JAMDA 15 (2014) 853e859

JAMDA

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Editorial

Frailty, Sarcopenia and Diabetes

John E. Morley MB, BCh a,*, Theodore K. Malmstrom PhD b,Leocadio Rodriguez-Mañas MD, PhD c, Alan J. Sinclair MSc, MD, FRCP d

aDivisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St Louis, MObDepartment of Neurology and Psychiatry and Division of Geriatric Medicine, Saint Louis University School of Medicine, St Louis, MOc Service of Geriatrics, Getafe University Hospital, Getafe, SpaindUniversity of Bedfordshire, Bedfordshire, UK

It is estimated that 26.9% of persons 65 years and older in theUnited States have diabetes mellitus (www.cdc.gov/diabetes/pubs/estimates11.htm).1 A systematic review has shown that personswith diabetes are at increased risk of mobility disability and disabilityin instrumental activities of daily living and activities of daily living.2

Frailty has been defined as a predisability state, which increases thevulnerability of a person to have a poorer outcome (eg, disability,hospitalization, nursing home placement, or death) when exposed toa stressor.3,4 The major cause of frailty is sarcopenia. Modern defi-nitions have redefined sarcopenia as lacking muscle strength, asmeasured by gait speed or grip strength, in the presence of a lowmuscle mass.5e8 In this review, we explore the relationship of frailtyand sarcopenia to diabetes mellitus.

Frailty

The viability of frailty as a clinical tool was strongly enhanced bythe development by Fried et al9,10 of the physical frailty phenotypemodel. This model has been validated in multiple studies as being anexcellent predictor of poor outcomes.11e14 It consists of 5components:

� Exhaustion� Physical activity� Walking speed� Grip strength� Weight lossA person with any 3 of these is considered frail, and with 1 or 2 is

considered prefrail. The Study of Osteoporotic Factors model is asimpler model with 3 components,15 which is also well validated forproducing unfavorable outcomes.16,17

A competing model is that developed by Rockwood and col-leagues18e21 using the Canadian Health Study. In its simplest form itrepresents the addition of all the deficits (illnesses) the person has,with the larger score indicating a greater likelihood of the person

* Address correspondence to John E. Morley, MB, BCh, Division of GeriatricMedicine, Saint Louis University School of Medicine, 1402 S. Grand Boulevard,M238, St Louis, MO 63104.

E-mail address: morley@slu.edu (J.E. Morley).

http://dx.doi.org/10.1016/j.jamda.2014.10.0011525-8610/� 2014 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

being frail. This is more a comorbidity index than a unique index offrailty.

Recently a simple screening questionnaire with components ofboth the approaches described previously has been developed thattakes less than 15 seconds to do (Table 1). This index, known as theFRAIL, has been validated in Australia,22e24 Hong Kong,11 the UnitedStates,16,25 and Europe.26,27 It is highly predictive of adverse outcomeseven when persons who have functional deficits are excluded.16,25

Another set of frailty questionnaires includes psychosocialvariables.28e31 These measure cognitive frailty, which is briefly dis-cussed at the end of this article.

Frailty and Diabetes

At 65 years or older, diabetic individuals are more likely to be frailthan nondiabetic older adults (Table 2).32e34 The frailty prevalence of32% to 48% in persons with diabetes older than 65 is much higherthan the 5% to 10% seen in the general population.35e38 In persons55 years and older, frailty is still common in diabetic individuals butmuch less so than in the older group.39,40

All the studies found that frail diabetic individuals had a highermortality than nonfrail diabetic individuals.32e41 These studies sug-gest that persons older than 55 with diabetes should be screened forfrailty and, when present, should have their frailty treated.

