Sarcopenia and diabetes: Hyperglycemia is a risk factor for age-associated muscle mass and functional reduction

Skeletal muscle maintains our posture and produces body movement. Muscle is essential to make all movements required in daily life. Skeletal muscle has several other roles. It is a major target of insulin. Insulin receptors in the muscle play a major role in glucose regulation, and muscle is a major site of glucose disposal. Muscle is also a fuel source under certain conditions, such as starvation, and provides amino acids for gluconeogenesis in the liver. Recent studies have shown that skeletal muscle secretes several factors, so-called myokines, which are associated with maintaining healthy conditions. From the age of approximately 30 years, human muscle mass and function (power) progressively decrease. Gait speed and hand grip decrease with age. The age-associated decrease of muscle mass and function is called sarcopenia. Sarcopenia has been reported to be associated with several unhealthy age-related conditions including mobility disorders, falls and fractures, impaired activities of daily living, disabilities, loss of independence and increased risk of death. Sarcopenia and central obesity are both agerelated body compositional changes, and are often combined in older individuals. Central obesity with sarcopenia is known as sarcopenia obesity. It is reportedly a higher risk factor for metabolic syndrome and atherosclerosis than simple obesity. Insulin resistance is involved in one of several underlying mechanisms of sarcopenia induction. Insulin is a catabolic hormone, which stimulates protein synthesis including the synthesis of muscle. The process of protein degradation and synthesis constantly repeats in skeletal muscle. Defects in insulin signaling can lead to reduced muscle synthesis. Chronic inflammation and mitochondrial dysfunction are also considered to be involved. Age-related sex hormone reduction or other hormonal changes including changes in growth hormone, insulin-like growth factor-1 and corticosteroids have been reported to be associated with sarcopenia. The loss of neuromuscular integrity might also be involved in sarcopenia. In older individuals, muscle disuse because of physical inactivity and malnutrition are also associated with sarcopenia. In turn, the reduced muscle mass due to sarcopenia results in a diminished target of insulin, and can alter insulin sensitivity and glucose regulation. Sarcopenia is also associated with frailty. 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 phenotype contains five components: low grip strength, exhaustion, physical inactivity, slow walking speed and weight loss. Sarcopenia is a major component of frailty, and sarcopenia and frailty often overlap. Many older subjects who exhibit frailty have sarcopenia, and many people with sarcopenia exhibit frailty syndrome. Frailty is associated with a number of adverse health outcomes, such as disability, falls, hospitalization, institutionalization and mortality. Frailty is also associated not only with physical function, but also mental function. There is evidence that frailty increases the risks of dementia and depression, which are also closely associated with diabetes mellitus. Frailty, however, is a reversible condition. Frequent transitions among frail, prefrail and non-frail conditions have been reported. Therefore, frailty is a good target for the prevention of disability states. Thus far, interventions with nutrition including amino acids and exercise in individuals with sarcopenia/frailty have been carried out; however, the effects of these interventions are relatively limited, and more efficacious measures are warranted. It has been well established that type 2 diabetes mellitus is a risk factor for functional disability and for mobility limitations. Several reports have shown that type 2 diabetes mellitus is associated with sarcopenia and frailty. In a study carried out in Korea, patients with diabetes had a threefold higher risk of sarcopenia (odds ratio 3.06, 95% confidence interval 1.42–6.62) than subjects without diabetes after adjusting for several confounding factors. Sarcopenia is likely to be involved in the underlying mechanisms of increased functional disability and mobility limitations in older diabetes mellitus patients. Although ample evidence has suggested that older diabetes mellitus patients have increased risks of sarcopenia and frailty, so far the underlying mechanism of the association between sarcopenia/frailty and type 2 diabetes mellitus has not been clarified. Insulin resistance is common in older diabetes mellitus 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 associ*Corresponding author. Hiroyuki Umegaki Tel.: +81-52-744-2364 Fax: +81-52-744-2371 E-mail address: [email protected] Received 6 April 2015; revised 12 April 2015; accepted 13 April 2015