Geriatr Gerontol Int 2016; 16: 293–299


Sarcopenia and frailty in older patients with diabetes mellitus Hiroyuki Umegaki Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Sarcopenia is defined as age-associated loss of muscle mass and function, and is frequently accompanied by diabetes mellitus (DM) in older adults. Some of the mechanisms of the development of sarcopenia including insulin resistance, chronic inflammation and mitochondrial dysfunction are also associated with the pathogenesis of DM. Sarcopenia provides the basis for frailty, which is a state that is highly vulnerable to stressors, and can lead to disability, dependency and mortality, and older DM patients are often in a state of frailty. Given the background of an increasing number of older DM patients, the screening and early detection of sarcopenia/frailty and appropriate intervention would be expected to improve the prognosis and quality of life in older patients. Geriatr Gerontol Int 2016; 16: 293–299. Keywords: dementia, diabetes mellitus, frailty, sarcopenia.

The prevalence of diabetes mellitus (DM) is increasing worldwide. With the advancement of the management of DM and of DM comorbidity, life expectancy in DM patients has been extended mainly as a result of decreased cardiovascular mortality, which has led to an increase in the number of older individuals with DM.1 This increase in the number of patients has led to the development of many research interests in this population, which has shown that older DM patients are often in a state of sarcopenia and/or frailty. Sarcopenia and frailty are associated with one another and often coexist. Sarcopenia/frailty has been shown to have a poor prognosis; however, recent research achievements suggest that it is a potentially reversible or preventable condition. It is, therefore, urgent that more research evidence be accumulated to ensure healthier lives for older DM patients. The current review addresses the issue of sarcopenia/ frailty in older DM patients.

What is sarcopenia? Aging is accompanied by a loss of skeletal muscle mass, power and function. The age-associated change of skel-

Accepted for publication 16 October 2015. Correspondence: Dr Hiroyuki Umegaki, MD, PhD, Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. Email: [email protected]

© 2016 Japan Geriatrics Society

etal muscle is called sarcopenia. Sarcopenia is a progressive and generalized loss of skeletal muscle mass and strength. Skeletal muscle is essential to maintaining our postures and making movements, while it also plays a major role in glucose metabolism. In addition, recent studies have shown that skeletal muscle works as an endocrine organ that secretes myokines.2 Therefore, it has been shown that sarcopenia is associated with several age-related mobility disorders, falls and fractures, impaired activities of daily living scores, disabilities, loss of independence, and increased risk of death.3 The decline of muscle strength does not solely result from the reduction of muscle mass, but also from the reduction of muscle quality. Muscle mass measurement is not sufficient for the screening of sarcopenia; measurements of muscle performance, such as muscle power or gait speed, would be required to identify sarcopenia. An algorithm for identifying sarcopenia was suggested by the European Working Group on Sarcopenia in Older People. It recommends starting the screening of sarcopenia with gait speed measurement, followed by measuring grip strength or muscle mass.3 Modifications for Asian populations were recently proposed by the Asian Working Group for Sarcopenia.4

Mechanism of development of sarcopenia in older adults The underlying mechanisms of the development of sarcopenia are likely multifactorial and largely remain to doi: 10.1111/ggi.12688

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be elucidated; however, significant progress has been made in this field, and has shed light on the mechanism of age-associated skeletal muscle functional decline and volume decrease. Skeletal muscle is a dynamic organ that keeps turning over through constant synthesis and degradation. The turning over of the proteins in the skeletal muscle is regulated through complicated mechanisms. Insulin resistance increases with aging, and is involved in several underlying mechanisms of sarcopenia induction.5 Insulin is a catabolic hormone, which stimulates protein synthesis including that in muscle. Defects in insulin signaling can lead to reduced muscle synthesis.6 Chronic inflammation, probably along with oxidative stress, has been shown to increase with aging, and is considered to be involved in the mechanism of sarcopenia.7 Mitochondria dysfunction leads to less efficient energy production, and increased production of reactive oxygen species is also considered to be involved.8,9 Age-related sex hormone reduction10 or other hormonal changes including growth hormone and insulin-like growth factor 1 have been reported to be associated with sarcopenia.11 It is also suggested that the functional decline of neuromuscular junction with aging might also be involved.12 Neuronal loss and impaired re-innervation might be associated with the development of sarcopenia.

