Diabetes increases the risk of frailty through inducing sarcopenia or muscle mass loss. Frailty eventually leads to a decline in function, increased risk of hypoglycaemia and mortality. Prevention programmes in the pre-frail state through exercise training, nutrition and glycaemic control may delay or prevent the development of frailty.
|BOX 1: FRAILTY PHENOTYPES5|
|1. Unintentional weight loss (10lbs in the prior year)|
|2. Exhaustion (self-reported)|
|3. Weakness (grip strength)|
|4. Slow walking speed|
|5. Reduced physical activity|
|Presence of ≥3 phenotypes indicates frailty, 1-2 indicates pre-frail state.|
The prevalence of diabetes in old age is likely to reach epidemic proportions in the upcoming years as the population ages.1 The age range with the greatest proportional increase is likely to occur in those aged 60–79 years.2 In these individuals we can see that alongside the micro/macrovascular complications of diabetes, frailty appears to be another complicating factor.3
Frailty is a condition characterised by a reduction in physiological reserve and a lack of ability to resist physical or psychological stressors.4 Its definition is based on the presence of three or more of the following phenotypes: difficulties in mobility and slow gait speed; muscle weakness; decreased physical activity.; exhaustion and weight loss.5 The presence of one or two of these phenotypes describes a pre-frail state (box 1). Frailty is regarded as a wasting disease, characterised by sarcopenia or muscle loss, primarily due to poor nutrition and weight loss. This is a fundamental concept and is intrinsically linked with diabetes.
The biological processes that underpin frailty are still unclear and likely to be complex and multifactorial. Frailty is thought to develop as a result of abnormalities at a molecular, cellular, and physiological level. The physiological systems believed to be associated with frailty are the cardiovascular, neuroendocrine, metabolic, immune and nervous systems.6 Further to this, frailty has also been shown to be associated with exaggerated glucose and insulin responses after two-hour oral glucose tolerance test in individuals without diabetes. This suggests that these individuals have reduced physiologic reserve, and dysregulation of glycaemic control is a component of the physiological vulnerability associated with frailty.7
Poor muscle quality is also linked to diabetes. Participants with diabetes in the CHIANTI study had lower knee and ankle muscle strength and poor muscle quality (defined as the ratio of lower limb muscle strength over muscle area) and slower gait speed on both four metre and 400-metre walking tests compared to participants without diabetes. Lower-limb muscle characteristics accounted for 24.3% and 15.1% of walking speed differences in persons with diabetes compared to those without diabetes in the 4 and 400 metre walks, respectively8 (Figure 1).
Sarcopenia or muscle mass loss is a contributor to the frailty syndrome, which seems to be accelerated when diabetes is present. In a community study of 3,153 participants ≥65 years of age, appendicular lean mass loss in men with diabetes was twice that of men without diabetes (3.0% versus 1.5%) and in women with diabetes was 1.8 times that of those without diabetes (3.4% versus 1.9%) over four years of follow up. The mechanisms explaining these results may be related to reduced protein synthesis due to lower testosterone and insulin like growth factor 1, and increased muscle protein breakdown due to a higher rate of inflammation.9
Diabetes also causes sarcopenia due to the catabolic effect of insulin deficiency, and by increasing intra-myocellular lipid accumulation.10 In another study, older persons with type 2 diabetes had accelerated decline in leg lean mass, muscle strength, and had longer sit-to-stand time compared to normoglycaemic controls.11 Other factors may be related to the oral health of older people with diabetes. For example, optimal nutrition may not be maintained due to poor dentition, a dry mouth, reduced taste sensation, palatability and appetite change with increasing age (Figure 1).12
The emergence of frailty will have a negative impact on older people with diabetes, leading to reduced physical and cognitive functions, increased risk of hypoglycaemia and increased mortality.
Frailty is associated with a functional decline that leads to increased risk of falls, hospitalisation, dependency, disability and institutionalisation.8 Frail persons have increased risk of poor mobility and impaired performance of activities of daily living.13 Frailty is also associated with increased risk of cognitive dysfunction.14 Frailty therefore appears to be a contributing factor for decline in both physical and cognitive functions that ultimately leads to disability and difficulties in performing self-care tasks.
