Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function.
Although the two anti-diabetic drugs, dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RAs), have distinct effects on the dynamics of circulating incretins, little is known of the difference in their consequences on morphology and function of pancreatic islets. We examined these in a mouse model of β cell injury/regeneration. The model mice were generated so as to express diphtheria toxin (DT) receptor and a fluorescent protein (Tomato) specifically in β cells. The mice were treated with a DPP4i (MK-0626) and a GLP1RA (liraglutide), singly or doubly, and the morphology and function of the islets were compared. Prior administration of MK-0626 and/or liraglutide similarly protected β cells from DT-induced cell death, indicating that enhanced GLP-1 signaling can account for the cytoprotection. However, 2-week intervention of MK-0626 and/or liraglutide in DT-injected mice resulted in different islet morphology and function: β cell proliferation and glucose-stimulated insulin secretion (GSIS) were increased by MK-0626 but not by liraglutide; α cell mass was decreased by liraglutide but not by MK-0626. Although liraglutide administration nullified MK-0626-induced β cell proliferation, their co-administration resulted in increased GSIS, decreased α cell mass, and improved glucose tolerance. The pro-proliferative effect of MK-0626 was lost by co-administration of the GLP-1 receptor antagonist exendin-(9-39), indicating that GLP-1 signaling is required for this effect. Comparison of the effects of DPP4is and/or GLP1RAs treatment in a single mouse model shows that the two anti-diabetic drugs have distinct consequences on islet morphology and function.
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Asuka
A
Morita
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Eri
E
Mukai
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Ayano
A
Hiratsuka
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Tomozumi
T
Takatani
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, N15W7, Kita-ku, Sapporo, 060-8638, Japan.
Toshihiko
T
Iwanaga
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Eun Young
EY
Lee
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. tmiki@faculty.chiba-u.jp.
Takashi
T
Miki
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D000069450:Liraglutide / Q000494:pharmacology; D051379:Mice; D010186:Pancreatic Function Tests; D010446:Peptide Fragments / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; C570834:MK0626; D010446:Peptide Fragments; D014230:Triazoles; C083773:exendin (9-39); D000069450:Liraglutide; D005947:Glucose; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
Apoptosis; DPP-4 inhibitor; GLP-1 receptor agonist; Glucose tolerance; Insulin secretion; β cell proliferation