a heterogeneous body of literature encompassing three principal exercise modalities: aerobic training, resistance training (RT), and concurrent training (CT), each exerting distinct physiological effects on glucose homeostasis.
Aerobic exercise training represents the most popular exercise modality in T2DM management. A systematic review and meta-analysis of 34 randomised controlled trials (RCTs; n = 1,391) demonstrated that aerobic exercise produced significant reductions in glycated haemoglobin (HbA1c; SMD = -0.79%), fasting blood glucose (FBG; SMD = -0.49 mmol/L), and insulin resistance as measured by the homeostatic model assessment (HOMA-IR; SMD = -0.72) in adults with T2DM and concurrent overweight or obesity, relative to standard treatment (Al-Mhanna, Alghannam, et al., 2025). High-intensity interval training (HIIT), a form of aerobic exercise involving alternating bouts of near-maximal and recovery effort, has additionally demonstrated superiority over moderate-intensity continuous training (MICT) for reducing FBG and improving maximal oxygen uptake (VO2max) in T2DM populations, based on a meta-analysis of 21 RCTs involving 831 patients (Ren et al., 2026). A further meta-analysis of 26 RCTs (n = 790) confirmed that HIIT produced significantly greater reductions in fasting insulin (SMD = -0.43) and HOMA-IR (SMD = -0.52) compared to MICT, alongside superior cardiorespiratory fitness gains (VO2max; SMD = 0.53) (Al-Mhanna, Poon, et al., 2025)
Resistance training, characterised by progressive mechanical loading of skeletal muscle through free weights, machines, or body-weight exercises, has emerged as an equally efficacious modality with mechanistic pathways that are complementary to, and in some respects superior to, aerobic exercise in the context of T2DM. A systematic review and meta-analysis of 18 RCTs (n = 1,180) published in the British Journal of Sports Medicine demonstrated that RT as a standalone intervention produced significant improvements in FBG (SMD = -0.65 mmol/L), fasting insulin (SMD = -0.74 uIU/mL), HbA1c (SMD = -0.32%), waist circumference (SMD = -0.85 cm), and lipid profile versus standard care (Al-Mhanna, Franklin, et al., 2025) . In middle-aged and older adults with T2DM specifically, a meta-analysis of 33 RCTs (n = 1,396) reported that RT reduced HbA1c by -0.62%, HOMA-IR by -0.90, and systolic blood pressure by -3.91 mmHg, while also increasing VO2max (effect size = 0.53) (Zhang et al., 2026). Importantly, a network meta-analysis incorporating 29 RCTs and 10 distinct exercise interventions identified high-intensity resistance training (HIRT) as the highest-ranking modality for HbA1c reduction (MD = -0.62%, 95% CI: -0.93 to -0.30; SUCRA = 78.6%), while moderate-intensity resistance training (MIRT) ranked first for fasting plasma glucose reduction (MD = -29.13 mg/dL; SUCRA = 80.5%) (Yu et al., 2026). These findings collectively position RT not merely as a “sidekick” to aerobic training but as an independent and clinically impactful therapeutic modality.
Concurrent training, defined as the combination of both aerobic and resistance exercise within a structured programme, has been proposed as a strategy to capture the complementary benefits of both modalities. A meta-analysis of 16 RCTs confirmed that concurrent exercise significantly improved HbA1c, FBG, and HOMA-IR in T2DM populations (Amin et al., 2024). A further systematic review and meta-analysis of six studies similarly demonstrated that concurrent exercise training produced significant improvements in glucose levels, HbA1c, HOMA-IR, body composition, lipid profile, inflammatory markers (TNF-α), and cardiorespiratory fitness (VO2peak) in adults with T2DM (Zaki et al., 2024). However, the additional logistical burden, longer session duration, and greater adherence demand associated with concurrent training present practical implementation challenges, particularly in resource-limited clinical settings.
While the therapeutic efficacy of exercise across all three modalities is well-established, critical questions pertaining to the optimal exercise prescription remain unresolved. The existing evidence base is predominantly derived from studies employing heterogeneous and often relatively high training doses, rendering it difficult to identify the minimum threshold of exercise required to produce clinically meaningful metabolic improvements. This dose-response gap is of particular relevance in the context of T2DM management, where patient adherence, time constraints, and physiological tolerance impose real-world limits on exercise volume. The following sections address this gap systematically, first by examining the mechanisms underlying RT's glycaemic effects, and then by outlining the theoretical and empirical framework for the minimal effective dose.
Chapter 2 · Section 2.2
Mechanisms of Glycaemic Adaptation
How contraction restores glucose uptake when insulin signalling is impaired.
2.2Resistance Training in T2DM: Mechanisms of Glycaemic Adaptation
Skeletal muscle is the dominant site of insulin-stimulated glucose disposal under post eating conditions, accounting for approximately 70-80% of whole-body glucose uptake (Młynarska et al., 2025). This quantitative dominance renders skeletal muscle the principal therapeutic target in T2DM, where chronic insulin resistance at the myocellular level drives the progressive deterioration of glycaemic control. Resistance training acts directly upon this target organ, engaging a cascade of biochemical events that promote glucose uptake through mechanisms that are both acute and chronic in nature. The mechanistic understanding of RT's glycaemic effects has advanced substantially over the past decade, revealing a complex interplay between membrane glucose transporter regulation, intracellular signalling kinetics, muscle mass accretion, and systemic endocrine signalling through myokines.
The principal molecular mechanism through which RT improves glucose uptake in T2DM involves the regulation of glucose transporter type 4 (GLUT4). In cellular level, GLUT4 is located intracellularly within specialised vesicles. In T2DM, the insulin signalling cascade responsible for GLUT4 translocation to the plasma membrane, which proceeds via insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt/PKB), and Akt substrate of 160 kDa (TBC1D4/AS160), is fundamentally impaired at multiple stage, most prominently at IRS-1 serine phosphorylation and PI3K activation (Ramos-Jimenez et al., 2026). Critically, however, muscle contraction during RT activates entirely distinct, insulin-independent signalling pathways that converge on the same GLUT4 translocation process. Specifically, contraction-induced activation of AMP-activated protein kinase (AMPK), calcium-calmodulin-dependent protein kinase II (CaMKII), and p38 mitogen-activated protein kinase (p38 MAPK) collectively phosphorylate TBC1D4 and TBC1D1 at Akt-independent residues, releasing the inhibitory constraint on GLUT4 vesicles and driving their translocation to the sarcolemma (Ramos-Jiménez et al., 2026; T. Zhang et al., 2025). The therapeutic implication is of considerable significance: because these contraction-activated pathways bypass the insulin-resistant IRS-1/PI3K axis, RT can restore near-normal acute glucose uptake in T2DM myocytes irrespective of the prevailing degree of insulin resistance.