The weight loss associated with frailty may increase insulin sensitivity and improve glucose tolerance due to the loss of visceral fat. The development of frailty may improve insulin sensitivity, due to changes in insulin/glucose dynamics. Poor nutrition and weight loss will however lead to increased risk of hypoglycaemia. Chronic diseases associated with protein energy malnutrition, muscle wasting and frailty have been shown to be associated with spontaneous resolution of hyperglycaemia and normalisation of HbA1c levels, a condition termed ‘‘burnt out diabetes.’’15
The mortality events observed in the ACCORD and ADVANCE studies were not directly explained by the high rate of hypoglycaemia, but were due to the vulnerability of the populations who suffered from such events.16,17 Other studies that demonstrated an increased risk of mortality in older people with low HbA1c showed evidence of increased inflammation and malnutrition. These findings are suggestive of a population with poor general health and likely with underlying frailty.18 Therefore, frailty is likely to be a causative unmeasured factor leading to these adverse events, and hypoglycaemia is the marker of frailty, vulnerability and poor outcome (Figure 2).
|FIGURE 2: Relationship Between Diabetes and Frailty: Consequences|
|REDUCED FUNCTION||HYPOGLYCAEMIA||INCREASED MORTALITY|
|↓ Physical function||Malnutrition||↑ Vunerability to stressors|
|↓ Cognitive function||Weight loss||Poor nutrition|
|↑ Disability||Muscle wasting||↑ Inflammation|
|↑ Hospitalisation||↓ Visceral fat||↓ Immunity|
|↑ Institutionalisation||Improved insulin sensitivity||Poor general health|
Frailty is a dynamic process, and can be prevented in the pre-frail state. Once frailty is established, particularly in patients who have had significant weight loss, hypoglycaemic medications need to be regularly reviewed to reduce the risk of hypoglycaemia (Figure 3).
|Relation Between Diabetes and Frailty: Therapeutic Implications|
|High protein nutrition|
|Good glycaemic control|
|Deintensification in high risk patients|
Sarcopenia occurs because of a loss of skeletal muscle protein due to diminished protein synthesis. Therefore, increasing dietary protein intake to 20–30% of the total calorie intake is recommended.19 It has recently been shown that nutritional therapy in diabetes may have a protective effect against the development of frailty.20 Progressive resistance training (PRT) exercise combined with adequate protein nutrition have synergistic effects in improving muscle function and reducing the risk of frailty.21
The role of tight glycaemic control in the prevention of disability is less clear. Some studies have shown that tight glycaemic control may have a role in delaying frailty and disability, although this has not been demonstrated in other studies and it may in fact lead to increased risk of hypoglycaemia, falls, fractures and eventually disability.22,23,24
|BOX 2: HYPOGLYCAEMIC MEDICATION DEINTENSIFICATION WITH FRAILTY26|
Once frailty is established the risk of hypoglycaemia significantly increases. Therefore, blood glucose targets in frail older people should aim to avoid extremes of high or low that can lead to recurrent hospitalisation and reduced quality of life. A focus on the short-term blood glucose targets is more appropriate given the short life expectancy in this group of patients. A comfortable day-to-day target of a random blood glucose between >4 but <15 mmol/L seems to be suitable to avoid the development of symptoms as blood glucose outside this range is likely to be symptomatic.25
Deintensification or even complete withdrawal of hypoglycaemic agents may be considered in certain patients with frailty. Indications for consideration of withdrawal of hypoglycaemic medications would include patients with significant weight loss, those with tight glycaemic control and recurrent hypoglycaemia or those with dementia and subsequent erratic eating pattern, which can increase the risk of hypoglycaemia (Box 2).26
Diabetes is associated with frailty through increasing the risk of sarcopenia. Screening older people with diabetes at the pre-frail state with consideration of intervention through exercise training, adequate nutrition and glycaemic control may delay the development of frailty. Once frailty is established, consideration should be given to reduction or withdrawal of hypoglycaemic medications especially in those with significant weight loss.
Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherha
Conflict of interest: none declared
6. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006; 54: 991-1001
11. Leenders M, Verdijk LB, van der Hoeven L, et al. Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging. J Am Med Dir Assoc 2013; 14: 585–92
16. Bonds DE, Miller ME, Bergenstal RM et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340, b4909
20. 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; 16: 748–54
21. Rahi B, Morais JA, Dionne IJ, et al. The combined effects of diet quality and physical activity on maintenance of muscle strength among diabetic older adults from the NuAge cohort. Exp Gerontol 2014; 49: 40–6
23. Yau CK, Eng C, Cenzer IS, et al. Glycosylated hemoglobin and functional decline in communitydwelling nursing home-eligible elderly adults with diabetes mellitus. J Am Geriatr Soc 2012; 60: 1215–21