Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice.
It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic β-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on β-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after the intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, β-cell mass was larger in Luse groups compared to control group which was due to the increase of β-cell proliferation and decrease of β-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFβ, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic β-cell mass and function.
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan. Electronic address: okauchi@med.kawasaki-m.ac.jp.
Seizo
S
Okauchi
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Masashi
M
Shimoda
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Atsushi
A
Obata
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Tomohiko
T
Kimura
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Hidenori
H
Hirukawa
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Kenji
K
Kohara
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Tomoatsu
T
Mune
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Kohei
K
Kaku
Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Japan.
Hideaki
H
Kaneto
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
D007004:Hypoglycemic Agents; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol
Pancreatic β-cells; SGLT2 inhibitor; β-cell mass and function