Show the original Figure 2.1 as printed in the proposalFigure 2.1 Insulin Signalling Cascade for GLUT4 Translocation: Impairment in Type 2 Diabetes and the Modulating Effect of Resistance Training (RT) (source: Ramos-Jimenez et al., 2026)
Beyond the acute translocation response, chronic RT induces quantitatively important adaptations that amplify long-term glucose disposal capacity. Foremost among these is skeletal muscle hypertrophy, the increase in myofibre cross-sectional area consequent to repeated mechanical loading and mTOR-mediated protein synthesis. By expanding the total mass of metabolically active skeletal tissue, hypertrophic adaptations proportionally increase the aggregate surface area available for GLUT4-mediated glucose uptake, the total GLUT4 protein pool per kilogram of body mass, and the capacity for non-oxidative glucose disposal via glycogen synthesis. This body ability to adapt is known as glucose sink. A systematic review and meta-analysis comparing hypertrophy-oriented training (HT) against muscular endurance resistance training (MERT) in T2DM adults confirmed that both modalities produce clinically meaningful improvements in HbA1c, insulin sensitivity, body mass index, waist circumference, and fat mass, with HT additionally improving lean body mass, lipid profile, and C-reactive protein (Acosta-Manzano et al., 2020). These findings indicate that the degree of the anabolic stimulus, and by extension the degree of muscle hypertrophy, is a meaningful modulator of the metabolic response to RT in this population.
Resistance training also exerts systemic glycaemic effects through the secretion of myokines, bioactive peptides produced and released by contracting skeletal muscle that function in both autocrine and endocrine capacities. In the past muscular system was only considered as an organ that move our body. That is not the case today, muscle also known as endocrine organ that secrete messenger hormone into our bloodstream. Among the most extensively characterised are interleukin-6 (IL-6), irisin (encoded by FNDC5), and brain-derived neurotrophic factor (BDNF), each of which has been shown to independently enhance GLUT4 expression, promote mitochondrial biogenesis, and improve whole-body insulin sensitivity. In the context of T2DM, where baseline myokine secretion is often attenuated due to reduced muscle mass and physical inactivity, RT serves to restore and amplify this endocrine signalling network (Młynarska et al., 2025). Concurrent mitochondrial adaptations, including increases in mitochondrial density, oxidative enzyme activity, and electron transport chain capacity, further enhance the skeletal muscle's capacity for oxidative glucose disposal and lipid oxidation, reducing intramyocellular diacylglycerol and ceramide accumulation that are mechanistically linked to IRS-1 serine phosphorylation and insulin receptor dysfunction (X. Zhang et al., 2026).
A substantial body of randomised controlled trial (RCT) evidence supports resistance training (RT) as a treatment for T2DM. A meta-analysis of 33 RCTs (N = 1,396) found that RT reduced HbA1c by 0.62% and HOMA-IR by 0.90% in middle-aged and older adults with T2DM, an effect comparable to first-line oral hypoglycaemic agents in drug-naive patients (Zhang et al., 2026). The sarcopenia-T2DM axis should also be taken into consideration. The vicious cycle of loss of muscle mass and insulin resistance: decreased muscle uptake of glucose leads to further glycaemic deterioration, which further decreases muscle protein mass due to systemic inflammation and glucotoxicity (Młynarska et al., 2025). RT is special because it helps to stimulate muscle growth, enhance insulin-dependent glucose uptake, and decrease systemic inflammation. Although the mechanistic and clinical evidence is compelling, the RT prescription for T2DM, specifically the minimum dose required to induce and sustain these benefits, remains undefined. Identifying this minimum dose is the central aim of this research programme.
Chapter 2 · Section 2.3
The Dose-Response Problem
What is known about resistance training dose and glycaemic response, and what is not.
2.3The Dose-Response Problem in Resistance Training for T2DM
Although the therapeutic efficacy of RT in T2DM is well established, what has not been defined is the minimum training dose required to produce these benefits. Exercise prescriptions for T2DM are typically derived by extrapolation from general strength-training literature or from expert consensus, rather than from T2DM-specific dose-response data (Umpierre et al., 2013). A systematic review of dose-response evidence conducted as Study 1b of the exploration phase of the present research programme identified this gap as a primary unresolved question in the field. Following a combined search of PubMed, Scopus, and Web of Science yielding 544 records, with 77 unique sources after de-duplication, 12 sources met eligibility criteria for narrative synthesis: four secondary analyses that statistically isolated an RT-specific dose parameter, and five primary RCTs or registered trial protocols directly contrasting RT volume or intensity (Alias et al., in review). Critically, a targeted search for the phrase 'minimal effective dose' combined with resistance training and diabetes returned zero results across all three databases, confirming that the RT-specific minimal effective dose question has not previously been the explicit focus of any published systematic review.
The most methodologically direct evidence on RT dose-response in T2DM derives from a meta-regression of 26 RCTs involving 2,253 participants, which modelled the association between exercise dose parameters and HbA1c change separately for aerobic, resistance, and combined training (Umpierre et al., 2013). For aerobic training, session frequency explained a substantial proportion of between-study variance in glycaemic response (weighted r = -0.64), and weekly RT volume was significantly associated with HbA1c change within combined-training trials (weighted r = -0.70). However, when resistance training was analysed as an isolated modality, no dose variable, including frequency, session duration, or intensity, was significantly associated with glycaemic response. This null finding was independently corroborated by a post-hoc dose-response analysis of the Diabetes Aerobic and Resistance Exercise (DARE) trial, which modelled the relationship between individual-participant adherence (percentage of prescribed sessions completed) and HbA1c change across 185 participants (Benham et al., 2020). A significant and clinically interpretable dose-response relationship was observed for aerobic training (beta = -0.0142, p = .016) and combined training (beta = -0.0109, p = .041), but not for resistance training alone (beta = 0.0068, p = .233), with the point estimate directionally opposite to the expected dose-response pattern. An earlier meta-analysis pooling 13 RCTs across populations with abnormal glucose regulation similarly found a clinically meaningful overall RT effect on HbA1c (weighted mean difference -0.48%, 95% CI: -0.76, -0.21) but could not attribute this effect to any specific combination of volume, intensity, or frequency in supplementary dose analyses (Strasser et al., 2010). The convergence of these three independent analyses establishes a striking empirical contrast: unlike aerobic exercise, where a dose-response relationship between training volume and glycaemic benefit is both theoretically expected and empirically confirmed, no such relationship has been demonstrated for RT when examined in isolation. Table 2.1 provides a structured summary of the studies contributing to this evidence base.
