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.

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.

• Authors: Tracy P O'Brien, Erin C Jenkins, Shanea K Estes, Antonio V Castaneda, Kiichiro Ueta, Tiffany D Farmer, Allison E Puglisi, Larry L Swift, Richard L Printz, Masakazu Shiota
• Journal: Diabetes (Diabetes) Vol. 66 Issue 5 Pg. 1172-1184 (05 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28246292 (Publication Type: Journal Article)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Sodium-Glucose Transporter 2 Inhibitors
• Canagliflozin
• Glucokinase
• Glucose

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Canagliflozin (pharmacology)
• Glucokinase (drug effects, metabolism)
• Glucose (metabolism)
• Glucose Clamp Technique
• Glucose Intolerance (metabolism)
• Hyperglycemia (metabolism)
• Hypoglycemic Agents
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Oxidation-Reduction
• Postprandial Period (drug effects)
• Rats
• Rats, Zucker
• Sodium-Glucose Transporter 2 Inhibitors