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Diabetes and Frailty: Two Converging Conditions?

Published:December 09, 2015DOI:https://doi.org/10.1016/j.jcjd.2015.09.004

      Abstract

      Diabetes mellitus is a disabling, chronic cardiovascular and medical disease with a tremendous health, social and economic burden in our ageing communities. It has a prevalence of 10% to 30% in people older than 65 years of age, and more than half of all subjects with diabetes in the United States are older than 60 years of age.
      The main impact of diabetes in older adults stems from its effect on function, both physical and cognitive, that finally impairs their quality of life, although the impact on survival is modest.
      Frailty has emerged during the past 2 decades as the most powerful predictor of disability and other adverse outcomes, including mortality, disability and institutionalization in older adults.
      In this article we explore the relationship between diabetes and frailty, and we recognize that they are intimately related chronic medical conditions that result in huge societal and personal health burdens.

      Résumé

      Le diabète sucré est une affection médicale et cardiovasculaire invalidante de longue durée qui représente un fardeau social et économique énorme en matière de santé au sein de nos communautés vieillissantes. Sa prévalence est de 10 % à 20 % chez les personnes âgées de plus de 65 ans, et plus de la moitié de tous les sujets diabétiques des États-Unis ont plus de 60 ans.
      Les principales conséquences du diabète chez les personnes âgées découlent de son effet sur le fonctionnement physique et cognitif, qui finalement dégrade leur qualité de vie, bien que les conséquences sur la survie soient modestes.
      La fragilité est apparue au cours des 2 dernières décennies comme le plus puissant prédicteur de l'invalidité et d'autres résultats indésirables, dont la mortalité, l'invalidité et l'institutionnalisation des personnes âgées.
      Dans le présent article, nous explorons la relation entre le diabète et la fragilité, et nous reconnaissons le lien intime entre les affections médicales de longue durée et les fardeaux immenses sur la société et l'individu.

      Keywords

      Mots clés

      Introduction

      Diabetes mellitus is a highly prevalent metabolic disease that can lead to marked disability. Evidence supports reduced survival in older adults with diabetes. Diabetes has a prevalence of up to 30% in persons above 65 years of age in some populations (
      • Wilson P.N.F.
      Epidemiology of diabetes in the elderly.
      ,
      • Harris M.I.
      • Hadden W.C.
      • Knowler W.C.
      • Bennett P.H.
      Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in US population aged 20–74 years.
      ,
      • Manton K.G.
      • Stallard E.S.
      • Liu K.
      Forecasts of active life expectancy: Policy and fiscal implications.
      ,
      • Resnick H.E.
      • Harris M.I.
      • Brock D.B.
      • Harris T.B.
      American Diabetes Association diabetes diagnostic criteria, advancing age, and cardiovascular disease risk profiles: Results from the Third National Health and Nutrition Examination Survey.
      ), and more than half of all people with diabetes in the United States are older than 60 years of age (
      • Resnick H.E.
      • Harris M.I.
      • Brock D.B.
      • Harris T.B.
      American Diabetes Association diabetes diagnostic criteria, advancing age, and cardiovascular disease risk profiles: Results from the Third National Health and Nutrition Examination Survey.
      ). It is estimated that as much as 40% of people who have diabetes have not been diagnosed (
      • Halter J.B.
      Diabetes mellitus in older adults: Underdiagnosis and undertreatment.
      ). Men and women with diabetes diagnosed at age 60 have estimated reductions in life expectancy of 7.3 to 9.5 years and good quality of life of 11.1 to 13.8 years, respectively (
      • Narayan K.M.
      • Boyle J.P.
      • Thompson J.
      Lifetime risk for diabetes mellitus in the United States.
      ).
      The burden of diabetes is high and has been ranked as the seventh and eighth causes of years of life lost and disability-adjusted life years (DALYs), respectively, in Western societies, and there was an increase of more than 60% in 2010 as compared with 1990. Taking into account that 1) the ageing of the population is involved in generating the increase in DALYs due to noncommunicable diseases; 2) there is a shift to the burden in older ages; and 3) there is a tendency to a greater weight placed on years lived with disability in determining DALYs. Therefore, it is predicted that an increasingly relevant role of diabetes in older adults in the burden of disease will occur (
      • Murray C.J.
      • Lopez A.D.
      Measuring the global burden of disease.
      ,
      • Sloan F.A.
      • Bethel M.A.
      • Ruiz D.
      • et al.
      The growing burden of diabetes mellitus in the US elderly population.
      ).
      Thus, function becomes of great importance in the care of older people with diabetes. A key strategy is to prevent the functional decline instead of attempting to recover lost function. This focus on prevention stems from 2 generalized observations: to recover functional independence when disability has been developed is rather unlikely (
      • Boyd C.M.
      • Landefeld C.S.
      • Counsell S.R.
      • et al.
      Recovery of activities of daily living in older adults after hospitalization for acute medical illness.
      ); and it is possible to prevent incident disability's intervening in some conditions that predict the risk for disability (
      • Espeland M.A.
      • Gill T.M.
      • Guralnik J.
      • et al.
      Designing clinical trials of interventions for mobility disability: Results from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) trial.
      ). In addition, in 2014 the results of Lifestyle Interventions and Independence for Elders (LIFE) study were published (
      • Pahor M.
      • Guralnik J.M.
      • Ambrosius W.T.
      • et al.
      Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomised clinical trial.
      ) and showed that direct interventions in frail older people, based on an exercise and an education program, successfully improved the physical conditions of these patients. This new approach in the quest for successful ageing results in a new challenge for the management of older patients.
      Threats to functional status in older age include medical comorbidities, other chronic conditions, such as dementia and diabetes, and the onset of frailty. Frailty has emerged during the past 2 decades as the most powerful predictor of disability and other adverse outcomes, including mortality, disability and institutionalization in older adults (
      • Fried L.P.
      • Ferruci L.
      • Darer J.
      • et al.
      Understanding the concepts of disability, frailty and comorbidity: Implications for improved targeting and care.
      ). As a consequence, frailty is becoming 1 of the central issues in the assessment of older adults in clinical scenarios (
      • Rodriguez-Mañas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      ). It is described as a state of increased vulnerability to stressors that result from decreased physiologic reserve in multiple systems that cause limited capacity to maintain homeostasis (
      • Fried L.P.
      • Kronmal R.A.
      • Newman A.B.
      • et al.
      Risk factors for 5-years mortality in older adults: The Cardiovascular Health Study.
      ). The prevalence of frailty in older adults has been described to be between 7% and 30% in differing population studies, depending on the nature of the populations and the criteria used (
      • Collard R.M.
      • Boter H.
      • Schoevers R.A.
      • Oude Voshaar R.C.
      Prevalence of frailty in community-dwelling older persons: A systematic review.
      ).
      Although several mechanisms are involved in the pathophysiology of frailty, all of them appear to converge in a final common pathway toward frailty, with sarcopenia as an important contributor. Sarcopenia is the loss of muscle mass associated with ageing. Its prevalence ranges from of 8% to 50% in older people (
      • Kallman D.A.
      • Plato C.C.
      • Tobin J.D.
      The role of muscle loss in the age-related decline of grip strength: Cross-sectional and longitudinal perspectives.
      ,
      • Morley J.E.
      • Baumgartner R.N.
      • Roubenoff R.
      • et al.
      Sarcopenia.
      ).
      It is known that diabetes accelerates loss of muscle mass, a process that may be exacerbated by sarcopenia and frailty (
      • Kalyani R.R.
      • Corriere M.
      • Ferrucci L.
      Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases.
      ), but research has not yet delved deep enough into the close relationship among these 3 entities. The hypothesis of this short review is that diabetes, frailty and sarcopenia are related conditions, and the objectives are to explain the nature of this relationship. Is diabetes a direct factor in the development of frailty? Is sarcopenia an intermediate step in the progression of diabetes to frailty? Or are both statements true? Unless indicated specifically, this review involves all older subjects with diabetes, although we must accept that research findings in older persons with type 1 diabetes is limited.