Protocol/baseline only; completed glycaemic outcome results not located in this search
Table 2.1 Summary of studies examining resistance training dose-response in type 2 diabetes mellitus
A few primary RCTs with low volume, high-intensity of effort have yielded clinically relevant results in T2DM. Giessing et al., (2022)randomized adults with T2DM into a baseline intervention group or an RT intervention group that was supervised and prescribed to momentary muscular failure, and conducted two to three sessions of either RT or baseline intervention per week. The results were impressive, showing that all the outcomes measured (HbA1c, fasting glucose, waist circumference, body fat mass and lean mass) reached significant improvements that remained stable over an 18-month follow up, despite such low volume. A four-arm RCT by Piralaiy et al., (2025)also showed that a reduced dose RT arm, with one set per exercise and two sessions per week, as well as an embedded combined training arm, led to statistically significant increases in first and second-phase insulin secretion and glucose effectiveness compared to control, without any indication that the higher dose, full-resistance arm (2-3 sets, 3 sessions per week) was superior on these specific metabolic outcomes. Together, these results indicate a threshold, rather than linear dose-response, relationship exists with respect to glycaemic adaptation in T2DM induced by RT: applying a sufficient mechanical stimulus at an appropriate intensity may yield a metabolic return that is less than proportional to increased volumes.
The FORTE study (Yang et al., 2017) is the only study to directly and prospectively test this intensity hypothesis using a volume-equated design (adults with T2DM were randomly assigned to either a high-intensity low-repetition or low-intensity high-repetition arm of RT and aerobic training was kept constant between the two arms). No significant difference in HbA1c levels emerged among the three arms. However, the trial was stopped early for futility, after showing that the likelihood of detecting any between-group difference was low at the planned sample size, causing the null results to have limited inferential power. Given that the early termination was not based on safety, the number of patients enrolled could not be correlated to the likelihood of a true null intensity effect or an underpowered study with a clinically relevant difference, but unable to be detected. Because of this ambiguity, the FORTE trial does not reject the intensity-related hypothesis, but the trial doesn't prove it either, which leaves the matter up to the test.
Evidently, the available dose-response evidence supports a novel and previously inconclusive hypothesis: that training intensity, operationalised as proximity to momentary muscular failure or percentage of one-repetition maximum (%1RM), rather than training volume or session frequency, may be the operative dose parameter governing RT-induced metabolic adaptation in T2DM. This hypothesis is mechanistically plausible. Unlike aerobic exercise, where glycaemic benefit scales substantially with total energy expenditure and cumulative duration of GLUT4 translocation, RT-induced improvements in insulin sensitivity are thought to depend more heavily on the magnitude of mechanical tension and metabolic stress applied to skeletal muscle fibres, stimuli that are more closely coupled to the degree of motor unit recruitment at high relative intensity than to total set volume (Umpierre et al., 2013). An umbrella review of 43 systematic reviews and meta-analyses confirmed that RT produces reliable small-to-moderate HbA1c reductions across a wide range of protocols (Trybulski et al., 2026), but no prior review has examined whether this effect is dose-dependent for RT specifically, or whether a low-intensity, high-volume RT prescription could substitute for a high-intensity, low-volume one without loss of glycaemic efficacy. The absence of an adequately powered, dose-comparison RCT in T2DM represents the principal evidence gap identified by this doctoral research programme, and it is precisely this gap that the RCT phase will prospectively address.
Chapter 2 · Section 2.4
The Minimal Effective Dose
The proposed dose boundary, parameter by parameter. Test a prescription against it below.
2.4The Minimal Effective Dose Concept in Resistance Training
In the context of exercise science, the minimal effective dose (MED) is the smallest training stimulus to elicit a clinically or physiologically meaningful training-induced adaptation, beyond which training-induced adaptations represent less benefit for the additional costs of recovery, tolerability, and adherence. The structure of the concept is similar to pharmacological dose-response modelling, which uses the therapeutic index to indicate the therapeutic window between the minimum effective dose and the maximum tolerated dose; in the case of RT for T2DM, the latter is especially clinically relevant due to the physiological fragility, exercise intolerance, and motivational deficits of this patient population. The MED framework is thus not about the minimum dose but about the precision prescription approach: the lowest dose needed to ensure efficacy will not be sacrificed and patient burden will not be unnecessarily increased, which optimises the adherence and, thus, the long-term metabolic benefit that adherence provides.
Training volume is defined as the total number of sets per muscle group performed within a week, and has been shown to be the most important and modifiable dose parameter for promoting muscle growth and other health benefits in the general RT literature (Figueiredo et al., 2018). The empirical evidence implied that there is a dose-response relationship between weekly volume and hypertrophic adaptation, with the posterior probability that increasing the number of weekly sets increases muscle size being greater than 100%, indicating a monotonic positive between the two variables (Pelland et al., 2026). This relationship, however, is one with strong diminishing returns and Bayesian meta-regression modelling suggests that there is a minimum volume below which reliable hypertrophic adaptation does not occur. The literature from meta-regression and systematic reviews suggests that the minimum threshold is about 4 sets per muscle group per week, and that marginal hypertrophic benefits are smaller with additional sets after this point (Pelland et al., 2026).
The second most important MED parameter is the intensity of the exercise (percentage of 1RM or closer to the momentary muscular failure). A re-examination of the repetition continuum by Schoenfeld et al., (2021) found that loads between 60% and 80% 1RM set for 6 to 15 reps are the optimal hypertrophic zone, and there was no statistically significant difference between hypertrophy gains of heavier loads (>80% 1RM) when training to or near failure. Importantly, a systematic review and meta-analysis of 15 studies that compared training to momentary muscular failure against non-failure training revealed a trivial benefit of MF training on hypertrophy (ES 0.19; 95% CI 0.00, 0.37) and no significant benefit of momentary failure training compared to set failure training (ES 0.12; 95% CI -0.13, 0.37)(Refalo et al., 2023). The results suggest that 1-3 repetitions in reserve (1-3 RIR) is as effective as training to absolute failure for inducing a hypertrophic response, but also significantly decreases the risk of injury, excessive delayed onset muscle soreness and exercise induced hypoglycaemia, which are of particular concern in T2DM populations.
The third MED parameter, training frequency, refers to the number of sessions per muscle group per week. A Bayesian network meta-analysis of resistance training prescription across 172 studies established that two sessions per week per muscle group produce hypertrophic adaptations statistically comparable to higher frequencies, provided that total weekly volume is equated (Currier et al., 2023). A frequency of two sessions per week also aligns precisely with the ADA's minimum resistance training recommendation for adults with T2DM, avoiding the scheduling burden associated with three-to-five-day-per-week programmes that contributes to high dropout rates in clinical exercise trials. The fourth parameter, intervention duration, requires a minimum of 12 weeks for the detection of meaningful changes in lean mass by bioelectrical impedance analysis, the body composition measurement modality most feasible for routine clinical deployment. Together, these four parameters, namely a minimum of four sets per muscle group per week, at 60-80% 1RM within one-to-three RIR, performed across two non-consecutive sessions per week, sustained for a minimum of 12 weeks, define the theoretical MED prescription boundary for RT-induced hypertrophic adaptation in a clinical population.
