title: Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice.
abstract: Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8 weeks. In the long-term study, GKA71 was provided in the diet for 4 weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3 mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity.
authors.affiliation: Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden. maria.sorhede-winzell@astrazeneca.com
authors.forename: Maria Sörhede
authors.initials: MS
authors.lastname: Winzell
authors.forename: Matthew
authors.initials: M
authors.lastname: Coghlan
authors.forename: Brendan
authors.initials: B
authors.lastname: Leighton
authors.forename: Georgia
authors.initials: G
authors.lastname: Frangioudakis
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Storlien
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051381:Rats; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C561743:3-(2-methoxy-1-methylethoxy)-5-(4-methylsulfonylphenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D013450:Sulfones; D013830:Thiadiazoles; D005941:Glucokinase