Frail persons are more likely to have glucose dysregulation duringa glucose tolerance test.42 The ideal level of glucose control for a fraildiabetic patient has not been established, although consensus panelshave suggested an HbA1C between 7.5% and 8.0%.43e45 A single trialwith vildagliptin attempted to determine the optimum glucose-lowering effect in frail compared with nonfrail diabetic in-dividuals.46 In this study, individualized HbA1C targets were set byinvestigators who knew the frailty status of the patients. Unfortu-nately, the end HbA1C targets were similar in both frail and nonfrailpatients, not allowing a determination of an optimum glycemic targetfor older diabetic patients.47

Overall, the management of frailty requires a focus on decreasingsarcopenia (vide infra). In a small study, Pariser et al48 examined theeffects of the “Active Steps for Diabetes” program on type 2 diabetesand frailty. They found the program lowered HbA1C and reducedfrailty in persons using a walker. This is in concert with numerous

Table 1The Frail Scale: A Rapid, Validated Scale for the Detection of Frailty

3 or more positive answers: frail1 or 2 positive answers: prefrailFatigue (have felt tired most or all of the time in past 4 weeks)Resistance (have difficulty or unable to climb a flight of stairs)Aerobic (have difficulty or unable to walk a block)Illness (have more than 5 illnesses)Loss of weight (have lost more than 5% of weight in past 6 months)

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studies in generalized frail communities suggesting that exercise candecrease frailty.49

Besides focusing on sarcopenia, the treatment of frailty has 3 otherelements:

(1) Management of treatable causes of fatigue: People with dia-betes have higher levels of fatigue and this is related toincreased complications.50 Treatable causes of fatigue includevitamin B12 deficiency, hypoadrenalism, hypothyroidism,anemia, sleep apnea, hypotension, syncope, and depression.Treatment of sleep apnea in diabetic individuals results inlower blood pressure, better glycemic control, and animprovement in quality adjusted life years.51 Depression ismore common in diabetic individuals and psychological andpharmacological interventions positively affect depression andimprove glycemic control.52 Diabetes is commonly associatedwith autonomic neuropathy, which leads to orthostatic hypo-tension, arrhythmias, and syncope.53

(2) Management of polypharmacy: Older persons with diabetesare likely to be on many medicines. Polypharmacy has beenidentified as a major cause of frailty and disability in olderpersons.54 Anticholinergic medicines can cause cognitivedecline and frailty.55 Overtreatment of blood pressure results inhypotension and falls.56 Statins can lead to myopathy in olderpersons and this should be looked for bymeasuring an aldolaseas well as a creatine phosphokinase.57 Hypoglycemia canfurther aggravate frailty.58

(3) Management of weight loss: Although in younger personsweight loss is a cornerstone of treatment for type 2 diabetesmellitus, in older persons, in general, including diabetic in-dividuals, weight loss has been shown to be associated withaccelerated mortality.59 Weight loss leads to a loss of muscleand bone, increasing frailty, falls, and hip fractures. There arenumerous treatable causes of weight loss; for example,depression, medications, dysphagia, dental problems, noso-comial infections (tuberculosis and Helicobacter pylori),hyperthyroidism, hypercalcemia, pheochromocytoma, malab-sorption (celiac disease, pancreatic insufficiency), eatingproblems (tremors), shopping problems, therapeutic diets, and

Table 2Prevalence of Frailty in Persons With Diabetes Mellitus

Author n Age, y Scale % D

Con

Ottenbacher et al32 2049 65þ Fried 24Hubbard et al33 2305 65þ 7-point scale 42.Cacciatore et al34 1288 65þ FSS* 40.

Bouillon et al39 2707 55 � 5 Fried 7.Tang et al40 3257 55þ Frailty Index Men 12.

(Rockwood) Women 18.Lee et al38 3018 65þ Fried

Dashes, no data available.*Frailty staging system (functioning, disability, mobility, cognition, vision, hearing, in

cholecystitis.60 There is evidence that caloric supplements,which should be given between meals, can improve out-comes.61 Finally, it should be recognized that frailty may occurdue to weight loss associated with the Sodium GlucoseTransporter inhibitors and other antidiabetic drugs (eg, alpha-1-glucose inhibitors) that can cause weight loss.62

Sarcopenia and Diabetes

Muscle loss occurs at the rate of 1% per year after 30 years of age.63

Excessive muscle loss has been called sarcopenia and leads to func-tional deterioration.64 Aging also is associated with a decrease in gaitspeed65 and handgrip strength.66 The new definitions for sarcopenia,which include low walking speed or grip strength, as well as lowmuscle mass, have been shown to be better at predicting adverseoutcomes compared with low muscle mass alone.67e69