The novel MED-informed RT programme, which constitutes the intervention arm of the RCT phase of the present research programme, represents the first systematic operationalisation of the MED framework within a T2DM-specific clinical trial conducted in the Malaysian primary care setting. The protocol prescribes the minimum volume threshold of four sets per muscle group per week, intensity within the 60-80% 1RM hypertrophic range, a proximity-to-failure criterion of one-to-three repetitions in reserve (RIR), and twice-weekly sessions sustained over a 12-week intervention period. This prescription is explicitly designed to test whether a minimal but sufficient RT dose, derived from the best available dose-response evidence synthesised across the exploration phase studies and contextualised within the Malaysian clinical environment through the validation phase protocol appraisal, produces clinically meaningful improvements in HbA1c, change in muscle thickness, body composition, and functional capacity in non-insulin-dependent adults with T2DM. The primary scientific value of this approach lies not in demonstrating that RT works in T2DM, which is already established, but in identifying whether a precisely calibrated, minimal prescription is sufficient to produce benefit: a finding that would directly resolve the translational gap between efficacy evidence and real-world clinical implementability in a resource-constrained Southeast Asian primary care context.
Chapter 2 · Sections 2.5 - 2.6
Conceptual Framework
A mechanistic framework linking the three modalities to impairments in type 2 diabetes.
2.5Conceptual Framework
Figure 2.2 sets out an integrated, mechanistically grounded conceptual framework depicting the pathophysiological basis of exercise limitation in T2DM alongside the modality-specific adaptive pathways by which structured exercise training restores metabolic and cardiorespiratory function. The framework maps the principal biological impairments of T2DM across four interconnected domains: vascular and peripheral limitation, myocardial stiffness and reduced cardiac reserve, pulmonary and respiratory mechanical dysfunction, and mitochondrial dysfunction with associated sarcopenia or dynapenia. Each domain is represented as an active pathological node that collectively produces a supply-demand oxygen mismatch, impairs substrate utilisation, and constrains functional exercise capacity in the T2DM population.
The framework includes three exercise modalities (aerobic training, resistance training and concurrent training) and highlights their different therapeutic effects with colour-coded pathways (see figure 2.1). The training named aerobic training is shown to mainly target the oxygen supply system by increasing the cardiovascular efficiency, increasing the cardiac reserve, decreasing the cardiac torsion, enhancing the endothelial nitric oxide (NO) bioavailability, and enabling structural remodelling of the arteries which dampen down the vascular and cardiac contribution to exercise intolerance. Resistance training is documented to work primarily on the oxygen demand system, by both inducing a hypertrophic response which increases the amount of skeletal muscle available for glucose and oxygen utilization, and by activating translocation of the insulin independent GLUT4 to the sarcolemma via AMPK/CaMKII pathway, followed by a restoration of the capacity to utilize glucose without any defect in the impaired insulin signalling axis. Concurrent training encompasses and extends both pathways, additionally improving oxidative phosphorylation (OXPHOS) efficiency through mitochondrial biogenesis mediated by increased citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (BHAD) activity, and augmenting peripheral oxygen extraction through the arteriovenous oxygen difference mechanism.
The conceptual framework is directly relevant to the research questions of the present doctoral programme in two respects. First, it provides the mechanistic basis for selecting resistance training as the primary modality of investigation: the framework demonstrates that RT uniquely targets the demand-side impairments of T2DM, specifically sarcopenia, dynapenia, and impaired insulin-stimulated GLUT4 signalling, through pathways that are structurally independent of insulin resistance and therefore of particular therapeutic relevance to the T2DM phenotype. Second, it contextualises the MED hypothesis within a mechanistic model: if insulin-independent GLUT4 translocation via AMPK/CaMKII is the primary mechanism through which RT produces acute glycaemic benefit, and if this pathway is governed more by the intensity of mechanical stimulus than by the total volume of training, then the intensity-primacy hypothesis proposed in Section 2.3 is mechanistically plausible and merits prospective empirical testing through the RCT phase of this programme.
In this chapter literature has been reviewed which provides a sound theoretical and empirical base for the current research programme. The evidence base also supports the insulin independence of resistance training as a therapeutic modality, its mechanistically distinct effects, and its clinical efficacy in the treatment of T2DM, in part through contraction-induced GLUT4 translocation by activation of the AMPK/CaMKII/p38 MAPK signalling axis, and in part through hypertrophy-enhanced whole-body glucose disposal capacity and systemic effects on insulin sensitivity via secretion of myokines and mitochondrial biogenesis. Aerobic and concurrent training modalities have complementary, but mechanistically different, benefits, with the oxygen supply system and cardiorespiratory reserve being important, while the significant deficit in skeletal muscle substrate utilisation associated with the T2DM phenotype is not the primary target.
Critically, the dose-response evidence reviewed in Section 2.3 reveals that the glycaemic response to RT does not follow the volume-dependent pattern demonstrated for aerobic exercise. Two of the most methodologically rigorous secondary analyses in the field, the Umpierre et al. (2013) meta-regression and the Benham et al. (2020) DARE trial individual-participant analysis, independently found no significant association between RT volume, frequency, or adherence and HbA1c improvement when RT was examined as an isolated modality. In contrast, low-volume, high-intensity protocols trained near or to muscular failure have produced durable glycaemic improvements, supporting the intensity-primacy hypothesis as a plausible mechanistic explanation. The MED framework, grounded in dose-response evidence identifying four weekly sets per muscle group at 60-80% 1RM with one-to-three RIR as the minimum effective prescription boundary, provides the evidence-derived prescription structure for the RCT phase of this programme. The conceptual framework presented in Section 2.5 integrates these mechanistic and clinical bodies of evidence, situating resistance training's demand-side therapeutic mechanisms within the broader exercise-T2DM pathophysiological model and providing the theoretical basis for the intensity-focused MED intervention design.
The evidence reviewed in this chapter supports the conclusion that the minimal effective dose question for the RT is unresolved and is clinically important and that the three-phase research structure outlined in Chapter 1 is a suitable and scientifically sound approach to address it. The research methodology for each phase of the programme is described in Chapter 3, which outlines the study designs, eligibility criteria, outcome measures and statistical analysis plans that will be used to empirically answer the research questions defined in Chapter 1.
Chapter 3 · Sections 3.0 - 3.1
Research Design
A sequential three-phase design, from evidence synthesis to trial.
