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Publication
Correcting Postprandial Hyperglycemia in Zucker Diabetic Fatty Rats With an
SGLT2 Inhibitor Restores Glucose Effectiveness in the Liver and Reduces Insulin
Resistance in Skeletal Muscle.
Authors O'Brien TP, Jenkins EC, Estes SK, Castaneda AV, Ueta K, Farmer TD, Puglisi AE,
Swift LL, Printz RL, Shiota M
Submitted By Submitted Externally on 1/3/2018
Status Published
Journal Diabetes
Year 2017
Date Published 5/1/2017
Volume : Pages 66 : 1172 - 1184
PubMed Reference 28246292
Abstract Ten-week-old Zucker diabetic fatty (ZDF) rats at an early stage of diabetes
embody metabolic characteristics of obese human patients with type 2 diabetes,
such as severe insulin and glucose intolerance in muscle and the liver,
excessive postprandial excursion of plasma glucose and insulin, and a loss of
metabolic flexibility with decreased lipid oxidation. Metabolic flexibility and
glucose flux were examined in ZDF rats during fasting and near-normal
postprandial insulinemia and glycemia after correcting excessive postprandial
hyperglycemia using treatment with a sodium-glucose cotransporter 2 inhibitor
(SGLT2-I) for 7 days. Preprandial lipid oxidation was normalized, and with
fasting, endogenous glucose production (EGP) increased by 30% and endogenous
glucose disposal (E-Rd) decreased by 40%. During a postprandial
hyperglycemic-hyperinsulinemic clamp after SGLT2-I treatment, E-Rd increased by
normalizing glucose effectiveness to suppress EGP and stimulate hepatic glucose
uptake; activation of glucokinase was restored and insulin action was improved,
stimulating muscle glucose uptake in association with decreased intracellular
triglyceride content. In conclusion, SGLT2-I treatment improves impaired glucose
effectiveness in the liver and insulin sensitivity in muscle by eliminating
glucotoxicity, which reinstates metabolic flexibility with restored preprandial
lipid oxidation and postprandial glucose flux in ZDF rats.




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