Epidemiological studies show that diabetes mellitus (DM) is a highly prevalent metabolic chronic disease with an associated heavy personal and public health burden of disability, morbidity and mortality. The prevalence of DM has been shown to be up to 30% in those aged older than 65 years in some populations 1–4. Furthermore, because of the atypical presentation of disease with advanced age and the often asymptomatic nature of diabetes in older patients, there is a large cohort of those with DM who remain undiagnosed as yet 5. DM has been estimated to reduce not only life expectancy but also functional autonomy and quality of life; this impact is increasing over time as DM becomes more prevalent in our ageing populations.
The burden of disability and reduced function is therefore increasing because of an increase in chronic disease in older individuals and an increasing tendency for older individuals to live a greater number of years with impaired function and disability. The focus of care for older patients with diabetes should therefore include prevention of functional decline, with early intervention rather than attempting to recover function that has already been lost. This focus on prevention has developed from some important observations; recovery of functional independence once disability has developed is unlikely 6, but is more likely if intervention occurs early when precursors to disability are present. For instance, the Lifestyle Interventions and Independence for Elders study in 2014 reported that a direct intervention in frail older individuals, comprising of exercise and educational programmes, was successful in improving the physical status of participants 7.
Diabetes poses a significant threat to the functional status of older individual and is a risk factor for the development of frailty, more than doubling the risk over 3.5 years of follow-up 8. The concept of frailty has become extremely important over the last two decades in Geriatric Medicine and is now known to be the most powerful predictor of disability, mortality and other adverse outcomes such as institutionalization in older individuals 9. Frailty must be seen as a biological state and a predisability state, and has been defined as an increased vulnerability to stressors resulting from a decreased physiological reserve in multiple systems, leading to a limited capacity to maintain homeostasis 10. This leads to otherwise small events having a large impact on the health and function of a frail individual.
There are multiple contributing factors such as chronic medical comorbidities including diabetes to the development of frailty in an individual, a pathway that leads from normal function to prefrailty to frailty and finally to disability. An important contributor to the physical frailty pathway is sarcopaenia, which manifests as an age-related loss of skeletal muscle volume and power. Diabetes is also known to accelerate loss of muscle mass in older patients, but there has not yet been detailed work into the relationship between these three conditions: diabetes, frailty and sarcopaenia. This review examines the evidence supporting such inter-relationships.
Diabetes is a condition underlined by disturbances of carbohydrate, fat and protein metabolism and associated with insulin deficiency and/or resistance. Prevalence increases with age because of age-related metabolic disturbance, alongside other environmental, genetic and behavioural factors 11. Older patients with DM have higher rates of premature death and medical comorbidities, such as hypertension, cardiovascular disease and cerebrovascular disease, than nondiabetic older individuals. Furthermore, they have also been shown to be at higher risk of other common geriatric conditions such as cognitive impairment, incontinence, falls, chronic pain, depression and polypharmacy 12.
Numerous studies have supported a greater functional and cognitive decline in older patients with diabetes compared with their nondiabetic counterparts. This decline is evident irrespective of age. For instance, the Octabaix study focused on a sample of community-dwelling older adults aged 85 or older without evidence of severe functional impairment at baseline living in Spain. The study compared the incidence of functional or cognitive impairment and its associated factors in diabetic and nondiabetic participants. Those with diabetes were more than twice as likely to develop a new disability over 2 years compared with their nondiabetic counterparts, indicating that diabetes increases the risk of incident disability, which is evident in only a short period of follow-up 13. This greater rate of functional impairment is associated with increased disability, morbidity, mortality and institutionalization 14. Other studies support findings that older patients with diabetes show a reduction in physical function and health status compared with age-matched and sex-matched control individuals living in the same community 15. In this latter cohort, even after controlling for age and various comorbidities, diabetes remains significantly associated with mobility limitation.
Table 1 summarizes the key publications in the field of diabetes and physical function. Diabetes causes an excess loss of physical function, although the exact mechanisms underlying this have not yet been fully elucidated. Contributing factors are mentioned in the table below, with muscle atrophy and impaired muscle performance emerging as key contributors.
The management of DM in older individuals is made more complex because of the variations in functional status, comorbidities and vascular complications in individual patients. This has led to a greater focus on comprehensive function assessment, individualized therapeutic interventions and glycaemic targets 16. Aligning therapeutic targets to functional status is key and very tight glucose control is often not necessary nor desirable 17. Recent studies have shown a U-shaped relationship between mortality and HbA1c in older patients, indicating an increased mortality with low HbA1c, the underlying mechanism of which is unclear. There is no direct causal relationship, although malnutrition, inflammation and functional decline were factors that were shared by the populations that showed increased mortality and low HbA1c, allowing the inference that frailty and decline in functional status may be the main confounding factors to explain this relationship 18. A focus on frailty is therefore a key in the management of older individuals with diabetes.
