title: Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice.
abstract: Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1(PB)-CreER(TM); CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions.
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Fumiyo
authors: F
authors: Kubo
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: miyatsuka-takeshi@umin.net.
authors: Takeshi
authors: T
authors: Miyatsuka
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shugo
authors: S
authors: Sasaki
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Mitsuyoshi
authors: M
authors: Takahara
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yuichi
authors: Y
authors: Yamamoto
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Naoki
authors: N
authors: Shimo
authors: Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Hirotaka
authors: H
authors: Watada
authors: Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan Okayama 701-0192, Japan.
authors: Hideaki
authors: H
authors: Kaneto
authors: Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2220 Pierce Ave. 746 PRB, Nashville, TN 37232-6303, USA.
authors: Maureen
authors: M
authors: Gannon
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Taka-aki
authors: TA
authors: Matsuoka
authors: Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Iichiro
authors: I
authors: Shimomura
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D005947:Glucose
keywords: Diabetes; Exendin-4; GLP-1; GLP-1 receptor; β Cell failure