Kim et al,70 in studying 414 men 65 years or older, found that inmen, low muscle mass, defined by appendicular muscle mass/height2

was lower in diabetic than in nondiabetic individuals. The data wereless clear in women, but muscle quality (total skeletal mass/weight)was lower in diabetic individuals in both sexes. In another study inKorea of 610 individuals, sarcopenia was present in 15.7% in patientswith diabetes and 6.9% in the control group.71 Leenders et al72 foundthat both appendicular skeletal mass and leg extension strength waslower in individuals with type 2 diabetes mellitus compared withnormoglycemic controls. In middle-aged Asian Indians, skeletal masswas lower in diabetic than nondiabetic individuals.73

In the Hertfordshire (UK) cohort study of 1391 persons aged 60 to70 years, there was a significant reduction in grip strength in personswith diabetes.74 In the Health, Aging and Body Composition Studycohort consisting of 1840 persons aged 70 to 79 years, diabetic in-dividuals had greater declines in muscle mass and leg musclestrength and poorer muscle quality over 3 years.75 Thigh musclecross-sectional area declined twice as fast in older women withdiabetes than in their nondiabetic counterparts over 6 years. Midupper arm muscle area and handgrip strength are lower in diabeticcompared with nondiabetic individuals who have undergone coro-nary artery bypass.76 Impaired mobility has been shown to be asso-ciated with reduced lower extremity muscle strength in persons withtype 2 diabetes.77 Gait speed is reduced in persons with diabetes.78

Data from the National Health and Nutrition Examination Survey(1999e2002) found that persons with diabetes had reduced quadri-ceps strength and power, as well as a reduced gait speed.79

In diabetic rats, there is fiber atrophy with a relative increase infast oxidative/glycolytic (Type IIA) fibers and a decrease in slowoxidative (Type I) fibers.80 This muscle atrophy with a switch toglycolytic fibers also has been seen in humans with diabetes.81e83

There is also a marked decrease in muscle capillary density.84 In

iabetes Outcome

trol Prefrail Frail

31 32 Predicted mortality and frailty at 10 years2 d 43.4 Frail had shorter survival2 d 48.4 Frail had higher mortality at 12 years

4 11.2 d

8 d 9.8 Frailty Index predicts diabetes6 d 20.3

Not reported Women with diabetes had worseoutcomes over 2 years

continence, social support).

Fig. 1. Factors associated with muscle loss in diabetes mellitus.

Fig. 3. Schematic representation: Combined effects of aging, diabetes, and sarcopeniaon lower limb dysfunction.

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diabetic mice, there is impaired muscle regeneration associated withfailed satellite cell activation.85 In a high glucose medium, stem cellstend to differentiate into adipocytes rather than satellite cells.86

Epigenetic changes in satellite cells obtained from persons withtype 2 diabetes mellitus appear to result in permanent changes in theability of these cells to express proteins involved in myogenesis.87

Proteomic studies have demonstrated a decrease in cytoskeletalproteins (desmin and alpha actinin-2) and increased proteasomeunits (involved in protein degradation).88

Pathophysiology of Sarcopenia

Multiple factors lead to the muscle wasting associated with oldage.89 The addition of diabetes mellitus accelerates the rate of muscleloss seen due to glucose toxicity, insulin resistance, and possibly somegenetic factors associated with diabetes.

Fig. 2. Effects of diabetes mellitus and insulin resistance on mitochondrial activity.

Genetic factors that have been suggested to play a role in sarco-penia include myostatin, Notch, and angiotensin-converting enzyme,among others.90 Myostatin is a member of the transforming growthfactor b superfamily and is an inhibitor of skeletal muscle growth.Myostatin mRNA levels are increased in muscle from type 2 diabeticindividuals as well as their nonobese relatives.91 Myostatin levels areincreased in persons with type 2 diabetes.92 Expression of mRNA formyostatin and its receptor (activin R2B) was increased in mice withstreptozotocin-induced diabetes.93 The upregulation of myostatingene expression was reduced by insulin.94 These findings support arole for myostatin in the muscle wasting seen in diabetic individuals.

