Advanced glycation, diabetes, and dementia

Glycation involves the covalent interaction of sugar molecules with proteins, lipids, and nucleotides in a nonenzymatic posttranslational manner. The irreversible end products of this chemistry can occur both in vitro and in vivo and are termed advanced glycation end products (AGEs) (Vlassara, 2005). A clear example of the use of this chemistry in routine clinical practice is the measurement of AGE glycated hemoglobin (A1C) as a marker of longer term glycemic control in diabetes patients. A1C formation occurs when an excess of circulating glucose covalently binds to hemoglobin of erythrocytes. Indeed, an elevation in A1C imparts a 50% increased risk of retinopathy and is a globally recommended diagnostic test for type 2 diabetes (T2D) (Florkowski, 2013). Apart from A1C, there are a number of other endogenously formed AGEs that accumulate at accelerated rates in patients with T2D, including pentosidine, N-ε-carboxymethyllysine (CML), N-ε-carboxyethyllysine (CEL), and N-δ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (Angoorani, Ejtahed, Mirmiran, Mirzaei, & Azizi, 2016; Negre-Salvayre, Salvayre, Augé, Pamplona, & Portero-Otín, 2009; Singh, Bali, Singh, & Jaggi, 2014; Uribarri et al., 2015). In addition, highly reactive α-dicarbonyl compounds and other AGE precursors are also produced excessively in vivo in patients with T2D (Ott et al., 2014). AGEs and their precursors have a major role in worsening the complications of T2D (Forbes & Cooper, 2013), such as retinopathy (Milne & Brownstein, 2013; Sharma, Saxena, Mishra, Saxena, & Natu, 2012), neuropathy (Wada & Yagihashi, 2005), and nephropathy (Forbes, Cooper, Oldfield, & Thomas, 2003; Yamagishi & Matsui, 2010). Aligned with increases in AGE accumulation, a number of studies showed that individuals with T2D also develop cognitive impairment (Gao et al., 2016; Umegaki, 2014; van den Berg, Kessels, de Haan, Kappelle, & Biessels, 2005; Zhou et al., 2014) and dementia (Chatterjee et al., 2016; Ravona-Springer & Schnaider-Beeri, 2011) at a greater frequency than in people without T2D. This has led to the hypothesis that AGEs or their precursors may be pathological mediators of cognitive impairment or dementia in patients with T2D. The following subsections of this chapter introduce the chemistry of advanced glycation, how they are produced excessively in T2D, and their contribution to brain injury.