3.0Introduction
This chapter sets out the methodical approach adopted throughout the present research programme. The study's methodology has been planned as a series of sequential mixed methodology, wherein evidence will be gathered to validate guidelines and to test the guidelines in practice. The two systematic investigations in phase 1 (Exploration) will aim to explore and characterise the landscape of exercise programming for type 2 diabetes mellitus (T2DM) and to operationally define the minimal effective dose (MED) of resistance training. Phase 2 (Validation) will be an external review of the evidence synthesised and the formal protocol development. This will culminate in a two-arm, parallel-group randomised controlled trial (RCT) comparing the clinical effectiveness of the MED-informed resistance training programme against usual care in Malaysian primary care settings (Phase 3). The different phases are methodologically independent but epistemically dependent on each other, where the results of the previous phases will inform design decisions in the next phases. Reporting standards followed in the programme are PRISMA 2020, AGREE II, SPIRIT 2013, and CONSORT 2010, which allow for methodological transparency, reproducibility and compatibility with international peer-review.
3.1Overall Research Design
The overall design is a sequential explanatory mixed method design, in which quantitative evidence-based approach (Phase 1) supports prescriptive parameter refinement (Phase 2) to guide the experimental intervention (Phase 3). This is consistent with the architecture of the complex exercise intervention research field with evidence mapping and protocol fidelity assurance preceding valid randomised evaluation (Craig et al., 2008). The three phases are directly related to the three main research objectives outlined in Chapter 1: (i) to systematically identify and synthesize evidence related to exercise programming parameters and MED in T2DM; (ii) to appraise current clinical guidelines and formally register a manualised RCT protocol; and (iii) to determine the effect of the MED-informed resistance training programme on glycaemic and cardiometabolic outcomes among Malaysian adults with T2DM.
Chapter 3 · Section 3.2
Phase 1: Exploration
Studies 1a and 1b: two systematic reviews that build the evidence base.
3.2Phase 1: Exploration Phase
The Exploration Phase will consist of two studies (Studies 1a-1b) aimed at building an evidence base that will be robust and internally consistent about exercise programming for T2DM and, specifically, the operational definition of the MED of RT. These studies will not be independent research projects, but rather will form a logically ordered evidence cascade: systematic reviews with meta-analyses (Studies 1a) quantify comparative training effects; and a focused systematic review (Study 1b) synthesizes dose-response data and anchors the MED construct. All systematic review studies will be prospectively registered in PROSPERO and will follow the reporting guidelines of the PRISMA 2020.
3.2.1Exercise Vs Control: Systematic Review and Meta-Analysis
Study 1a will include a systematic review and meta-analysis of the effectiveness of structured exercise interventions (aerobic, resistance, and combined) for glycaemic control and cardiometabolic risk factors in adults with T2DM. This study is intended to establish the general comparative-effectiveness framework subsequently used to analyse resistance training dose-response relationships in Study 1b.
The eligibility criteria will be structured under PICO as follows: Population: adults aged 18 years or older, with confirmed diagnosis of T2DM; Intervention: any structured supervised exercise programme of at least four weeks' duration; Comparator: no exercise or usual care (attention matched); Outcome: primary outcome will be glycated haemoglobin (HbA1c) and secondary outcomes will be fasting plasma glucose, body mass index, blood pressure, and lipid profile. Completed randomized controlled trials and quasi-experimental designs with concurrent control groups will be included but pre-post studies without concurrent control groups will not be included.
The following electronic databases will be systematically searched: MEDLINE (PubMed), Scopus and World of Science (WoS), and manual reference list screening will be performed. Titles and abstracts will be screened by two independent reviewers and then full text by a third with a second reviewer in case of a conflict. Details will be harvested by a pre-piloted standardised data collection form, which will include study design, participant characteristics, intervention parameters, comparator characteristics and data on outcome.
The Cochrane Risk of bias 2.0 tool (RoB 2.0) will be used to assess the risk of bias in the studies at the level of the study, by evaluating the five domains: randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Certainty of the evidence will be graded using the GRADE approach. A random-effects model (DerSimonian-Laird estimator) will be used for meta-analysis because of the expected heterogeneity due to differences in modalities, intensities and durations of the training, as well as differences in participant characteristics, such as their comorbidity profiles. The weighted mean differences (WMD) with 95% confidence intervals will be used to express effect sizes. Heterogeneity will be assessed with the I-squared value with values of 25%, 50% and 75% representing low, moderate and high heterogeneity respectively. Subgroup analyses will be pre-specified based on training modality, duration of intervention and baseline HbA1C, and will be examined for potential sources of heterogeneity. To address the issue of publication bias, Egger regression test and visual inspection of funnel plot asymmetry will be used for outcomes that have 10 or more included studies in each. RevMan 5.4 and R (meta and metafor packages) will be used for all statistical analyses.
3.2.2Minimal Effective training Dose in T2DM Population: Systematic review
Study 1b will perform a systematic review and synthesise, operationally define, and extrapolate the MED of resistance training for glycaemic control in adults with T2DM. Because of the likely variation in dose-reporting conventions, and the essentially dose-exploratory rather than comparative nature of the inquiry, narrative synthesis reporting, instead of a meta-analysis pooling of doses, will be used in this Review, following the Synthesis Without Meta-analysis (SWiM) reporting guideline (Campbell et al., 2020).
The MED construct will be defined as the smallest set of training frequency, intensity, volume and session structure that would result in a clinically significant reduction of HbA1c (0.5% absolute reduction) with no additional glycaemic benefit from further dosage. This definition is a combination of theoretical elements from muscle physiology and prescriptive imperative in T2DM management for parsimony (Schoenfeld et al., 2021; Refalo et al., 2023).
Eligibility will be limited to RCTs and controlled trials reporting on at least two distinct doses of resistance training (allowing for dose-response inference) for adults with confirmed T2DM for interventions of 8 weeks or more. Studies will need to include at least one of the following dose parameters: Sets per muscle group per session (SPMS), Repetitions in range, percentage of one-repetition maximum (%1RM), or Repetitions in reserve (RIR). A dose-response matrix will be developed, presenting extracted parameters as columns and HbA1c as rows, allowing for the identification of thresholds. The review will generate an operationally defined MED parameter set which will directly inform the design of the intervention in Phase 3.
Chapter 3 · Section 3.3
Phase 2: Validation
Studies 2a and 2b: guideline appraisal and trial protocol.
3.3Phase 2: Validation Phase
The Validation Phase will involve checking the evidence that has been gathered in the Exploration Phase for two parallel types of formal evaluation and structuring. The methodological quality of current exercise guidelines for T2DM will be assessed in Study 2a, employing the internationally recognized AGREE II instrument, which will place the proposed intervention in the context of clinical exercise guidelines. Study 2b will build up and register a comprehensive RCT protocol, operationalising Phase 1 outputs of MED into a replicable, externally auditable trial design.