Sarcopenia and frailty Recently, the concept of frailty syndrome has attracted a great deal of research interest. It has been generally agreed that frailty is a state in which one is highly vulnerable to stressors that lead to disability, dependency and mortality with decreased physical reserves. Frailty has been defined as a predisability condition, and the validity of the framework of the frailty phenotype, which was developed by Fried et al., has been well established. This framework contains five components: exhaustion, physical inactivity, muscle weakness, slow walking speed and weight loss.13 Two of these components, muscle weakness and slow walking speed, are parts of the sarcopenia phenotype. Because sarcopenia is a major component of frailty, sarcopenia and frailty often overlap. Many older adults with frailty have sarcopenia, and some individuals with sarcopenia show frailty syndrome. Frailty is associated with a number of adverse health outcomes, such as disability, falls, hospitalization, institutionalization and mortality. Frailty, however, is a reversible condition. Frequent transitions among frail, prefrail and non-frail conditions have been reported.14 Therefore, frailty is a good target in the prevention of disability states. So far, interventions with nutrition including amino acids and exercise have been carried 294 |

out in the treatment of sarcopenia/frailty; however, the effects of these interventions are relatively limited, and more efficacious measures are warranted.15

Sarcopenia/frailty in DM patients It has been well established that DM is a risk factor for functional disability and mobility limitations. Several reports have shown that DM is associated with sarcopenia and frailty.16 In a study in Korea, subjects with diabetes had a threefold higher risk of sarcopenia (odds ratio 3.06, 95% CI 1.42–6.62) than subjects without diabetes after adjusting for several confounding factors.17 The prevalence of frailty in older diabetes subjects was reportedly approximately 32–48%, which is higher than that of 5–10% in non-diabetic older subjects.18–22 So far, the underlying reason why DM often coexists with sarcopenia/frailty has not been fully elucidated, however, several lines of evidence have shown that some mechanisms of sarcopenia/frailty are closely associated with DM pathophysiology.23,24 Insulin resistance is common in older DM patients. Reduced insulin signaling leads to decreased protein synthesis and increased protein degradation, which can ultimately lead to reduced muscle mass. Chronic inflammation, oxidative damage, and mitochondria dysfunction have also been suggested to be associated with both DM and sarcopenia. The relationship between hyperglycemia per se and sarcopenia, however, has been relatively underinvestigated so far. Diabetic neuropathy, a frequent diabetic complication, is associated with sarcopenia.25–29 Diabetic neuropathy is responsible for deficits in muscle strength, and denervation leads to muscle atrophy through the impairment of motor nerve conduction. The muscle power reduction in DM patients might be partially due to the intrinsic impairment of the generation of muscle force. Several mechanisms including mitochondria dysfunction and myosin glycation have been hypothesized.30,31 One study investigated the association between blood glucose levels and sarcopenia.32 The authors showed that higher glycated hemoglobin was associated with sarcopenia. Because high glucose is reportedly associated with inflammation,33 which might also be associated with sarcopenia,34 high glucose per se and/or inflammation can be involved in the development of sarcopenia. A prospective study also reported that poor glycemic control is associated with frailty risk.35 Several other studies showed that poor blood glucose control was associated with sarcopenia.36 Sarcopenia most likely formed the basis of frailty in type 2 DM patients. Because frailty might be caused by the accumulation of subclinical damage in multiple organ systems, diabetes patients with many comorbidities, mainly cardiovascular diseases, would be at risk of falling into a state of frailty.37 © 2016 Japan Geriatrics Society

Sarcopenia and frailty in DM

It was shown that risk factors for diabetes also predict frailty.38 Low physical activity and a lack of daily consumption of fruits and vegetables were considered the risks for developing DM, and were associated with subsequent frailty. This could suggest that frailty and DM have some common pathogenetic basis. Repeated hypoglycemia is often seen in older diabetics, and the negative impact of repeated hospitalization as a result of hypoglycemia might be responsible for frailty in older patients with DM.39 Older patients with DM are often taking many kinds of medication.40 Polypharmacy is associated with adverse drug reactions through drug–drug interactions, and can contribute to adverse health outcomes.41

