O’Brien TP, Jenkins EC, Estes SK et al.
Department of Molecular Physiology and Biophysics.
Diabetes. Feb 2017.
Ten-week-old ZDF rats at an early stage of diabetes embody metabolic characteristics of obese type 2 diabetic patients, severe insulin and glucose intolerance in muscle and 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 Zucker diabetic fatty (ZDF) rats during fasting and near normal postprandial insulinemia and glycemia after correcting excessive postprandial hyperglycemia by treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2-I) for 7 days. Preprandial lipid oxidation was normalized, as well as with fasting, endogenous glucose production (EGP) increased by 30% and 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 in association with restored activation of glucokinase, as well as by improving insulin action to stimulate 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.