3.3.1Novel program Appraisal using AGREEII Checklist
Study 2a will critically evaluate current exercise guidelines for adults with T2DM with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The AGREE II is a 23-item, six domain validated instrument to evaluate the rigour in guideline development, clarity of guideline recommendation presentation, and implementation feasibility. The six domains evaluated are: Scope and Purpose; Stakeholder Involvement; Rigour of Development; Clarity of Presentation; Applicability; and Editorial Independence. All items are rated on a 7-point Likert scale and all domain scores are reported as scaled percentages to aid in comparing between guidelines (Brouwers et al., 2010).
Current exercise program will be evaluated by at least two separate appraisers who have been trained in the AGREE II methodology. Each appraiser will have a domain score computed based on the scoring manual for AGREE II and inter-rater reliability will be tested using an intraclass correlation coefficient (ICC, two-way mixed, absolute agreement model) with scores ≥ 0.75 regarded as acceptable. Descriptive reporting of mean domain scores and overall guideline quality ratings will be provided. Guidelines developed at high rigour and > 60% on the Rigour of Development dimension will be considered methodologically high quality and will be used to theorise the Phase 3 intervention manual. A notable lack of domain, specifically Applicability and Stakeholder Involvement for low-resource multi-ethnic settings like Malaysia will be recorded as evidence gaps that will drive the present study programme.
3.3.2Protocol for Randomised Controlled Trial
Study 2b will design a comprehensive protocol for the Phase 3 randomised controlled trial (RCT) to meet the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist, which is required for creating a peer-review quality protocol. SPIRIT 2013 checklist comprises 33 items which cover administrative, introduction, methods, ethics and dissemination aspects, and it is recognized by major clinical trial journals as the standard for reporting transparency of protocols.
All procedures of the Phase 3 trial will be defined in advance of enrolment of study participants, such as eligibility criteria, recruitment procedures, randomisation methodology, blinding arrangements, manuals for the intervention and comparator, schedules for outcome assessment, safety monitoring procedures, data management plans and statistical analysis plans. A completed protocol will be submitted for prospective registration on WHO International Clinical Trials Registry Platform (clinicaltrial.gov) in accordance with the requirements outlined in the Declaration of Helsinki for prospective registration. Registration will take place before the first participant is enrolled. The published protocol will be submitted for independent scientific review through the publication process of peer-reviewed journals, in order to have the trial design assessed by other scientists.
Chapter 3 · Section 3.4
Phase 3: Randomised Controlled Trial
A 12-week, two-arm, outcome assessor-blinded trial.
3.4Phase 3: Randomised Controlled Trial
Phase 3 will be the main experiment of the research programme. A 2-arm parallel group randomized controlled trial (RCT) will be conducted to assess the effect of a 12-week MED-informed resistance training programme and usual care for Malaysian adults with T2DM on glycaemic and cardiometabolic outcomes. The trial design, performance, analysis and reporting will be in accordance to Consolidated Standards of Reporting Trials (CONSORT) 2010 statement.
3.4.1Study Design
The Phase 3 study will be a 2-arm, parallel group, outcome assessor-blinded randomized controlled trial (RCT) allocation of 1:1. The trial will be conducted at Hospital Sultan Al-Abdullah (HASA), Puncak Alam, Selangor - a Universiti Teknologi MARA (UiTM)-affiliated teaching hospital and health centre where T2DM patients receive chronic disease management under the institution's own clinical services. A UiTM-affiliated hospital/health centre setting is chosen as it maximises ecological validity for community-based clinical translation, while remaining within the institution's own clinical governance structure.
The trial will have a 12-week intervention period of active resistance training, the same length of intervention time that will be established in Study 1b as an adequate amount of time for the production of a clinically meaningful change in HbA1c through structured resistance training. The primary endpoint of the study will be at 12 weeks (T1), and assessments will take place at baseline (T0) and at 12 weeks (T1). All outcome assessors will be blinded to group allocation during the whole trial duration, while the participants and the facilitators of the exercise intervention will be necessarily unblinded due to the nature of the exercise intervention.
Recruitment of participants will be from Hospital Sultan Al-Abdullah (HASA), Puncak Alam, Selangor. Eligibility criteria have been designed to represent the clinical population that the MED intervention will target.
The eligibility age range will span 18 to 70 years. The lower bound is set at the standard adult threshold rather than a higher cut-off, in view of converging evidence that early- and young-onset T2DM is now the fastest-growing segment of the disease burden: age-standardised incidence has risen significantly among adults aged 20-29 and 30-39 years even as it has declined among those aged 60-79 (Holman et al., 2026). Restricting recruitment to an older population, as in earlier resistance training trials, would systematically under-represent this expanding group. The upper bound of 70 years is retained to preserve comparability with the RCTs from which the effect size used for sample size estimation (Section 3.4.3) was derived (Castaneda et al., 2002; Sigal et al., 2007), while remaining within a range that supports safe, community-based delivery of a 60-80% one-repetition maximum resistance protocol without requiring specialised geriatric exercise supervision.
The inclusion criteria will include: (i) confirmed diagnosis of T2DM based on the criteria from the WHO 2006 (fasting plasma glucose of ≥ 7.0 mmol/L or 2-hour plasma glucose of ≥ 11.1 mmol/L on 2 occasions, or current use of pharmacological treatment for T2DM); (ii) age between 18 and 70 years; (iii) HbA1C levels between 7.0% and 10.0% at screening; (iv) physician clearance to participate in moderate intensity resistance exercise; and (v) physical inactivity (defined as less than 150 minutes of moderate intensity physical activity per week for at least 3 months before enrolment) assessed through International Physical Activity Questionnaire Short Form (IPAQ-SF).
Exclusion criteria will be: (i) current participation in a structured exercise programme; (ii) current insulin therapy; (iii) uncontrolled hypertension (resting blood pressure elevation >160/100 mmHg on two consecutive measurements); (iv) musculoskeletal injury or orthopaedic contraindication to resistance exercise; (v) severe peripheral neuropathy precluding safe exercise participation; (vi) recent cardiovascular event within the preceding 6 months; (vii) pregnancy or intention to become pregnant during trial period; (viii) cognitive impairment precluding written informed consent; and (ix) clinical suspicion of type 1 diabetes mellitus or latent autoimmune diabetes in adults (e.g., diabetic ketoacidosis at diagnosis, rapid progression to insulin dependence within 6 months of diagnosis).
