title: Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions.
abstract: Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced β-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key β-cell factors critical for β-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions.
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimo
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. Electronic address: matsuoka@endmet.med.osaka-u.ac.jp.
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Matsuoka
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunky-ku, Tokyo, 113-8421, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyatsuka
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Takebe
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tochino
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Takahara
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama, 701-0192, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.affiliation: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D000818:Animals; D017209:Apoptosis; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001629:Bezafibrate / Q000494:pharmacology; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D005960:Glucosides / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000633:toxicity*; D051379:Mice
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D008055:Lipids; C570240:empagliflozin; D005947:Glucose; D001629:Bezafibrate
keywords: Fibrate; Glucotoxicity; Insulin transcription factors; Lipotoxicity; SGLT2 inhibitor; islet β-cell dysfunction