The Notch signaling pathway plays a role as a regulator of stemcells.95 High glucose levels inhibit Notch leading to disruption ofangiogenesis.96 Angiotensin II acts on myocellular AT1 receptors toproduce oxidative stress and results in insulin resistance.97 Expres-sion of angiotensin-converting enzyme II inhibitor is increased inpatients with type 2 diabetic nephropathy.98 There is much workrequired to understand the role of genetic interactions with diabetesin the pathogenesis of sarcopenia.

A major component of sarcopenia in older persons is a decrease inmotor and plates and thus nerve input to muscle function.99 In dia-betes, neuropathy leads to muscle wasting and weakness of distalskeletal muscles.27 Andreasson et al99 showed that neurotrophin-3 isreduced in diabetic muscle and is related to muscle weakness. Theyfound no relationship to brain-derived neurotrophic factor or ciliaryneurotrophic factor.

Intermuscular adipose tissue volume is increased in persons withdiabetes, especially those with peripheral neuropathy.100 This accu-mulation of fat is associated with poorer muscle strength and func-tion, and is the basis of obese sarcopenia.

Advanced glycation end products (AGEs) are markers of long-termglucose toxicity. AGEs are associated with poor grip strength in olderpersons.101 AGEs accumulate in skeletal muscle in persons with dia-betes. AGEs in skin in Japanese men is correlated with grip strengthand leg-extension power.102 AGEs are associated with slow walkingspeed.103 AGEs increase reactive oxygen species and oxidativedamage.104

Diabetes is associated with an increase in inflammatory cyto-kines.105 Interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha havebeen related to muscle loss and a decrease in muscle strength andfunction.106

The decline of anabolic hormones with aging has been consideredto play a major role in sarcopenia.107 Testosterone levels aredecreased in men with diabetes108 and in obesity.109 Testosterone

Table 3Future Research in Frailty, Sarcopenia, and Diabetes Mellitus

Research How to Address Gaps/Shortfalls in the Field

Exploring the role of diabetes and sarcopenia in the etiology of the frailty stateand how this is related to adverse functional effects and related clinicalconsequences

� Use of the FRAIL scale to determine the prevalence of frailty in varied clinicalpopulations of those with sarcopenia and/or diabetes mellitus

� Longitudinal studies in patients with type 2 diabetes examining the interplaywith sarcopenia and diabetes and the emergence of frailty

Examining the influence of impaired mitochondrial function in thedevelopment of insulin resistance in frailty and sarcopenia

� Cross-sectional and prospective basic science and clinical evaluation studiesin older people with frailty and/or sarcopenia

Developing clinical trial methods: influencing major pharmaceutical companiesto participate

� Randomized controlled trials in aged subjects (>75 years) to examine benefitsof exercise and adjunct treatmentmodalities using outcomemeasures such aspredisability/disability, incidence of dementia, frailty, falls rate, quality of life,mood level, hypoglycemia, and hospitalization rates

� Demonstration of likely benefits in a broad range of older people with dia-betes and sarcopenia: frail, care home residency/housebound, dementia

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deficiency leads to a decline in muscle protein synthesis as well assatellite cell activation through an increase in beta-catenin activity.110

The vascular system regulates the delivery of nutrients and hor-mones to muscles. Peripheral vascular disease can lead to a decreasein blood flow to muscle. In diabetes, a more important factor is therecruitment of muscle capillaries to increase the delivery of nutrients,insulin, and oxygen to muscle during exercise.111 This involves a nitricoxideedependent vasodilation and is insulin dependent. Impairedinsulin recruitment of capillaries can lead to decreased glucose up-take in muscle. In persons with diabetes, there is a marked decreasein muscle perfusion and muscle oxygen extraction.112 Capillary den-sity is reduced in diabetic individuals and was increased withtreatment with troglitazone.113 Metformin stimulates arteriolarvasomotion and improves functional capillary density.114

Approximately a quarter of weight loss is due to loss of muscle andbone.115 Weight loss is also associated with a decrease in musclestrength.116 When weight loss is done together with resistance ex-ercise, these negative effects on muscle can be attenuated.117 Weightloss is common in diabetic individuals either when done deliberatelyas part of a lifestyle intervention or due to uncontrolled hypergly-cemia or medications such as the glucagon-peptide like-1 agonistsand the sodium glucose transporter-2 inhibitors.