3.4.3Sample size
The sample size is determined by the key parameter of HbA1c change from baseline to 12 weeks. The primary analysis will use analysis of covariance (ANCOVA), in which the baseline (T0) HbA1c value serves as a covariate for the follow-up (T1) HbA1c value; this adjustment removes the portion of outcome variance explained by baseline differences between participants and therefore requires a smaller sample size than an unadjusted comparison of change scores for any positive baseline-to-follow-up correlation (Vickers & Altman, 2001). Based on a conservative effect size estimate (WMD ~ 0.60%, SD 0.90%) drawn from published meta-analyses (Umpierre et al., 2011; Strasser et al., 2010), cross-validated against the higher-quality RCTs identified in Study 1b, and an assumed baseline-to-follow-up correlation of r = 0.70 for HbA1c under an active resistance training intervention, the effective standard deviation after covariate adjustment is 0.90% x √(1 − 0.70²) = 0.64%, yielding a standardised effect size of d = 0.94. A sample size of 20 per arm (n = 40) is required for a two-tailed ANCOVA-based comparison with alpha = 0.05 and power = 0.80. Based on the attrition rate observed in a comparable 12-week structured exercise randomised controlled trial in patients with type 2 diabetes mellitus, in which the exercise intervention arm retained 75 of 80 participants (6.25% attrition) over an equivalent 12-week period (Amaravadi et al., 2024), the target enrolment for each arm is 23 (n = 46 total), with a 10% dropout rate. Sample size calculations will be verified with the use of GPower 3.1 and independently by a qualified statistician before the protocol is registered. This calculation will be revisited after Study 1b is completed, using the updated literature-derived effect size synthesised from the higher-quality RCTs identified therein.
3.4.4Randomization
Participants will be randomly allocated to the intervention and control arms in a 1:1 ratio using block randomisation stratified by age, to ensure balanced distribution of age, a clinically relevant prognostic factor for glycaemic response to exercise, across the two arms despite the modest per-arm sample size. Participants will be stratified into two age bands (18-59 years and 60 years and above), reflecting the conventional definition of older adulthood used in Malaysian public health policy. Within each age stratum, an independent statistician will generate the randomisation sequence using randomly permuted blocks of varying size (4 and 6) via a validated computer-based random number generator, before the start of recruitment. Block sizes will be withheld from all study personnel involved in enrolment to preserve allocation concealment.
Allocation concealment will be used through the use of sequentially numbered and opaque, sealed envelopes (SNOSE) prepared and kept by an independent statistician. Envelopes will only be opened after a participant has been determined eligible and baseline assessments are finished. This is a process that ensures allocation is not known to the clinician who is recruiting the participant, or to the participant themselves, until randomisation, thus avoiding selection bias.
3.4.5Novel Exercise Program
The intervention arm will receive a 12-week, twice weekly, supervised resistance training programme that is operationally derived from the MED parameter set determined in Study 1b. The core prescription will consist of the following parameters: (i) frequency (two sessions per week separated by at least 48 hours to allow optimal neuromuscular recovery); (ii) intensity (60-80% of 1RM, estimated at baseline using validated submaximal prediction protocol (Brzycki equation) and reassessed at weeks 4 and 8 to ensure progressive overload); (iii) volume (4 sets per major muscle group per week delivered as 2 sets per major muscle group per session with a minimum rest period between sets of 90 to 120 seconds); (iv) proximity to failure (assigned as a repetitions-in-reserve (RIR) target of 1-3, operationalised via RIR-based rating of perceived exertion (RPE) scale, which prevents volitional failure and ensures mechanical tension across the muscle groups); (v) exercise selection (6 dumbbell-based multi-joint compound movements, organised into 3 antagonist/non-competing supersets to preserve session time-efficiency within the 45-60 minute window: Superset 1, dumbbell chest press paired with dumbbell bent-over row, an upper-body push-pull antagonist pair; Superset 2, dumbbell shoulder press paired with dumbbell squat (glute-biased), a non-competing upper-body push and lower-body hip-dominant pairing; Superset 3, dumbbell squat (quad-biased) paired with dumbbell Romanian deadlift, a lower-body knee-dominant/hip-dominant antagonist pair), with machine-based variants allowed where free-weight execution cannot be safely supervised. The complete exercise-by-exercise load, repetition and reassessment schedule is presented in Appendix 3.
Individual supervision will be provided by a qualified exercise physiologist or trained physiotherapist to ensure technique fidelity, adherence to intensity and real-time monitoring for safety in each session. The duration of the session will be around 45 – 60 minutes, including warm up and cool down. A manual for interventions will be created as part of Study 2b to standardize all the elements of intervention and to offer guidance for facilitator training to reduce inter-facilitator variations. Adherence will be documented at the session level using a standardised attendance log, and a pre-specified adherence threshold of 80% or more of scheduled sessions will be required for inclusion in per-protocol analysis. Exercises within each superset will be performed back-to-back with minimal inter-exercise rest, followed by the prescribed 90-120 second rest before the next round, so that the twice-weekly full-body prescription is delivered within the 45–60-minute session window.
3.4.6Usual care
The participants in the control arm will receive standard care as offered at Hospital Sultan Al-Abdullah (HASA), based on the clinical practice guideline (CPG) by the Ministry of Health Malaysia (2020) for the management of Type 2 Diabetes Mellitus. Usual care includes review of pharmacological management, dietary counselling by a registered dietitian and routine health education at scheduled clinic visits. The research team will not provide any exercise structure to the control subjects throughout the 12-week intervention. Once they have finished the trial, they will be offered all the intervention to tackle the issue of equipoise and also to promote retention. Activities will be carried out for both arms to monitor co-intervention contamination by having participants complete IPAQ-SF at each time-point.
3.4.7Primary and Secondary Outcome
The primary outcome will be haemoglobin glycated (HbA1c, %), measured at T0, T1 from venous blood samples. HbA1c will be measured by high-performance liquid chromatography (HPLC) in a certified clinical laboratory that meets the NGSP/IFCC harmonisation standards. A between-group difference of 0.5% or greater at T1 is pre-specified as the minimum clinically important difference (MCID) per the Ministry of Health Malaysia. (2020) clinical practice guideline for clinical significance.
Secondary outcomes will be the following domains. Muscle thickness will be measured using B-mode ultrasound by a certified technician. Body composition will be measured using bioelectrical impedance analysis (BIA) with the InBody 270 segmental body composition analyser (Biospace Co., Ltd., Seoul, South Korea), which will provide fat mass (kg), fat-free mass (kg), skeletal muscle mass (kg), and visceral fat rating. The Incremental Shuttle Walk Test (ISWT) is a progressive field test which has been shown to have acceptable criterion validity to maximal oxygen uptake in clinical populations with T2DM (Benham et al., 2020) and will be used to estimate cardiorespiratory fitness. Cardiopulmonary exercise testing (CPET) using a modified Bruce protocol on a cycle ergometer with breath-by-breath gas exchange analysis will also be conducted as the direct, criterion-standard measure of maximal oxygen uptake. Resting blood pressure (BP) and resting heart rate (HR) will be taken after 5 minutes of seated rest, using a validated automated sphygmomanometer, three measurements will be taken at 2 minutes intervals and the mean value will be recorded. Fasting plasma glucose (FPG) will be collected at the same time as the HbA1c blood sample. Intervention adherence will be measured by the number of sessions completed to the number of sessions scheduled, in percentage format. Exercise self-efficacy will be assessed using the Malay-validated version of the Exercise Self-Efficacy Scale [citation to be confirmed], administered at each assessment time-point. Health-related quality of life will be assessed using the Malay-validated version of the 36-Item Short Form Health Survey (SF-36) [citation to be confirmed], administered at each assessment time-point.
