Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity.
A loss of glucose effectiveness to suppress hepatic glucose production as well as increase hepatic glucose uptake and storage as glycogen is associated with a defective increase in glucose phosphorylation catalyzed by glucokinase (GK) in Zucker diabetic fatty (ZDF) rats. We extended these observations by investigating the role of persistent hyperglycemia (glucotoxicity) in the development of impaired hepatic GK activity in ZDF rats. We measured expression and localization of GK and GK regulatory protein (GKRP), translocation of GK, and hepatic glucose flux in response to a gastric mixed meal load (MMT) and hyperglycemic hyperinsulinemic clamp after 1 or 6 wk of treatment with the sodium-glucose transporter 2 inhibitor (canaglifrozin) that was used to correct the persistent hyperglycemia of ZDF rats. Defective augmentation of glucose phosphorylation in response to a rise in plasma glucose in ZDF rats was associated with the coresidency of GKRP with GK in the cytoplasm in the midstage of diabetes, which was followed by a decrease in GK protein levels due to impaired posttranscriptional processing in the late stage of diabetes. Correcting hyperglycemia from the middle diabetic stage normalized the rate of glucose phosphorylation by maintaining GK protein levels, restoring normal nuclear residency of GK and GKRP under basal conditions and normalizing translocation of GK from the nucleus to the cytoplasm, with GKRP remaining in the nucleus in response to a rise in plasma glucose. This improved the liver's metabolic ability to respond to hyperglycemic hyperinsulinemia. Glucotoxicity is responsible for loss of glucose effectiveness and is associated with altered GK regulation in the ZDF rat.
Department of Molecular Physiology and Biophysics and.
Kiichiro
K
Ueta
Department of Molecular Physiology and Biophysics and.
Tracy P
TP
O'Brien
Department of Molecular Physiology and Biophysics and.
Gregory A
GA
McCoy
Department of Molecular Physiology and Biophysics and.
Kuikwon
K
Kim
Department of Molecular Physiology and Biophysics and.
Erin C
EC
Healey
Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Tiffany D
TD
Farmer
Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
E Patrick
EP
Donahue
Department of Molecular Physiology and Biophysics and.
Audree B
AB
Condren
Department of Molecular Physiology and Biophysics and Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Richard L
RL
Printz
Department of Molecular Physiology and Biophysics and Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee masakazu.shiota@Vanderbilt.edu.
Masakazu
M
Shiota
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000096:biosynthesis / Q000633:toxicity*; D015309:Glucose Clamp Technique; D005960:Glucosides / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000494:pharmacology
D005960:Glucosides; D012333:RNA, Messenger; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; D005934:Glucagon; D005941:Glucokinase; D005947:Glucose
glucokinase; glucotoxicity; hepatic glucose flux; sodium-glucose cotransporter 2 inhibitor; type 2 diabetes