Adverse outcomes associated with sarcopenia/frailty in older DM patients Falls Sarcopenia is reportedly a risk for falls,42 while DM is an established risk for falls.43,44 A Japanese study showed that lower walking speed, which is one of the manifestations of sarcopenia/frailty, was associated with falls in type 2 DM patients.45 Elderly diabetic patients with the sarcopenia/frailty phenotype and their caregivers should be educated regarding the standard pharmacological and non-pharmacological methods of prevention of falls and fracture, and these methods should be implemented.46

Depression DM is a risk factor for depression.47,48 The vascular depression as a result of the cerebrovascular burden that is associated with vascular risk factors including DM is reportedly associated with frailty.49 Frailty is manifested not only physically, but also mentally. Some evidence has shown that frailty increases the risk of depression.50,51 Furthermore, subjects with frailty tend to have less frequent social communications and poor networks, which are also risk factors for depression.

Cognitive dysfunction Cognitive impairment is associated with physical frailty independently of diabetes and sarcopenia.23 Insulin resistance, which is often associated with type 2 DM, might be involved in the underlying mechanism of sarcopenia/frailty, and has been suggested to accelerate the pathology of Alzheimer’s disease in the brain. Several lines of evidence suggest that insulin resistance is associated with amyloid deposition in human brains,52,53 and that insulin plays a role in the regulation of tau phosphorylation, which is closely associated with the formation of neurofibrillary tangles in Alzheimer’s © 2016 Japan Geriatrics Society

disease pathology.54,55 Both cross-sectional and longitudinal studies have shown that frailty is associated with cognitive impairment,56,57 whereas cognitive impairment might be one of the phenotypes of frailty.58

Hypoglycemia Loss of appetite and weight reduction, which are often seen in frail elderly individuals, are risk factors for hypoglycemia. Severe hypoglycemia often leads to hospitalization in older people. Repeated hospital admission could lead to the deterioration of a patient’s general condition and lead to frailty.39 Cognitive impairment, which often coexists with frailty syndrome, has a bidirectional association with hypoglycemia. Cognitive impairment is a risk for hypoglycemia, and hypoglycemia induces cognitive impairment.59 In the treatment of frail diabetic older individuals, the prevention and avoidance of hypoglycemia should always be considered a priority.

Risk of cardiovascular and non-cardiovascular mortality Older DM patients, especially those with a long disease history, often have cardiovascular comorbidity. Frailty is an established risk factor for cardiovascular disease incidence and death in patients with cardiovascular disease, whereas cardiovascular comorbidity is a risk for frailty.60,61 A recent report from China showed that frailty is a risk factor independent from other classic vascular risk factors for adverse health outcomes including death in older adults with type 2 DM.62

Treatment and management of older DM patients with sarcopenia/frailty The mechanism of development of sarcopenia/frailty includes insulin resistance, hyperglycemia and inflammation, and these factors are also included in the pathophysiologies associated with DM. The treatment for these factors in patients with DM, especially in its early stages, could contribute to preventing the development of sarcopenia/frailty in later life stages in older DM patients. So far, however, there is little evidence regarding the effects of the prevention of sarcopenia/frailty through pharmacological antidiabetic treatments. Future research and accumulation of evidence on this issue is warranted. Non-pharmacological intervention has potential efficacy in the treatment of sarcopenia/ frailty.

Exercise Resistance training has beneficial effects on sarcopenia in an older general population,63 and has also been | 295

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shown to be effective to counteract the exacerbation of the loss of muscle mass and performance in older type 2 DM patients.64 The effect of aerobic exercise on sarcopenia/frailty in older DM patients has not been investigated extensively yet; however, the effects of the combination of resistance and aerobic training on glycemic control were established in older DM patients;65 therefore, the combination of resistance and aerobic exercise would be appropriate in this population when contraindications do not exist, and might have beneficial effects in terms of the prevention of sarcopenia/frailty.

Nutrition The protein needs with aging study group recommended 1.0–1.2 g/kg bodyweight of dietary protein intake for adults aged 65 years and older to keep and regain lean body mass and function.66 A study showed that 1 g protein/kg bodyweight helped maintain muscle strength in older diabetic women.67 Although an appropriate diet for good blood glucose maintenance is important in patients with DM, malnutrition should be avoided in older subjects, especially in frailty or prefrailty conditions.

