Aging is characterized by a profound reshaping of the body composition (Hughes et al., 2004). There is a typical decline in the lean body mass, while the fat cell mass is increasing. The reduction of lean body mass is explained mainly by loss of muscle mass, a process called sarcopenia (Nair, 2005; Clarke, 2004). The decline of muscle mass has been estimated to be about 6% per decade between the age of 30 and 80. The exact cause of this decline is not known, but neuro-endocrine factors, reduced spontaneous and conscious physical activity, and intrinsic protein metabolic changes in muscles contribute to sarcopenia (Balagopal et al., 1997). Reduced mito-chondrial function in muscle associated with impaired production of ATP is felt to play an important role in the pathogenesis of age-associated sarcopenia (Nair, 2005). It is also of interest to note that reduced muscle production of ATP is present very early in young, insulin-resistant offspring of patients with type 2 diabetes (Petersen et al., 2004), suggesting a link between mitochondrial dysfunction and muscle insulin resistance. However, mitochondrial dysfunction and biogenesis improve with aerobic training, whereas insulin sensitivity does not in the elderly (Short et al., 2003). Why, then, is sarcopenia a serious risk factor for insulin resistance and consequently for type 2 diabetes in elderly subjects? The muscle is the primary site for insulin-mediated glucose disposal and, therefore, the reduction of muscle mass with aging may seriously affect glucose metabolism.
Furthermore, the frailty syndrome in the elderly is characterized by a frailty phenotype described by Fried et al. (2001) including sarcopenia, thus being a risk factor for insulin resistance. Moreover, as mentioned, the decreased supply in proteins and energy in utero and during the first year of life is a risk factor for IGT and type 2 diabetes. These factors associated with low birth weight also indicate a higher risk for frailty. Thus, the early growth retardation is a risk factor for both frailty and type 2 diabetes mellitus via perhaps the development of sarcopenia with aging.
Most dramatically, not only is there an increase in the fat cell mass but also its distribution is changing, because this enhancement is due to an enrichment at the abdominal site (central distribution). This central redistribution of the fat cell mass has dramatic consequences for the metabolic environment and is a risk factor for several obesity and age-related metabolic abnormalities. Thus, the frontier between aging and obesity is very thin (Harris, 1999). Interestingly, the normal relationship between total body fat mass and circulating leptin levels appears to be disrupted in the elderly, suggesting that abnormal secretion of this adipostat may play a role in body fat changes with aging (Moller et al., 1998). The increase in visceral and central fat cell mass with or without reduction of peripheral fat mass has dramatic consequences for the metabolic environment and is a risk factor for several obesity and age-related metabolic abnormalities, such as hypertension and hyperlipidemias (Lewis et al., 2002). Weight gain or central redistribution of fat clearly has been associated with the development of type 2 diabetes (Koh-Banerjee et al., 2004).
This anatomical distribution is accompanied by an increase in plasma free fatty acid (FFA) levels (Raz et al., 2005) and appearance rate, reduced adiponectin secretion, and the enhanced secretion of pro-inflammatory molecules (e.g., tumor necrosis factor (TNF)-a and interleukin-6) (Unger, 2003; Eckel et al., 2005; Sharma et al., 2005). Altogether, these changes favor the apparition of insulin resistance and may also have an untoward impact on beta cell function over time (Lewis et al., 2002). However, as long as the pancreatic beta cell insulin secretory response can compensate for this increase of insulin resistance, euglycemia will be maintained. Once this compensation is overwhelmed, insulin resistance leads to a progressive reduction of glucose tolerance and, eventually, to type 2 diabetes.
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