      Diabetes Mellitus

      Diabetes is a syndrome characterized by chronic hyperglycemia and disturbances of carbohydrate, fat and protein metabolism that is associated with an absolute or relative deficiency in insulin secretion and/or insulin action. The development of type 2 diabetes in older adults represents the progressive worsening of multiple age-related metabolic disturbances plus a contribution from environmental, genetic and behavioural factors (
      • Meneilly G.S.
      • Elahi D.
      Metabolic alterations in middle-aged and elderly lean patients with type 2 diabetes.
      ).
      At a functional level, numerous studies have found that persons with diabetes have greater functional decline than older counterparts; this is associated with disability, morbidity, mortality and institutionalization (
      • Wong E.
      • Backholer K.
      • Gearon E.
      • et al.
      Diabetes and risk of physical disability in adults: A systematic review and meta-analysis.
      ). Diabetes is also considered an independent risk factor in older people for falling and developing hip fractures (
      • Stotmeyer E.S.
      • Cauley J.A.
      • Schwartz A.V.
      • et al.
      Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: The health, aging and body composition study.
      ).
      Older individuals with diabetes have higher rates of premature death and of coexisting illnesses, such as hypertension, heart disease, cerebrovascular disease and stroke, than those without this condition (
      • Mac Leod K.M.
      • Tooke J.E.
      Direct and indirect costs of cardiovascular and cerebrovascular complications of type II diabetes.
      ), and they are also at greater risk for several common geriatric syndromes, such as polypharmacy, depression, cognitive impairment, urinary incontinence, injurious falls and persistent pain (
      • American Diabetes Association
      Standards of medical care in diabetes, 2015.
      ). Older patients with diabetes have increased prevalence of cognitive decline and are more likely to develop vascular dementia and possibly Alzheimer disease (
      • Wong E.
      • Backholer K.
      • Gearon E.
      • et al.
      Diabetes and risk of physical disability in adults: A systematic review and meta-analysis.
      ,
      • Nicolls M.R.
      The clinical and biological relationship between type II diabetes mellitus and Alzheimer's disease.
      ).
      We also know that diabetes is a risk factor for developing frailty, more than doubling the risk (odds ratio [OR]: 2.18) after 3.5 years of follow up. Overall, it is associated with a decline in quality of life and a decrease in leisure activities (
      • García-Esquinas E.
      • Graciani A.
      • Guallar-Castillón P.
      • et al.
      Diabetes and risk of frailty and its potential mechanisms: A prospective cohort study of older adults.
      ,
      • Sinclair A.
      • Dunning T.
      • Rodriguez-Mañas L.
      Diabetes in older people: New insights and remaining challenges.
      ).