Association of antidiabetic agents and sarcopenia/frailty An association between antidiabetic agents and sarcopenia/frailty has been reported; however, our knowledge regarding this issue is limited. More data should be accumulated.

Insulin Insulin stimulates protein synthesis, and is expected to have the potential to prevent sarcopenia in patients with type 2 DM; however, the beneficial effects of insulin on sarcopenia have not been proven in clinical settings.

Glitazones Some studies have shown that Peroxisome ProliferatorActivated Receptor gamma agonists, which are insulin sensitizers, have some beneficial effects on muscle performance in older diabetes patients.68–70 The accumulation of more evidence is warranted.

Biganides Metformin could increase lean body mass and decrease fat.71 Animal studies have, however, suggested that metformin might have some negative impacts on mitochondrial function in skeletal muscle.72,73 296 |

Sulfonylureas and glinides Sulfonylureas and glinides, which are ATP-sensitive potassium channel blockers, stimulate insulin release in pancreatic beta cells. Some reports have shown that the drugs in this class might be associated with muscle atrophy.74

Incretins Incretins have been shown to have beneficial effects on muscle.75 Dipeptidyl Peptidase-4 inhibitors and Glucagon-like peptide-1 agonists might be expected to have antisarcopenic effects. However, no clinical evidence of this has been accumulated so far.

SGLT2 inhibitors A newly developed class of antidiabetic drug, sodium glucose transporter 2 inhibitors, has recently been introduced in clinical settings. Currently, no evidence has been accumulated regarding the effects of this class of drug on muscle; however, the acceleration of catabolic effects by expelling a certain amount of calories through urine excretion in frail older adults should be considered.

Type 1 DM and sarcopenia/frailty The present review has dealt mainly with type 2 DM. However, because of recent advancements in the treatment of type 1 DM, the life expectancy of individuals with type 1 DM has been extended, and more old elderly type 1 DM patients are appearing in clinical settings.76 Because the main manifestation of type 1 DM is the impairment of insulin secretion, which is closely associated with protein synthesis, type 1 DM has been reported to result in muscle atrophy beginning at a relatively young age.77 So far, scarce data have been accumulated regarding sarcopenia/frailty in older type 1 DM patients.

Relevance of sarcopenia/frailty in clinical settings It is important to identify sarcopenia/frailty in clinical settings. Patients with sarcopenia/frailty generally have poor health status and poor prognosis. These patients easily lose their appetite and are also prone to adverse drug reactions, which puts them at high risk of hypoglycemia. If a patient is identified as having sarcopenia/ frailty, the treatment targets for blood glucose should be reviewed and might be relaxed. Recent guidelines from the International Federation of Diabetes that clearly state the treatment targets for frail DM patients should be referred to in the treatment of this population.78 The whole medication list should be reviewed to assess the © 2016 Japan Geriatrics Society

Sarcopenia and frailty in DM

relevance of all medications for patients whose backgrounds include poor prognosis and a high risk of adverse drug reactions in order to avoid polypharmacy. DM patients with sarcopenia/frailty are also at high risk of functional decline. Therefore, the identification of sarcopenia/frailty prompts a comprehensive geriatric assessment to identify problems and establish effective interventions to help patients and caregivers, and possibly to improve the patient’s functional status and quality of life. To improve the patient’s sarcopenia/frailty status or to prevent the onset of sarcopenia/frailty, the prescription of appropriate and individualized exercise and adequate nutritional intake should also be considered.

Conclusion Sarcopenia and frailty are mutually associated with one another and often coexist with DM. Sarcopenia/frailty in older DM patients is a marker of poor prognosis. The screening for and early detection of sarcopenia/frailty and the use of appropriate intervention would be expected to improve the prognosis and quality of life in older patients. More research should be carried out to help overcome sarcopenia/frailty in older DM patients, who represent a rapidly increasing population.

Disclosure statement The author declares no conflict of interest.

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Sarcopenia and frailty in older patients with diabetes mellitus.

Sarcopenia is defined as age-associated loss of muscle mass and function, and is frequently accompanied by diabetes mellitus (DM) in older adults. Som...
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