Figure 1 summarizes the factors involved in muscle loss (sarco-penia) in persons with diabetes mellitus.

Skeletal Muscle Insulin Resistance

Insulin stimulates the mammalian target of rapamycin pathway,leading to protein synthesis and decreases protein degradation.118

There are mild decreases in amino acid metabolism in type 2 dia-betes.119,120 Insulin resistance is associated with higher expression ofthe E2 enzymes, atrogin-1, and muscle ring finger-1.121 This leads toincreased activation of the ubiquitin-proteasome pathway, resultingin degradation of muscle protein.122

Insulin resistance is also associated with impaired mitochondrialfunction in muscles. In many, but not all, diabetic individuals there isa reduction in mitochondrial size.123e125 Increased circulating lipidsin older persons leads to accumulation of cytoplasmic fatty acids. Thisleads to increase stress on the mitochondrial respiratory chain. Aging,and perhaps some genes associated with diabetes, lead to a reductionin mitochondrial proteins.126 The increased stress on the mitochon-dria coupled with decreased mitochondrial proteins results inincreased production of reactive oxygen species and oxidative dam-age.127 Increased fatty acids in the cytoplasm results in phosphory-lation of the insulin receptor substrate, impairing the ability of insulinbinding to its receptors to activate its phosphorylation cascade andresulting in its ability to fully activate the glucose transporter, re-sulting in insulin resistance.128 These changes result in impairedmitochondrial function in type 2 diabetes.129 In addition, there is also

a decrease in the release of ATP in response to insulin in persons withtype 2 diabetes.130 Overall, these changes (Figure 2) lead to animpairment of muscle function together with an accumulation oflipids in skeletal muscle in persons with diabetes.

Treatment of Sarcopenia

The treatment of sarcopenia, no matter what the cause, is pri-marily resistance exercise.131,132 Exercise alters cytokine geneexpression in skeletal muscle133 and improves capillary blood flowand nutrient delivery to muscle134 in persons with diabetes.

Decreasing insulin resistance using insulin sensitizers and weightloss coupled with resistance exercise is the second approach toenhancing muscle function. There is also evidence to support the useof leucine-enriched essential amino acids with an intake of protein atapproximately the level of 1.0 to 1.2 g/kg per day.135

At present, the availability of drugs to improve muscle function islimited.89 There is evidence that testosterone will improve musclestrength and function even in frail older persons, but its potential sideeffects have not yet made it ready for prime time.136 Selectiveandrogen receptor molecules, such as enobosarm, have some evi-dence for their efficacy.137 Myostatin antibodies have not been over-whelmingly successful, but Regeneron has one molecule (REGN1033,Tarrytown, NY) in clinical trials.138 The original activin II soluble re-ceptor decoy was successful but then developed side effects.138 Adirect antibody to the activin II receptor from Novartis (Basel,Switzerland) is in clinical trials.139

Conclusion

Both frailty and sarcopenia are common occurrences in personsolder than 55 years with diabetes (Figure 3). They are highly corre-lated with poor outcomes and are treatable predominantly with ex-ercise interventions. An international frailty group has suggested thatfrailty should be screened for with the simple FRAIL questionnaire inolder persons (Table 2).140,141 The data reviewed here support theconcept that frailty should also be screened for in persons with dia-betes mellitus at middle age and beyond. Cognitive impairment iscommon in persons with diabetes mellitus.142e144 Table 3 provides anapproach to future research in frailty, sarcopenia, and diabetes mel-litus. There is increasing evidence that mild cognitive impairmentacts synergistically with frailty to accelerate poor outcomes.29,30,145

This interaction has not been studied in persons with diabetes.

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