      Sarcopenia

      Sarcopenia describes one of the most noticeable changes that occur with ageing; it is a progressive decline of muscle mass, leading to low and impaired strength and functioning. Although there is general agreement that older people tend to become sarcopenic, there is substantial disagreement about the criteria that should be used for the definition of sarcopenia (
      • Lourenço R.A.
      • Pérez-Zepeda M.
      • Gutiérrez-Robledo L.
      • et al.
      Performance of the European Working Group on Sarcopenia in Older People: Algorithm in screening older adults for muscle mass assessment.
      ).
      Sarcopenia affects all older people and does not discriminate on the basis of ethnicity, gender or wealth. After 50 years of age, muscle mass is reported to decline at an annual rate of approximately 1% to 2%, accelerates to as much as 1.5% to 3% per year after age 60, and becomes ever faster after age 75 (
      • Hughes V.A.
      • Frontera E.R.
      • Roubenoff R.
      • et al.
      Longitudinal changes in body composition in older men and women: Role of body weight change and physical activity.
      ). During ageing, the loss of muscle mass and strength is hypothesized to be due to progressive atrophy (decrease in myofibre cross-sectional area), loss of muscle fibres (
      • McNeil C.J.
      • Doherty T.J.
      • Stashuk D.W.
      • Rice C.L.
      Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men.
      ) and reduction in muscle quality due to the infiltration of fat and other noncontractile material such as connective tissue, as well as to changes in muscle metabolism and insulin resistance (
      • Cree M.G.
      • Newcomer B.R.
      • Katsanos C.S.
      • et al.
      Intramuscular and liver triglycerides are increased in the elderly.
      ). The loss of muscle mass is due primarily to a decrease in the number of both type I (slow twich) and type II (fast twich) muscle fibres and a reduction in the size of the remaining muscle fibres, with a preferential atrophy of the type II fibres (
      • Giresi P.G.
      • Stevenson E.J.
      • Theilhaber J.
      • et al.
      Identification of molecular signature of sarcopenia.
      ).
      Intimately linked to the decrease in muscle mass, there is a metabolic deregulation, which includes a reduction in insulin sensitivity, impaired oxidative defence and decreased mitochondrial function. Sarcopenia may be associated with a severe metabolic state that is characterized by increased insulin resistance, diabetes and hypertension. Sarcopenia is used interchangeably to describe age-related muscle loss and the clinical condition. The main effect of the loss of muscle mass is reduced muscle strength and power, which are important factors in maintaining stability and gait and are necessary to the performance of the activities of daily living (
      • Rolland Y.
      • Czerwinski S.
      • Abellan van Kan G.
      • et al.
      Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
      ).
      Increased clinical and epidemiologic interest in sarcopenia is related to the hypothesis that age-related loss of muscle mass and strength results in functional limitations and decreased mobility in older adults (
      • Amigues I.
      • Schott A.M.
      • Amine M.
      • et al.
      Low skeletal muscle mass and risk of functional decline in elderly community-dwelling women: The prospective EPIDOS study.
      ). Impaired muscle strength is highly predictive of incident disability and all-cause mortality in this population, and in older sarcopenic persons, a pathology-induced supplementary muscle weakness can very rapidly lead to disability and additional morbidity. Several epidemiologic studies have documented an association between low skeletal muscle mass and the risk for physical disability (
      • Amigues I.
      • Schott A.M.
      • Amine M.
      • et al.
      Low skeletal muscle mass and risk of functional decline in elderly community-dwelling women: The prospective EPIDOS study.
      ), and some authors have put forward the hypothesis that sarcopenia is an integral component of frailty (
      • Cesari M.
      • Leeuenburgh C.
      • Lauretani F.
      • et al.
      Frailty syndrome and skeletal muscle: Result from the InCHIANTI study.
      ).

      Frailty

      As previously stated, frailty is a complex clinical entity characterized by the imbalance of homeostatic capacity, which becomes particularly evident as the inability to regain stable homeostasis after a stressful destabilizing event.
      Although agreement between a standardized definition and an empirical basis is lacking (
      • Rodríguez-Mañas L.
      • Féart C.
      • Mann G.
      • et al.
      Searching for an operational definition of frailty: A Delphi method based consensus statement: The frailty operative definition-consensus conference project.
      ), Linda Fried and colleagues defined a clinical phenotype of frailty, which is identified by the presence of 3 or more of the following components (
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      ):
      • Weight loss: unintentional loss of ≥4.5 kg in the past year
      • Weakness: hand-grip strength in the lowest 20% quintile at baseline, adjusted for sex and body mass index
      • Exhaustion: poor endurance and energy, self-reported from the Center for Epidemiologic Studies Depression scale
      • Slowness: walking speed under the lowest quintile adjusted for sex and height
      • Low physical activity level: lowest quintile of kilocalories of physical activity during the past week, measured by the Minnesota Leisure Activity Scale.
      A biologic model, the cycle of frailty, which includes sarcopenia and neuroendocrine and immune dysfunction as potential causes, has been proposed. Frailty is not an inevitable consequence of the ageing process, and it has been stated that the downward spiral leading to this syndrome could be precipitated by trigger events (
      • Rodriguez-Mañas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      ,
      • Clegg A.
      • Young J.
      • Iliffe S.
      • et al.
      Frailty in older people.
      ). Because frailty appears to be a dynamic process and also potentially reversible, early recognition of frailty and early interventions should be major issues for general practice.

      Sarcopenia as an intermediate step between diabetes and frailty

      Several components involved in producing sarcopenia can explain some of the relationships between diabetes and sarcopenia with frailty. The maintenance of skeletal mass and function is the result of multiple factors, including hormonal, inflammatory, neurologic, nutritional and activity components (
      • Rolland Y.
      • Czerwinski S.
      • Abellan van Kan G.
      • et al.
      Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
      ). Thus, the development of sarcopenia can, in itself, be a result of alterations in multiple physiologic systems as well as from decline in activity and specific diseases. A very brief review of these factors follows.

      Nutritional factors

      Community-dwelling older subjects with diabetes may be at risk for malnutrition when compared with citizens without diabetes, and there is probably a causal relationship between malnutrition and functional decline in this group (
      • Turnbull P.J.
      • Sinclair A.J.
      Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes mellitus using the mininutritional assessment (MNA) tool: A preliminary investigation.
      ). Subclinical deficiencies in vitamin B have been found in persons with type 2 diabetes, especially those taking metformin (
      • Matthew C.
      • Robert C.
      • Aaron S.
      • et al.
      The prevalence of vitamin B12 deficiency in patients with type 2 diabetes: A cross-sectional study.
      ). Other factors also contribute to undernutrition in older people, including the presence of renal failure (
      • Visvanathan R.
      • McPhee I.
      Undernutrition and anorexia in the older person.
      ), which can be associated with protein-restrictive diets and vitamin D deficiencies that cannot maintain muscle mass and function.