Diabetes has previously been suggested to be a model of frailty and has a consistent effect towards increasing the risk of mobility disability and disability associated with instrumental activities of daily living 19. Frailty has thus emerged as a predictor state for disability and can be defined as a situation of extreme vulnerability to the effects of low-intensity stressors. It results from the difficulty of maintaining homeostasis because of loss of functional reserve 20. The concept of frailty as a clinical state was aided by the development of the physical frailty phenotype model by Fried and colleagues. This identified individuals with frailty by the presence of three or more of the following criteria 21:
- Weight loss: unintentional weight loss of at least 4.5 kg in the past year.
- Weakness: hand-grip strength in the lowest quintile adjusted for sex and BMI.
- Slowness: walking speed under the lowest quintile adjusted for age and sex.
- Exhaustion: poor endurance and energy, self-reported from the CES-D (Centre for Epidemiologic Studies Depression Scale) scale.
- Low physical activity level: lowest quintile of kilocalories of physical activity during the last week, measured using the Minnesota Leisure Activity Scale.
Frailty should be thought of as a biological condition rather than an inevitable consequence of the ageing process; it is a dynamic and potentially reversible condition, which highlights the importance of early recognition and intervention. In Fig. 1, we represent frailty as a functional state mainly associated with unsuccessful ageing and as a predisability phase as mentioned previously.
Various studies report widely varying prevalence estimates for frailty in different settings, which is exacerbated by the lack of a clear consensus on the definition of frailty (Table 2).
Frailty is associated with an increased risk of adverse health-related outcomes in older individuals, including falls, disability, hospitalization and mortality. It has also been associated with biological abnormalities (e.g. biomarkers of inflammation) irrespective of the definition used to assess frailty. There is increasing interest in the relationship between diabetes and frailty. The prevalence of diabetes increases with the presence of frailty. The Cardiovascular Health Study showed that the prevalence of diabetes was 18.8% in individuals without frailty, 24.5% in individuals with prefrailty and 32.4% in individuals with frailty 22. Similarly, the presence of frailty has been shown to be higher in patients with diabetes and diabetes is an independent risk factor for the development of frailty 23.
Recurrent hypoglycaemia, which is common in older patients with diabetes, is associated with significant morbidity and physical and cognitive functional decline. This negative impact increases the incidence of frailty and disability; however, the relationship also appears to be bidirectional. The important factors in this relationship are explored in Fig. 224.
Sarcopaenia has been considered to be the biological substrate of physical frailty in a manner similar to high-impact conditions such as congestive heart failure or peripheral arterial disease 25. In this latter review, reduced muscle mass may be considered to be the measurable substrate for physical frailty and sarcopaenia with measurable clinical symptoms including slow gait speed, weakness and poor balance and the use of say the (short physical performance battery – Appendix 1) to measure function.
Sarcopaenia describes the progressive loss of muscle mass with age, shown by impaired strength and functioning, with a subsequent impact on functional status. Despite agreement that sarcopaenia occurs with ageing, there is disagreement on the criteria used for the definition of sarcopaenia 26. Despite work carried out to establish the relationship between sarcopaenia and frailty, the challenge of outlining a consensus definition for both sarcopaenia and frailty, and how to assess them, remains. Agreement appears to be emerging that low muscle mass alone is insufficient and must be combined with assessment of muscle strength and functional status for appropriate clinical assessment 27.
Sarcopaenia affects all older individuals, irrespective of sex, ethnicity or socioeconomic status. Muscle mass is reported to decrease at an annual rate of 1–2% after the age of 50 years, accelerating to 1.5–3% a year after the age of 60 years and even higher rates after 75 years of age 28. Prevalence estimates for sarcopaenia in older individuals are shown in Table 3.
This age-related loss of muscle mass is hypothesized to be because of progressive atrophy, loss of muscle fibres and reduction in muscle quality because of infiltration of fat and connective tissue, alongside changes in muscle metabolism and insulin sensitivity 29,30. Sarcopaenia may therefore be a component of a severe metabolic state characterized by insulin resistance, DM and hypertension. There is a higher prevalence of sarcopaenia in diabetic than nondiabetic older individuals; the Korean Sarcopenic Obesity Study examined 810 patients using dual-energy X-ray absorptiometry (DEXA) and found the prevalence of sarcopaenia to be 15.7% in diabetics and 6.9% in nondiabetics 31. Diabetes appears to be an independent risk factor for sarcopaenia.
Both MRI and DEXA are imaging methodologies to demonstrate and quantify this age-related loss of muscle mass and change in muscle quality. Figure 3 demonstrates this loss of muscle mass in a 63 year old compared with a 25 year old and these type of changes, often accompanied by fatty infiltration and subcutaneous fat deposition has been demonstrated earlier by Vandervoort 32.
Sarcopaenia is associated with frailty and adverse outcomes related to this; for instance, older patients independently assessed to have sarcopaenia are over three times more likely to report incident falls over a 2-year period relative to nonsarcopaenic individuals, irrespective of age and sex 33. Impaired muscle strength and functioning is highly predictive of incident disability and mortality among older adults, leading to the hypothesis that sarcopaenia plays an integral role in the development of frailty 34.
Muscle function and quality in diabetes: are these modulated by sarcopaenia?