3.4.8Result analysis
The main statistical approach will be to use analysis of covariance (ANCOVA), with the post-intervention (T1) value of each outcome as the dependent variable, the baseline (T0) value of that outcome entered as a covariate, and group allocation as the fixed factor, to compare the intervention and usual care groups. Paired samples t-tests will also be used to determine within-group pre-to-post changes. Outcome variables will be the glycated haemoglobin (HbA1c), waist circumference and bioelectrical impedance analysis (BIA)-based body composition (fat percentage and lean mass), measured in the InBody 270 segmental body composition analyser (Biospace Co., Ltd., Seoul, South Korea) under standardised measurement condition. Univariate and multivariate associations between intervention allocation and change in outcome variables will then be examined to help describe the size and directionality of the treatment effects. Statistically significant results will be considered as P < .05; in analyses with multiple secondary outcomes, the Bonferroni correction will be used to adjust for familywise error rate. The Shapiro–Wilk test will be used to assess normality of all continuous variables, if they are not normally distributed, then appropriate non-parametric alternatives (between group comparison Mann–Whitney U test and within group comparison Wilcoxon signed rank test) will be used. The size of the treatment effect will be reported using Cohen's d that has been assigned to “small” (d = 0.2), “medium” (d = 0.5), and “large” (d = 0.8) according to the convention. IBM SPSS Statistics (Version 29.0; IBM Corp., Armonk, NY) will be used for all statistical analyses. All participants who decline to continue with the intervention rate or are lost to follow-up will be considered "no longer available" and primary analyses conducted according to the intention-to-treat principle with multiple imputation assuming missing at random.
Chapter 3 · Section 3.5
Ethical Considerations
Approvals, consent, safety monitoring and data protection.
3.5Ethical Considerations
Ethical approval for all studies within the present research programme, including Phase 3 trial-specific activities involving human participants, will be sought from the Ethics Committee of Universiti Teknologi MARA (UiTM REC) prior to any data collection or site access. As the trial will be conducted at Hospital Sultan Al-Abdullah (HASA), a UiTM-affiliated hospital and health centre, approval from the Medical Research and Ethics Committee of the Ministry of Health Malaysia (MOH MREC) is not required; UiTM REC approval alone is sufficient, since the site falls under the university's own institutional governance rather than a Ministry of Health facility. All studies will be conducted in full conformity with the Declaration of Helsinki (2013 revision) and the Malaysian Good Clinical Practice guidelines.
All Phase 3 participants will sign written informed consent before enrolling. The consent process will be carried out in both Bahasa Malaysia and English to cater for the convenience of the participants and time will be allowed for questions. The participants will be clearly informed that participation is not mandatory, that withdrawing at any time will not compromise their clinical care and that all data will be collected and handled in a de-identified manner as per the Personal Data Protection Act 2010 (PDPA) of Malaysia. The ethical approval process will not be required for Phase 1 systematic review studies, since this is a secondary data evidence synthesis, but prospective registration with PROSPERO will satisfy transparency requirements equivalent to ethical oversight.
Participant safety monitoring for Phase 3 will be overseen by an independent data safety monitoring board (DSMB), convened in advance of trial commencement. Adverse events (AEs) and serious adverse events (SAEs) will be defined in the trial protocol and reported to the DSMB and UiTM REC within specified time-frames (SAEs within 24 hours of occurrence; non-serious AEs at scheduled DSMB reviews). A pre-specified stopping rule will be applied if the interim analysis at 50% enrolment reveals a significant increase in SAE incidence in the intervention arm or a pre-specified efficacy signal meeting the O'Brien-Fleming boundary.
Chapter 3 · Sections 3.6 - 3.7
Timeline and Milestones
A 36-month plan across six semesters, with milestones.
3.6Research Timeline and Milestones
The present research programme will be executed over a 36-month period structured around the three phases described in Sections 3.2 to 3.4. Table 3.1 presents a Gantt chart delineating the anticipated timeline for each study component across six consecutive six-month periods spanning Years 1 to 3. The timeline reflects the epistemically sequential nature of the research design, wherein Phase 1 outputs constrain the design parameters of Phase 2, and the registered protocol emerging from Phase 2 directly governs the execution of the Phase 3 RCT. Overlapping periods between studies reflect legitimate parallel processing of writing and submission activities alongside ongoing data collection in subsequent studies. Completion dates are contingent on the receipt of ethics approvals, PROSPERO registration confirmations, and journal peer-review timelines, all of which introduce inherent schedule variance; the timeline should therefore be regarded as a normative projection rather than a deterministic schedule.
Note. Shaded cells () indicate primary activity periods. Y = Year; S = Semester; M = Month; SR = systematic review; MA = meta-analysis; RT = resistance training; T2DM = type 2 diabetes mellitus; RCT = randomised controlled trial; REC = Research Ethics Committee; ICTRP = International Clinical Trials Registry Platform.
Table 3.2 presents the key project milestones corresponding to the completion of each discrete study and the attainment of critical regulatory and procedural benchmarks. These milestones will serve as the formal progress evaluation criteria for supervisory committee reviews conducted at six-monthly intervals throughout the programme duration.
Table 3.2Project Milestones and Target Completion Dates
Note. PROSPERO = International Prospective Register of Systematic Reviews; SR = systematic review; MA = meta-analysis; RT = resistance training; T2DM = type 2 diabetes mellitus; AGREE II = Appraisal of Guidelines for Research and Evaluation II; RCT = randomised controlled trial; UiTM REC = Universiti Teknologi MARA Research Ethics Committee; T1 = 12-week assessment.
3.7Conclusion
The approach described in this chapter offers a well-established, internally consistent, and internationally referenced approach to exploring the minimal effective dose of resistance training for T2DM. The three-phase sequential design allows for each phase to address its own research question, while also providing outputs that will structurally limit, and then strengthen, the next sequential phase, which will reduce the risk of conducting a poorly powered and/or under-anchored clinical trial. Transparency, reproducibility and adherence to the highest current standards in clinical exercise research will be assured by using the internationally validated reporting frameworks throughout all phases, specifically PRISMA 2020, SWiM, AGREE II, SPIRIT 2013, and CONSORT 2010. The results of this programme are anticipated to inform the development of evidence-informed prescriptive recommendations for minimum dose resistance training in T2DM and to have clinical impact on the development of clinical practice guidelines, implementation in primary care, and resource optimisation in health systems in Malaysia and other middle-income countries.
Back matter
References
All 53 sources cited in Chapters 1 to 3. Select a citation anywhere in the text to preview its entry.