      Hormone disbalance

      Age-related alterations in hypothalamic-pituitary-testicular, hypothalamic-pituitary-adrenal and insulin-like growth factor I (IGF-1) and type 1 IGF receptor (IGF1r) axes are known to be associated with frailty via influences on muscle strength, bone strength and mobility (
      • Rolland Y.
      • Czerwinski S.
      • Abellan van Kan G.
      • et al.
      Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
      ). IGF-1 has been shown to be lower in those with diabetes (
      • Kalyani R.R.
      • Corriere M.
      • Ferrucci L.
      Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases.
      ) and to play a role in the protein synthesis of the muscle. Testosterone levels are involved in protein synthesis and satellite-cell formation, producing increased muscle mass (
      • Kalyani R.R.
      • Corriere M.
      • Ferrucci L.
      Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases.
      ). There is now accumulating evidence that low serum testosterone levels are associated with type 2 diabetes, and several mechanisms of the association of low serum testosterone levels and type 2 diabetes with insulin resistance and obesity as central features have been reported (
      • Cheung K.
      • Luk A.
      • So W.
      • et al.
      Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence.
      ).
      Vitamin D levels are lower in those with diabetes, and studies in animals and humans suggest that vitamin D deficiency may contribute to B-cell dysfunction, insulin resistance and inflammation that may result in type 2 diabetes (
      • Ozfirat Z.
      • Tahseen A.C.
      Vitamin D deficiency and type 2 diabetes.
      ). Additionally, small intervention studies show that vitamin D supplementation reduces systematic inflammation and improves glucose tolerance. Some, but not all studies, suggest that vitamin D levels correlate with muscle mass and strength. Finally, low levels of vitamin D are associated with falls and functional decline (
      • Latham N.K.
      • Anderson C.S.
      • Reid I.R.
      Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: A systematic review.
      ) and with the frailty syndrome (
      • Shardell M.
      • Hicks G.E.
      • Miller R.R.
      • et al.
      Association of low vitamin D levels with the frailty syndrome in men and women.
      ).
      Deficiency of the adipocyte hormone leptin results in hyperphagia, obesity and insulin resistance. It has been shown that leptin and ghrelin act as mutual antagonists to affect energy homeostasis, and this could be due to elevation in plasma insulin. Levels of both hormones change with ageing, and some recent studies have shown that older adults with frailty have the lowest levels of ghrelin (
      • Serra-Prat M.
      • Palomera E.
      • Clave P.
      • Puig-Domingo M.
      Effect of age and frailty on ghrelin and cholecystokinin responses to a meal test.
      ).

      Insulin and insulin resistance

      In patients with type 2 diabetes, insulin resistance per se may lead to impairment of muscle strength and performance (
      • Rolland Y.
      • Czerwinski S.
      • Abellan van Kan G.
      • et al.
      Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
      ) and, during ageing, insulin resistance seems to be involved in muscle protein loss and in other contributory changes, such as defects in the insulin signal transduction pathway and mitochondrial alterations, leading to a reduction in energy production required for muscle contraction. Although its effect on muscle synthesis remains controversial, loss of control of the anabolic action of insulin on ageing muscle is a key factor favouring sarcopenia (
      • Rolland Y.
      • Czerwinski S.
      • Abellan van Kan G.
      • et al.
      Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
      ). It has been reported that handgrip muscle strength is significantly associated with fasting insulin levels or insulin resistance as evaluated by the homeostasis model assessment (HOMA-IR). Nomura et al described that lower-extremity muscle strength is independently associated with IR (
      • Nomura T.
      • Ikeda Y.
      • Nakao S.
      • et al.
      Muscle strength is a marker of insulin resistance in patients with type 2 diabetes: a pilot study.
      ).
      Many other insulin-related observations underpin the close relationship between insulin and its potential role in muscle metabolism and function: inhibition of muscle protein degradation (
      • Louard R.J.
      • Fryburg D.A.
      • Gelfand R.A.
      • Barrett E.J.
      Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle.
      ), increase in protein synthesis and inhibition of proteolysis following infusion of insulin and amino acids (
      • Newman E.
      • Heslin M.J.
      • Wolf R.F.
      • et al.
      The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm.
      ), receptor autophosphorylation, and activation of insulin receptor substrate proteins that initiate the biochemical pathway of phosphatidylinositol 3-Kinasa (PI 3-Kinase) following the binding of insulin to its receptor, all of which are involved in key steps in protein regulation (
      • Guttridge D.C.
      Signaling pathways weigh on decisions to make or break skeletal muscle.
      ).

      Inflammation and anti-inflammation response

      The increase of proinflammatory cytokines (TNF alpha, IL 1, IL 5, IL 6), has been indicated as a potential explanation for several age-related phenotypic changes. Increases in inflammatory marker levels has been associated with sarcopenia, frailty and functional decline (
      • Payette H.
      • Roubenoff R.
      • Jacques P.F.
      • et al.
      Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: The Framingham Heart Study.
      ,
      • Walston J.
      • Arking D.E.
      • Fallin D.
      • et al.
      IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.
      ). Diabetes is associated with elevated cytokine levels, suggesting that cytokines play an important role in the association between sarcopenia and diabetes; higher plasma levels of cytokines (which can induce insulin resistance) are associated with lower muscle functioning (
      • Visser M.
      • Pahor M.
      • Taeffe D.R.
      • et al.
      Relationship of interleukin-6 and tumor necrosis factor-α with muscle mass and muscle strength in elderly men and women: The Health ABC Study.
      ).

      Obesity

      Obesity is a precipitating factor for the development of type 2 diabetes and frailty (
      • García-Esquinas E.
      • José García-García F.
      • León-Muñoz L.M.
      • et al.
      Obesity, fat distribution, and risk of frailty in two population-based cohorts of older adults in Spain.
      ). A progressive increase in body and intramyocellular fat mass is associated with an increasing risk for insulin resistance, and the rise in insulin resistance with ageing is associated with increased visceral adiposity (
      • Kanaya A.M.
      • Harris T.
      • Goodpaster B.H.
      • et al.
      Adipocytokines attenuate the association between visceral adiposity and diabetes in older adults.
      ).
      With higher fat mass and lower muscle mass, physical activity becomes progressively more difficult, and its usual level declines, promoting more muscle mass loss. This vicious circle potentially leads to “sarcopenic obesity,” a major risk factor for the onset of physical disability (
      • Baumgartner R.N.
      Body composition in healthy aging.
      ).

      Advance glycation end products

      Advanced glycosylation end product (AGE) formation is an important biochemical abnormality that accompanies diabetes mellitus. These products, obtained by the nonenzymatic glycosylation of protein adduct, have been hypothesized to play a role in the pathogenesis of sarcopenia through AGE-mediated increases in inflammation and endothelial dysfunction in the microcirculation of skeletal muscle and through the cross-linking of collagen in skeletal muscle (
      • Payne G.W.
      Effect of inflammation on the aging microcirculation: Impact on skeletal muscle blood flow control.
      ).

