Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice

• Published in: Metabolism, clinical and experimental clinical and experimental, 2019-09, Vol.98, p.27-36
• Main Authors: Omori, Kazuno, Nakamura, Akinobu, Miyoshi, Hideaki, Takahashi, Kiyohiko, Kitao, Naoyuki, Nomoto, Hiroshi, Kameda, Hiraku, Cho, Kyu Yong, Takagi, Ryo, Hatanaka, Kanako C., Terauchi, Yasuo, Atsumi, Tatsuya
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Beta cell mass; Db/db mice; Fatty Acids - biosynthesis; Gene Expression - drug effects; Glucose Intolerance; Glucosides - pharmacology; Glucosides - therapeutic use; Hepatic steatosis; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin Glargine - pharmacology; Insulin Glargine - therapeutic use; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - ultrastructure; Lipid Metabolism - drug effects; Liver - drug effects; Liver - metabolism; Male; Mice; Non-alcoholic Fatty Liver Disease - drug therapy; SGLT2 inhibitor; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Triglycerides - metabolism
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2019.06.006

To explore the beneficial effects of dapagliflozin and/or insulin glargine on the pancreatic beta cell mass and hepatic steatosis in db/db mice. Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), or treated with dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined glucose tolerance, beta cell mass, hepatic lipid content and gene expression. Glucose tolerance was significantly ameliorated in the three treated groups to the same degree compared with the Placebo group. Immunohistochemical analysis revealed that the pancreatic beta cell mass was significantly maintained in the Dapa and Dapa+Gla groups, but not in the Gla group, compared with the Placebo group (Placebo 2.25 ± 1.44 mg, Dapa 5.01 ± 1.63 mg, Gla 3.79 ± 0.96 mg, Dapa+Gla 5.19 ± 1.78 mg). However, the triglyceride content of the liver was markedly elevated in the Gla group compared with that in the other three groups (Placebo 24.1 ± 11.5 mg, Dapa 30.6 ± 12.9 mg, Gla 128 ± 49.7 mg, Dapa+Gla 54.4 ± 14.1 mg per gram liver). The expression levels of genes related to fatty acid synthesis and lipid storage were significantly upregulated in the Gla group. Our results showed that beta cell mass was sustained and hepatic steatosis was prevented, after 8 weeks of treatment with either dapagliflozin or dapagliflozin plus insulin glargine, but not with insulin glargine alone, in db/db mice. •We compare beta cell mass and hepatic steatosis at comparable level of blood glucose in db/db mice.•Treated with dapagliflozin, beta cell mass was sustained and hepatic steatosis was prevented.•Treated with insulin glargine alone, beta cell mass was not sustained and hepatic steatosis was induced.•Treated with dapagliflozin plus insulin glargine, beta cell mass was sustained and hepatic steatosis was prevented.