Analysis of the effect of canagliflozin on renal glucose reabsorption and progression of hyperglycemia in zucker diabetic Fatty rats
| Autor: | Jun Zhi Xu, Jenson Qi, Kumiko Hikida, Keiko Nakayama, Tetsuhiro Kakimoto, Yoshinori Watanabe, Kiichiro Ueta, Chiaki Kuriyama, Masaharu Shiotani, Kenji Arakawa, Akira Saito, Nobuhiko Taniuchi, Seunghun Paul Lee, Hirotaka Kimata, Yasuaki Matsushita |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Blood Glucose
medicine.medical_specialty endocrine system diseases Thiophenes Hypoglycemia Carbohydrate metabolism Kidney Diabetes Mellitus Experimental Islets of Langerhans Mice Dogs Glucosides Sodium-Glucose Transporter 2 Internal medicine Diabetes mellitus Insulin-Secreting Cells Medicine Animals Humans Hypoglycemic Agents Insulin Canagliflozin Pharmacology Glycated Hemoglobin business.industry Glucose transporter nutritional and metabolic diseases Kidney metabolism medicine.disease Renal glucose reabsorption Rats Rats Zucker Endocrinology Glucose Hyperglycemia Molecular Medicine SGLT2 Inhibitor business medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 351(2) |
| ISSN: | 1521-0103 |
| Popis: | Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption. To analyze the potential of insulin-independent blood glucose control, the effects of the novel SGLT2 inhibitor canagliflozin on renal glucose reabsorption and the progression of hyperglycemia were analyzed in Zucker diabetic fatty (ZDF) rats. The transporter activity of recombinant human and rat SGLT2 was inhibited by canagliflozin, with 150- to 12,000-fold selectivity over other glucose transporters. Moreover, in vivo treatment with canagliflozin induced glucosuria in mice, rats, and dogs in a dose-dependent manner. It inhibited apparent glucose reabsorption by 55% in normoglycemic rats and by 94% in hyperglycemic rats. The inhibition of glucose reabsorption markedly reduced hyperglycemia in ZDF rats but did not induce hypoglycemia in normoglycemic animals. The change in urinary glucose excretion should not be used as a marker to predict the glycemic effects of this SGLT2 inhibitor. In ZDF rats, plasma glucose and HbA1c levels progressively increased with age, and pancreatic β-cell failure developed at 13 weeks of age. Treatment with canagliflozin for 8 weeks from the prediabetic stage suppressed the progression of hyperglycemia, prevented the decrease in plasma insulin levels, increased pancreatic insulin contents, and minimized the deterioration of islet structure. These results indicate that selective inhibition of SGLT2 with canagliflozin controls the progression of hyperglycemia by inhibiting renal glucose reabsorption in ZDF rats. In addition, the preservation of β-cell function suggests that canagliflozin treatment reduces glucose toxicity via an insulin-independent mechanism. |
| Databáze: | OpenAIRE |
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