      Mitochondrial dysfunction

      The sequence of events between sarcopenia and diabetes may start with mitochondrial dysfunction; defects in mitochondrial oxidation and phosphorylation have been shown both in older adults without diabetes and in the young obese and nondiabetic offspring of persons with type 2 diabetes (
      • Petersen K.F.
      • Befroy D.
      • Dufour S.
      • et al.
      Mitochondrial dysfunction in the elderly: Possible role in insulin resistance.
      ,
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • et al.
      Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.
      ). In these patients, increased free fatty acid availability results in the accumulation of intramyocellular fatty acyl-coA, inducing a series of alterations:
      • Impaired insulin-stimulated oxidative phosphorylation (ATP synthesis)
      • Reduced expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma), coactivator-1 (PGC-1) and PGC-1-controlled genes involved in mitochondrial biogenesis and oxidative phosphorylation
      • Initiation of inflammatory processes by activation of protein kinase C (PKC) and nuclear factor kappa beta (NF- kappa beta) and decreased expression of matrix metalloproteinases.
      These abnormalities could lead to a vicious circle in which mitochondrial dysfunction, elevation of intramyocellular lipids, impaired lipid oxidation and insulin resistance amplify each other, leading to sarcopenia.

      Others factors

      Microvascular-related diabetes complications

      There is growing recognition that the vascular complications associated with type 2 diabetes translate into functional impairment in older adults (
      • De Rekeneire N.
      • Resnick H.E.
      • Shwartz A.V.
      • et al.
      Diabetes is associated with subclinical functional limitation in nondisabled older individuals: The Health, Aging, and Body Composition study.
      ). Diabetic polyneuropathy is frequently encountered in patients with type 2 diabetes, and alterations in neurotransmission and motor unit remodelling may provide a basis for changes in motor performance when neuropathy is present (
      • Allen M.D.
      • Stashuk D.W.
      • Kimpinski K.
      • et al.
      Increased neuromuscular transmission instability and motor unit remodelling with diabetic neuropathy as assessed using novel near fibre motor unit potential parameters.
      ).
      Type 2 diabetes is a major cause of chronic kidney disease (CKD), and frailty is common in patients with CKD because it is commonly associated with inactivity, loss of muscle mass, comorbid conditions and decline in physical and cognitive functioning (
      • Roshanravan B.
      Frailty in CKD: Is only seeing worth believing?.
      ).

      Atherosclerosis and diabetes

      Diabetes increases the propensity for coronary artery diseases, strokes and peripheral vascular diseases, which are conditions that can exacerbate physical inactivity, morbidity and mortality (
      • Sinclair A.
      • Dunning T.
      • Rodriguez-Mañas L.
      Diabetes in older people: New insights and remaining challenges.
      ). Atherosclerotic change and endothelial dysfunction underlie many of the features of insulin resistance in subjects with type 2 diabetes.
      Peripheral vascular disease may affect muscular performance (
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      ,
      • Clegg A.
      • Young J.
      • Iliffe S.
      • et al.
      Frailty in older people.
      ,
      • Turnbull P.J.
      • Sinclair A.J.
      Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes mellitus using the mininutritional assessment (MNA) tool: A preliminary investigation.
      ). Peripheral arterial disease in individuals with diabetes is more diffuse and often involves the popliteal and below-knee arteries, compared to that in those without diabetes. Also, impaired oxygen supply could affect striated muscle directly or indirectly via the peripheral nerves (
      • Rodríguez-Mañas L.
      • Bouzon C.A.
      • Castro M.
      Peripheral arterial disease in old people with diabetes.
      ).

      Cognitive decline

      Some studies have found that frailty is associated with an increased risk for mild cognitive impairment. Samper-Ternent et al (
      • Samper-Ternent R.
      • Al Snih S.
      • Raji M.A.
      • et al.
      Relationship between frailty and cognitive decline in older Mexican Americans.
      ) described that the frail status in older Mexican Americans with Mini-Mental State Examination (MMSE) scores of 21 or higher at baseline is an independent predictor of MMSE score decline over a 10-year period (
      • Samper-Ternent R.
      • Al Snih S.
      • Raji M.A.
      • et al.
      Relationship between frailty and cognitive decline in older Mexican Americans.
      ), although these findings may be explained by slow gait speed and weak grip strength seen in those with cognitive impairment accompanied by changes in mobility, body composition or comorbidity seen in dementia syndromes (
      • Buchman A.S.
      • Schneider J.A.
      • Leurgans S.
      • et al.
      Physical frailty in older persons is associated with Alzheimer disease pathology.
      ). Diabetes mellitus is associated with an increased risk for both types of dementia (
      • Cheng G.
      • Huang C.
      • Deng H.
      • Wang H.
      Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies.
      ), and people with known diabetes who experience repeated hypoglycemic episodes are more likely to develop dementia (
      • Whitmer R.A.
      • Karter A.J.
      • Yaffe K.
      • et al.
      Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
      ). An important challenge is to establish the importance of screening for cognitive impairment in people with diabetes and to identify those at increased risk for accelerated cognitive decline at early stages (
      • Koekkoek P.S.
      • Kappelle L.J.
      • van den Berg E.
      • et al.
      Cognitive function in patients with diabetes mellitus: Guidance for daily care.
      ).
      Diabetes-related formation of AGEs has been implicated in the development of Alzheimer disease (AD) (
      • Roriz-Filho J.S.
      • Sá-Rodriguez T.M.
      • Rosset I.
      • et al.
      Pre)diabetes, brain aging, and cognition.
      ), and cerebrovascular disease may exacerbate neurocognitive functioning via this mechanism, which may also exacerbate beta amyloid neurotoxicity (
      • Pasquier F.
      • Boulogne A.
      • Leys D.
      • Fontaine P.
      Diabetes mellitus and dementia.
      ). Decreased cholinergic transport across the blood-brain barrier observed in diabetic animals may also exacerbate cognitive impairment in AD (
      • Pasquier F.
      • Boulogne A.
      • Leys D.
      • Fontaine P.
      Diabetes mellitus and dementia.
      ).
      The term type 3 diabetes has been used to suggest that AD is a form of diabetes (
      • Monte S.M.
      • Wands J.R.
      Alzheimer's disease is type 3-evidence reviewed.
      ) on the basis of findings such as hyperinsulinemia that is linked to recent-onset AD in subjects without diabetes (
      • Kuusisto J.
      • Koivisto K.
      • Mykkanen L.
      • et al.
      Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: Cross-sectional population-based study.
      ), neurotropic properties of insulin, reduced amyloid-B clearance during brain hyperinsulinemia, inhibition of synaptic activity both at excessively high or low levels of insulin and downregulation of choline-acetyltransferase in vitro by insulin. However, clear-cut relationships in this area remain elusive.
      Some authors have hypothesized that different insults, either degenerative or vascular, may result in greater damage when a particular ApoE allelic variant is present. Vascular risk factors such as hyperglycemia interact with ApoE4 to increase the risk for cognitive decline above and beyond the effect of ApoE4 alone. Recent data from the Canadian Study of Health and Aging are also in favour of an association between possessing an apoE epsilon 4 allele and increased risk and having an increased risk for developing AD from existing cognitive impairment for developing AD from cognitive impairment (
      • Hsiung G.Y.
      • Sadovnik A.D.
      • Feldman H.
      Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: Data from the Canadian Study of Health and Aging.
      ).

