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Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral <jats:styled-content style=\"fixed-case\">GKA<\/jats:styled-content> administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Nine <jats:styled-content style=\"fixed-case\">GKA<\/jats:styled-content> candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat <jats:styled-content style=\"fixed-case\">INS<\/jats:styled-content>\u20101E cells. <jats:italic>In vivo<\/jats:italic> activity was monitored by plasma glucose and <jats:styled-content style=\"fixed-case\">HbA1c<\/jats:styled-content> measurements after oral administration in rodents. Risk\u2010associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content>, while efficiently decreasing glycaemia in acute conditions and <jats:styled-content style=\"fixed-case\">HbA1c<\/jats:styled-content> levels after chronic administration in hyperglycemic <jats:italic>db\/db<\/jats:italic> mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. <jats:styled-content style=\"fixed-case\">GKA<\/jats:styled-content> treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. <jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content> belonging to three distinct structural families induced hepatic steatosis in <jats:italic>db\/db<\/jats:italic> mice, arguing in favour of a target\u2010mediated, rather than a chemical class\u2010mediated, effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Given the risks associated with fatty liver disease in the general population and furthermore in patients with <jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content>, these findings represent a serious warning for the use of <jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content> in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Article<\/jats:title><jats:p>This article is commented on by Rees and Gloyn, pp. 335\u2013338 of this issue. 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