Recently, epidemiological studies have demonstrated an increased prevalence of cognitive impairment associated with diabetes. In the Third National Health and Nutrition Examination Survey (NHANES III), type 2 diabetes, combined with hypertension, was significantly associated with impaired cognitive function in subjects younger than 60 years old (Pavlik et al., 2005). Patients with
Alzheimer's disease suffer from a marked increase in prevalence of type 2 diabetes, whereas the presence of brain plaques in patients with type 2 diabetes correlates with the duration of diabetes (Janson et al., 2004). Experimental models have suggested that the brain mitochondrial toxicity associated with neurotoxic agents such as beta amyloid deposits may be exacerbated by the presence of diabetes (Moreira et al., 2003).
As described earlier, aging is associated with a low-grade inflammation. This manifests itself also at the neuro-endocrine level by a relative sustained increase of cortisol and adrenergic hormone levels in elderly subjects (Valenti, 2004). The stress hormones such as cortisol may contribute to the development of insulin resistance. In case of acute events, such as illnesses, the effect of these stress hormones may be accentuated, contributing to the occurrence of type 2 diabetes. The contributing effect of cortisol on impaired glucose tolerance or type 2 diabetes could be through its ill-defined age-dependent effects on the innate immune response or direct interference with insulin-mediated glucose disposal. The «-adrenergic effect of catechol-amines by inhibiting insulin secretion further accentuates the contribution of age-related hormonal changes to insulin resistance in diabetes mellitus. The activation of serine kinase via the catecholamine-mediated cAMP dependent kinase inhibits the tyrosine phosphorylation of the insulin receptor, contributing to insulin resistance with aging. Thus, the increase in cortisol and noradrenalin levels seen with aging may contribute in many ways to the development of IGT and type 2 diabetes.
Recently, the role of the enteroinsular axis was assessed in relation to the age-dependent glucose intolerance. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), two gut hormones whose secretion is stimulated by the ingestion of glucose, are incretin hormones that potentiate insulin secretion. Their basal levels as well as their levels after OGTT have been found unchanged in elderly obese and nonobese healthy elderly individuals. A study using the hyperglycemic clamp technique showed that GIP sensitivity may be impaired in older subjects (Meneilly et al., 1998). Recently, however, it has been shown that incretin-mediated muscle glucose uptake was markedly impaired in elderly type 2 diabetes patients (Chang et al., 2003). Further studies are needed to establish more firmly the role of incretins in the beta cell defect and type 2 diabetes associated with aging.
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