      Conclusions

      Diabetes, sarcopenia and frailty are associated with disability, morbidity and mortality. Diabetes accelerates the ageing process and could provide an early pathophysiologic environment for frailty, and the close relationship between diabetes and sarcopenia may be a common factor (Figure 1). We recognize that diabetes can contribute to frailty by increasing the incidence of the core components of frailty—weakness-strength impairment, exhaustion, slowness and low physical activity level—or through some of the comorbidities and complications associated with this condition: atherosclerosis, microvascular complication, cardiovascular dysautonomy or neuropathy and dementia or cognitive impairment.
      Figure thumbnail jcjd632-fig-0001
      Figure 1Schematic representation: combined effects of ageing, diabetes and sarcopenia on lower limb dysfunction: moving towards frailty. (Morley JE, Malmstrom TK, Rodriguez-Manas L, Sinclair AJ. Frailty, sarcopenia and diabetes. J Am Med Dir Assoc 2014;15:853–9.).
      We believe that early recognition of frailty and sarcopenia in older adults with diabetes should be a mandatory process (
      • Sinclair A.
      • Dunning T.
      • Rodriguez-Mañas L.
      Diabetes in older people: New insights and remaining challenges.
      ) in order to promote early multimodal interventions based on physical exercise and nutrition education and which also align with glycemic and other metabolic targets essential to proper functioning; the detection of frailty should be a prompt to physicians to review management goals (Figure 2). This approach is now being testing in the Multi-modal Intervention in Diabetes in Frailty (MID-FRAIL) study, a multinational interventional study currently running in more than 1500 frail/prefrail older adults with type 2 diabetes mellitus (
      • Rodríguez-Mañas L.
      • Bayer A.J.
      • Kelly M.
      • et al.
      An evaluation of the effectiveness of a multi-modal intervention in frail and pre-frail older people with type 2 diabetes: The MID-Frail study: Study protocol for a randomised controlled trial.
      ). The study aims revolve around the key need to enhance quality of life and well-being, combined with a commitment to improve or maintain functional status.
      Figure thumbnail jcjd632-fig-0002
      Figure 2Detection of frailty in diabetes: a prompt for clinicians to review management goals.

      Acknowledgments

      This review is based on an update of an article published in the British Journal of Diabetes and Vascular Disease in 2012 (Pilar A, Abizanda P, Guppy A, Sinclair AJ. Diabetes and frailty: An emerging issue. Brit J Diab Vasc Dis 2012;12:110–6) in which AJS was the senior and corresponding author. Figure 1 has been taken, with permission, from Morley JE, Malmstrom TK, Rodriguez-Manas L, Sinclair AJ. Frailty, sarcopenia and diabetes. J Am Med Dir Assoc 2014;15:853–9.

