Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice.
A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Kuralay
K
Atageldiyeva
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Yukihiro
Y
Fujita
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Tsuyoshi
T
Yanagimachi
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Katsutoshi
K
Mizumoto
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Yasutaka
Y
Takeda
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Jun
J
Honjo
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Yumi
Y
Takiyama
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Atsuko
A
Abiko
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Yuichi
Y
Makino
Division of Metabolism an Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Masakazu
M
Haneda
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D050528:Diet, Carbohydrate-Restricted; D002149:Energy Intake / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use; D006003:Glycogen / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000473:pathology; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000150:complications / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D005960:Glucosides; D012333:RNA, Messenger; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D014280:Triglycerides; C572941:ipragliflozin; D006003:Glycogen; D064429:Fatty Acid Synthases