Many patients with frailty will have evidence of sarcopaenia and vice versa, and both conditions can be seen as reversible states – sometimes called transition states. In the Korean Sarcopenic Obesity Study study 31, patients with diabetes had a three-fold increased risk of having sarcopaenia than individuals without diabetes, having adjusted for confounding factors, and this lends further support for sarcopaenia being a key underlying mechanism for the functional limitations observed in individuals with type 2 diabetes.
Accelerated loss of muscle mass is observed with ageing (the sarcopaenic process), and is a process that appears to be further exacerbated by the presence of diabetes. A growing body of evidence suggests that metabolic dysregulation associated with obesity and diabetes accelerates the progression of sarcopaenia, and subsequently functional decline in older adults 35. Park and colleagues examined the total body composition with DEXA over a 6-year period in a large cohort of older adults. Findings indicated that those with type 2 DM showed a significantly excessive reduction in appendicular lean mass and trunk fat mass than their nondiabetic counterparts. Older diabetic women also showed a decline in thigh muscle cross-sectional area that was double that of their nondiabetic counterparts 36. This reinforced earlier work by the group that indicated a greater rate of decline of leg muscle mass and strength in diabetic older adults 37.
Evidence for a causal association between diabetes and sarcopaenia is strengthened by work that has reported worsening muscle strength and function in worsening glucose states. The Hertfordshire Cohort Study 38 found significant reductions in grip strength with worsening glucose states, with no relation to insulin levels. Furthermore, Park et al. , reported that muscle quality, defined as muscle strength per unit regional muscle mass, was significantly lower in both the upper and the lower extremities in diabetic patients.
They also showed that muscle quality was affected further by glycaemic control; those with a longer duration of diabetes (≥6 years) and poor control (HbA1c≥8%) showed even poorer muscle quality.
The relationship between diabetes, sarcopaenia and frailty is complex. The maintenance of skeletal muscle mass and function is affected by a number of hormonal, inflammatory, neurological and genetic factors. Thus, the effect of sarcopaenia may operate by a number of underlying mechanisms: these factors are presented in Table 4.
As a consequence of these findings and inter-relationships, it is possible to create a schematic diagram linking diabetes, sarcopaenia and ageing with lower limb muscle dysfunction (Fig. 4).
The view is that at least four key components, increased fatigability, muscle weakness, decreased endurance and muscle wasting, contribute towards lower limb functional impairment and that depending on their relative contributions at any one stage, patients will either show the predisability state of frailty or have frank evidence of disability.
The recent International Diabetes Federation global guidance 39 on managing diabetes in older individuals has provided guidance to clinicians on assigning treatment targets and clinical recommendations according to the functional status of the patient with diabetes. Those with frailty are part of the dependent category and this is reflected for example in both the treatment advised and the recommended glucose targets:
- HbA1c target up to 8.5%/70 mmol/mol.
- Avoid or discontinue agents that might cause nausea or gastrointestinal disturbance or excess weight loss (e.g. metformin or a GLP-1 RA).
- Insulin may provide anabolic benefit.
Incorporation of functional assessment into clinical practice is of paramount importance and this can be accomplished using the method ‘comprehensive geriatric assessment’ 40. This is an objective, practical and measurable tool for assessing the functional status of older individuals that incorporates measures of their clinical, functional, social and cognitive status. In Appendix 1, we list a number of recommended instruments for evaluating frailty and functional status. All these instruments can be repeated regularly to monitor function, detect any functional decline and assess response to treatment.
In Fig. 5, we provide a modern approach to the effective management of type 2 diabetes in older adults in which we incorporate the key issues of functional status and presence of frailty 17.
It is important for the clinician to recognize that when frailty is detected in a patient, this should act as a ‘prompt’ to carry out further assessment and investigation – this must include a full functional (including physical, cognitive, mood and nutritional) assessment, realignment of frailty status with glycaemic targets and agreeing goals of care based around medication safety and quality of life.
Research is ongoing into the association between diabetes, frailty and sarcopaenia, and in Table 5, we list the areas that are a basis of further enquiry by research teams in the field. The MidFrail study is a randomized clinical trial that is ongoing and designed to evaluate the effectiveness of a multimodal intervention in older individuals with type 2 diabetes on frailty and quality of life, and the findings should be available in 2017 41.
A more recent study in civil servants (Whitehall II) has attempted to develop a risk score that characterizes the likelihood of developing frailty in patients with diabetes 23 – key associations with frailty or prefrailty (as defined by Fried and colleagues) included increased age, female sex, stopped smoking, low physical activity and lack of daily consumption of fruit and vegetables. Recent research suggests that previous infection with cytomegalovirus in those with diabetes may be associated with the development of frailty presumably because of a possible effect on immunosenescence 42. A recent paper from Indonesia suggests that the use of metformin may reduce the risk of frailty (on the basis of FI-40 criteria), which was speculated to result from beneficial effects on inflammatory markers, advanced glycosylation products and muscle function 43.
We are moving closer to determining the individual and combined contributions of frailty and sarcopaenia towards disability and functional impairment in diabetes, but high-quality, focused research is now mandatory.
Conflicts of interest
There are no conflicts of interest.
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