      References

        • Wilson P.N.F.
        Epidemiology of diabetes in the elderly.
        Am J Med. 1982; 80: 3-15
        • Harris M.I.
        • Hadden W.C.
        • Knowler W.C.
        • Bennett P.H.
        Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in US population aged 20–74 years.
        Diabetes. 1987; 36: 523-534
        • Manton K.G.
        • Stallard E.S.
        • Liu K.
        Forecasts of active life expectancy: Policy and fiscal implications.
        J Gerontol. 1993; 48: 11-26
        • Resnick H.E.
        • Harris M.I.
        • Brock D.B.
        • Harris T.B.
        American Diabetes Association diabetes diagnostic criteria, advancing age, and cardiovascular disease risk profiles: Results from the Third National Health and Nutrition Examination Survey.
        Diabetes Care. 2000; 23: 176-180
        • Halter J.B.
        Diabetes mellitus in older adults: Underdiagnosis and undertreatment.
        J Am Geriatr Soc. 2000; 48: 340-341
        • Narayan K.M.
        • Boyle J.P.
        • Thompson J.
        Lifetime risk for diabetes mellitus in the United States.
        JAMA. 2003; 290: 1884-1890
        • Murray C.J.
        • Lopez A.D.
        Measuring the global burden of disease.
        N Engl J Med. 2013; 369: 448-457
        • Sloan F.A.
        • Bethel M.A.
        • Ruiz D.
        • et al.
        The growing burden of diabetes mellitus in the US elderly population.
        Arch Intern Med. 2008; 168: 192-199
        • Boyd C.M.
        • Landefeld C.S.
        • Counsell S.R.
        • et al.
        Recovery of activities of daily living in older adults after hospitalization for acute medical illness.
        J Am Geriatr Soc. 2008; 56: 2171-2179
        • Espeland M.A.
        • Gill T.M.
        • Guralnik J.
        • et al.
        Designing clinical trials of interventions for mobility disability: Results from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) trial.
        J Gerontol A Biol Sci Med Sci. 2007; 62: 1237-1243
        • Pahor M.
        • Guralnik J.M.
        • Ambrosius W.T.
        • et al.
        Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomised clinical trial.
        JAMA. 2014; 311 (for the; LIFE Study investigators): 2387-2396
        • Fried L.P.
        • Ferruci L.
        • Darer J.
        • et al.
        Understanding the concepts of disability, frailty and comorbidity: Implications for improved targeting and care.
        J Gerontol Biol Sci Med Sci. 2004; 59: 255-263
        • Rodriguez-Mañas L.
        • Fried L.P.
        Frailty in the clinical scenario.
        Lancet. 2015; 385: e7-9
        • Fried L.P.
        • Kronmal R.A.
        • Newman A.B.
        • et al.
        Risk factors for 5-years mortality in older adults: The Cardiovascular Health Study.
        JAMA. 1998; 279: 585-592
        • Collard R.M.
        • Boter H.
        • Schoevers R.A.
        • Oude Voshaar R.C.
        Prevalence of frailty in community-dwelling older persons: A systematic review.
        J Am Geriatr Soc. 2012; 60: 1487-1492
        • Kallman D.A.
        • Plato C.C.
        • Tobin J.D.
        The role of muscle loss in the age-related decline of grip strength: Cross-sectional and longitudinal perspectives.
        J Gerontol. 1990; 45: M82-8
        • Morley J.E.
        • Baumgartner R.N.
        • Roubenoff R.
        • et al.
        Sarcopenia.
        J Lab Clin Med. 2001; 137: 231-243
        • Kalyani R.R.
        • Corriere M.
        • Ferrucci L.
        Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases.
        Lancet Diabetes Endocrinol. 2014; 2: 819-829
        • Meneilly G.S.
        • Elahi D.
        Metabolic alterations in middle-aged and elderly lean patients with type 2 diabetes.
        Diabetes Care. 2005; 28: 1498-1499
        • Wong E.
        • Backholer K.
        • Gearon E.
        • et al.
        Diabetes and risk of physical disability in adults: A systematic review and meta-analysis.
        Lancet Diabetes Endocrinol. 2013; 1: 106-114
        • Stotmeyer E.S.
        • Cauley J.A.
        • Schwartz A.V.
        • et al.
        Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: The health, aging and body composition study.
        Arch Intern Med. 2005; 165: 1612-1617
        • Mac Leod K.M.
        • Tooke J.E.
        Direct and indirect costs of cardiovascular and cerebrovascular complications of type II diabetes.
        Pharmacoeconomics. 1995; 8: 46-51
        • American Diabetes Association
        Standards of medical care in diabetes, 2015.
        Diabetes Care. 2015; 38:S4
        • Nicolls M.R.
        The clinical and biological relationship between type II diabetes mellitus and Alzheimer's disease.
        Curr Alzheimer Res. 2004; 1: 47-54
        • García-Esquinas E.
        • Graciani A.
        • Guallar-Castillón P.
        • et al.
        Diabetes and risk of frailty and its potential mechanisms: A prospective cohort study of older adults.
        J Am Med Dir Assoc. 2015;
        • Sinclair A.
        • Dunning T.
        • Rodriguez-Mañas L.
        Diabetes in older people: New insights and remaining challenges.
        Lancet Diabetes Endocrinol. 2015; 3: 275-285
        • Lourenço R.A.
        • Pérez-Zepeda M.
        • Gutiérrez-Robledo L.
        • et al.
        Performance of the European Working Group on Sarcopenia in Older People: Algorithm in screening older adults for muscle mass assessment.
        Age Ageing. 2015; 44: 334-338
        • Hughes V.A.
        • Frontera E.R.
        • Roubenoff R.
        • et al.
        Longitudinal changes in body composition in older men and women: Role of body weight change and physical activity.
        Am J Clin Nutr. 2002; 76: 473-481
        • McNeil C.J.
        • Doherty T.J.
        • Stashuk D.W.
        • Rice C.L.
        Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men.
        Muscle Nerve. 2005; 31: 461-467
        • Cree M.G.
        • Newcomer B.R.
        • Katsanos C.S.
        • et al.
        Intramuscular and liver triglycerides are increased in the elderly.
        J Clin Endocrinol Metab. 2004; 89: 3864-3871
        • Giresi P.G.
        • Stevenson E.J.
        • Theilhaber J.
        • et al.
        Identification of molecular signature of sarcopenia.
        Physiol Genomics. 2005; 21: 253-263
        • Rolland Y.
        • Czerwinski S.
        • Abellan van Kan G.
        • et al.
        Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives.
        J Nutr Health Aging. 2008; 12: 433-450
        • Amigues I.
        • Schott A.M.
        • Amine M.
        • et al.
        Low skeletal muscle mass and risk of functional decline in elderly community-dwelling women: The prospective EPIDOS study.
        J Am Med Dir Assoc. 2013; 14: 352-357
        • Cesari M.
        • Leeuenburgh C.
        • Lauretani F.
        • et al.
        Frailty syndrome and skeletal muscle: Result from the InCHIANTI study.
        Am J Clin Nutr. 2006; 83: 1142-1148
        • Rodríguez-Mañas L.
        • Féart C.
        • Mann G.
        • et al.
        Searching for an operational definition of frailty: A Delphi method based consensus statement: The frailty operative definition-consensus conference project.
        J Gerontol A Biol Sci Med Sci. 2013; 68: 62-67
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • et al.
        Frailty in older adults: Evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: M146-56
        • Clegg A.
        • Young J.
