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However, only S 50131 increased hepatic TGs, by 48% (P? http://www.selleckchem.com/screening/pfizer-licensed-library.html regulation of glucose homeostasis, pharmacological activation of GK has for long been viewed as an attractive target to treat type 2 diabetes. Activating GK mutations in humans and rodents, while causing hypoglycaemia, did not alter plasma lipid profiles (Gloyn et?al., 2003; Pino et?al., 2007; Wabitsch et?al., 2007), suggesting that manipulating GK could have a positive balance on the regulation of glucose metabolism. In contrast, naturally occurring genetic variations in GCKR, a liver-specific GK inhibitory protein and transgenic animal models of hepatic GK overexpression were associated http://en.wikipedia.org/wiki/Temsirolimus with altered hepatic and/or plasma lipid profiles (O'Doherty et?al., 1999; Jackerott et?al., 2002; Ferre et?al., 2003; Saxena et?al., 2007; Santoro et?al., 2012), casting doubt on the http://www.selleckchem.com/products/pifithrin-alpha.html safety of the pharmacological approach. We recently demonstrated that GKAs belonging to three distinct structural families effectively decreased plasma HbA1c levels but concomitantly increased hepatic TGs after chronic administration in hyperglycaemic db/db mice (De Ceuninck et?al., 2013). Syntheses with a new chemical scaffold resulted in S 50131 and S 51434, two GKAs with potent antihyperglycaemic activity after acute oral administration in diabetic mice, but surprisingly no effect on HbA1c levels after 4 weeks of oral treatment at pharmacological doses. In the 4-week study, these two GKAs markedly increased the plasma FFA levels, which for S 50131 was also associated with increased hepatic TGs. In contrast, no FFA increase could be seen with either compound after a 4-day treatment, although the hepatic TGs were clearly increased. These findings, together with those previously reported with different structural classes of GKAs, prompt serious reflection regarding the safety aspects of GKAs as treatment for patients with type 2 diabetes.