        • Iliffe S.
        • et al.
        Frailty in older people.
        Lancet. 2013; 381: 752-762
        • Turnbull P.J.
        • Sinclair A.J.
        Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes mellitus using the mininutritional assessment (MNA) tool: A preliminary investigation.
        J Nutr Health Aging. 2002; 6: 185-189
        • Matthew C.
        • Robert C.
        • Aaron S.
        • et al.
        The prevalence of vitamin B12 deficiency in patients with type 2 diabetes: A cross-sectional study.
        J Am Board Fam Med. 2009; 22: 528-534
        • Visvanathan R.
        • McPhee I.
        Undernutrition and anorexia in the older person.
        Gastroenterol Clin North Am. 2009; 38: 393-409
        • Cheung K.
        • Luk A.
        • So W.
        • et al.
        Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence.
        Diabetes Investig. 2015; 6: 112-123
        • Ozfirat Z.
        • Tahseen A.C.
        Vitamin D deficiency and type 2 diabetes.
        Postgrad Med J. 2010; 86: 18-25
        • Latham N.K.
        • Anderson C.S.
        • Reid I.R.
        Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: A systematic review.
        J Am Geriatr Soc. 2003; 51: 1219-1226
        • Shardell M.
        • Hicks G.E.
        • Miller R.R.
        • et al.
        Association of low vitamin D levels with the frailty syndrome in men and women.
        J Gerontol A Biol Sci Med Sci. 2009; 64A: 69-75
        • Serra-Prat M.
        • Palomera E.
        • Clave P.
        • Puig-Domingo M.
        Effect of age and frailty on ghrelin and cholecystokinin responses to a meal test.
        Am J Clin Nutr. 2009; 89: 1410-1417
        • Nomura T.
        • Ikeda Y.
        • Nakao S.
        • et al.
        Muscle strength is a marker of insulin resistance in patients with type 2 diabetes: a pilot study.
        Endocrinol J. 2007; 54: 791-796
        • Louard R.J.
        • Fryburg D.A.
        • Gelfand R.A.
        • Barrett E.J.
        Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle.
        J Clin Invest. 1992; 90: 2348-2354
        • Newman E.
        • Heslin M.J.
        • Wolf R.F.
        • et al.
        The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm.
        Metabolism. 1994; 43: 70-78
        • Guttridge D.C.
        Signaling pathways weigh on decisions to make or break skeletal muscle.
        Curr Opin Clin Nutr Metab Care. 2004; 7: 443-450
        • Payette H.
        • Roubenoff R.
        • Jacques P.F.
        • et al.
        Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: The Framingham Heart Study.
        J Am Geriatr Soc. 2003; 51: 1237-1243
        • Walston J.
        • Arking D.E.
        • Fallin D.
        • et al.
        IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.
        Exp Gerontol. 2005; 40: 344-352
        • Visser M.
        • Pahor M.
        • Taeffe D.R.
        • et al.
        Relationship of interleukin-6 and tumor necrosis factor-α with muscle mass and muscle strength in elderly men and women: The Health ABC Study.
        J Gerontol A Biol Sci Med Sci. 2002; 57: M326-32
        • García-Esquinas E.
        • José García-García F.
        • León-Muñoz L.M.
        • et al.
        Obesity, fat distribution, and risk of frailty in two population-based cohorts of older adults in Spain.
        Obesity (Silver Spring). 2015; 23: 847-855
        • Kanaya A.M.
        • Harris T.
        • Goodpaster B.H.
        • et al.
        Adipocytokines attenuate the association between visceral adiposity and diabetes in older adults.
        Diabetes Care. 2004; 27: 1375-1380
        • Baumgartner R.N.
        Body composition in healthy aging.
        Ann N Y Acad Sci. 2000; 904: 437-448
        • Payne G.W.
        Effect of inflammation on the aging microcirculation: Impact on skeletal muscle blood flow control.
        Microcirculation. 2006; 13: 343-352
        • Petersen K.F.
        • Befroy D.
        • Dufour S.
        • et al.
        Mitochondrial dysfunction in the elderly: Possible role in insulin resistance.
        Science. 2003; 300: 1140-1142
        • Petersen K.F.
        • Dufour S.
        • Befroy D.
        • et al.
        Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.
        N Engl J Med. 2004; 350: 664-671
        • De Rekeneire N.
        • Resnick H.E.
        • Shwartz A.V.
        • et al.
        Diabetes is associated with subclinical functional limitation in nondisabled older individuals: The Health, Aging, and Body Composition study.
        Diabetes Care. 2003; 26: 3257-3263
        • Allen M.D.
        • Stashuk D.W.
        • Kimpinski K.
        • et al.
        Increased neuromuscular transmission instability and motor unit remodelling with diabetic neuropathy as assessed using novel near fibre motor unit potential parameters.
        Clin Neurophysiol. 2015; 126: 794-802
        • Roshanravan B.
        Frailty in CKD: Is only seeing worth believing?.
        Am J Kidney Dis. 2014; 64: 489-491
        • Rodríguez-Mañas L.
        • Bouzon C.A.
        • Castro M.
        Peripheral arterial disease in old people with diabetes.
        in: Sinclair A.J. Diabetes in Old Age. 3rd edn. Wiley, Chichester, UK2009
        • Samper-Ternent R.
        • Al Snih S.
        • Raji M.A.
        • et al.
        Relationship between frailty and cognitive decline in older Mexican Americans.
        J Am Geriatr Soc. 2008; 56: 1845-1852
        • Buchman A.S.
        • Schneider J.A.
        • Leurgans S.
        • et al.
        Physical frailty in older persons is associated with Alzheimer disease pathology.
        Neurology. 2008; 71: 499-504
        • Cheng G.
        • Huang C.
        • Deng H.
        • Wang H.
        Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies.
        Intern Med J. 2012; 42: 484-491
        • Whitmer R.A.
        • Karter A.J.
        • Yaffe K.
        • et al.
        Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
        JAMA. 2009; 301: 1565-1572
        • Koekkoek P.S.
        • Kappelle L.J.
        • van den Berg E.
        • et al.
        Cognitive function in patients with diabetes mellitus: Guidance for daily care.
        Lancet Neurol. 2015; 14: 329-340
        • Roriz-Filho J.S.
        • Sá-Rodriguez T.M.
        • Rosset I.
        • et al.
        Pre)diabetes, brain aging, and cognition.
        Biochim Biophys Acta. 2009; 1792: 432-443
        • Pasquier F.
        • Boulogne A.
        • Leys D.
        • Fontaine P.
        Diabetes mellitus and dementia.
        Diabetes Metab. 2006; 32: 403-414
        • Monte S.M.
        • Wands J.R.
        Alzheimer's disease is type 3-evidence reviewed.
        J Diabetes Sci Technol. 2008; 2: 1101-1113
        • Kuusisto J.
        • Koivisto K.
        • Mykkanen L.
        • et al.
        Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: Cross-sectional population-based study.
        BMJ. 1997; 315: 1045-1049
        • Hsiung G.Y.
        • Sadovnik A.D.
        • Feldman H.
        Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: Data from the Canadian Study of Health and Aging.
        Can Med Assoc J. 2004; 171: 863-867
        • Rodríguez-Mañas L.
        • Bayer A.J.
        • Kelly M.
        • et al.
        An evaluation of the effectiveness of a multi-modal intervention in frail and pre-frail older people with type 2 diabetes: The MID-Frail study: Study protocol for a randomised controlled trial.
        Trials. 2014; 15: 34